Study protocol for a prospective, randomized controlled confirmatory clinical investigation to evaluate the safety and efficacy of a multidisciplinary digital therapeutics in patients with patellofemoral pain syndrome

Study protocol for a prospective, randomized controlled confirmatory clinical investigation to evaluate the safety and efficacy of a multidisciplinary digital therapeutics in patients with patellofemoral pain syndrome | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Study protocol for a prospective, randomized controlled confirmatory clinical investigation to evaluate the safety and efficacy of a multidisciplinary digital therapeutics in patients with patellofemoral pain syndrome Tae Hyun Park, Chan Yoon, Jae Hyeon Park, Sanghee Lee, Chi-hyun Choi, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5465840/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 01 Sep, 2025 Read the published version in Trials → Version 1 posted 5 You are reading this latest preprint version Abstract Background: Patellofemoral pain is a prevalent knee condition affecting up to 40% of individuals, especially females aged teens to 50s. Standard treatments, including exercise therapy, often yield insufficient long-term results, partly due to low compliance and psychological factors like depression and catastrophizing of pain. A digital therapeutics ‘ MORA Cure PFP’ which combine structured progressive exercise and cognitive behavioral therapy via an app, offers a solution to overcome the limitations of conventional treatment for patellofemoral pain patients. Methods: To evaluate the safety and efficacy of MORA Cure PFP , a two-arm controlled trial will enroll 216 patients diagnosed with patellofemoral pain randomly assigned in a 1:1 ratio to treatment and control groups. The treatment group will use the app, while the control group will perform self-guided exercises using educational materials. This trial aims to determine if the treatment group shows greater reduction in usual pain intensity scores at 8 weeks compared to the control group. Additional assessments include worst pain, knee function, depression, and pain catastrophizing levels. Discussion: Key design elements of the clinical trial, such as control group selection, inclusion/exclusion criteria, number of patients, and primary endpoint, were designed with consideration for not only medical perspectives but also regulatory aspects of software as a medical device, including device approval and health technology assessment. Trial registration: ClinicalTrials.gov., NCT06260865, registered 15th February 2024 (https://clinicaltrials.gov/study/NCT06260865) Digital therapeutics (DTx) Patellofemoral pain (PFP) Rehabilitative exercise Cognitive behavioural therapy (CBT) Software as a medical device (SaMD) ADMINISTRATIVE INFORMATION Note: the numbers in curly brackets in this protocol refer to SPIRIT checklist item numbers. The order of the items has been modified to group similar items (see http://www.equator-network.org/reporting-guidelines/ spirit-2013-statement-defining-standard-protocolitems-for-clinical-trials/). Title {1} Study protocol for a prospective, randomized controlled confirmatory clinical trial to evaluate the safety and efficacy of a multidisciplinary digital therapeutics in patients with patellofemo ral pain Trial registration {2a and 2b} ClinicalTrials.gov., NCT06260865, registered 15th February 2024 (https://clinicaltrials.gov/study/NCT06260865) Protocol version {3} The current protocol version is revision 3, dated 20 th March 2024. Funding {4} This study is funded by EverEx Inc., Seoul, Korea and partially funded by the Ministry of Health & Welfare, Republic of Korea (grant number: RS-2023-KH142023). EverEx is a manufacturer of the digital therapeutic app (medical device) and sponsor of this trial. Author details {5a} Tae Hyun Park 1 , MD; Chan Yoon 1 , MD; Jae Hyeon Park 2 , MD; Sanghee Lee 1 , MD; Chi-hyun Choi 1* , MD; Chong Bum Chang 3* , MD; Jin Goo Kim 4 , MD 1 EverEx Inc., Seoul, Korea 2 Department of Rehabilitation Medicine, Hanyang University College of Medicine 3 Department of Orthopaedic Surgery, Seoul National University Bundang Hospital 4 Department of Orthopaedic Surgery, Hanyang University Myongji Hospital Name and contact information for the trial sponsor {5b} EverEx Inc., 29-7 Seoripul-gil, Seocho-gu, Seoul, Korea Role of sponsor The study sponsor designed the study, drafted the protocol, conducted review and acceptance from the investigators, obtained approvals from the ministry of food and drug safety (MFDS) and institutional review boards (IRB), and executed funding contracts with the study sites. The sponsor has assigned the contract research organizations (CRO) to perform study monitoring, data management, and statistical analysis. Regarding publication, the sponsor and investigators will jointly publish under mutual agreement. The sponsor plans to apply for device approval from the MFDS based on the clinical trial data. INTRODUCTION Background and rationale {6a} Patellofemoral pain (PFP) is a common condition with a prevalence ranging from 3% to 40% (1), accounting for 25% of knee pain originating from running (2) and 7% to 10% of all medical consultations (3,4). It is more prevalent in females and affects individuals from their teens to their 50s (1,3). The pathophysiology of PFP remains unclear (5), and various non-surgical and surgical treatments have been attempted (6,7). Without proper diagnosis and treatment, PFP does not improve spontaneously (8); over 50% of patients may experience persistent pain for more than two years (9), potentially leading to the progression of patellofemoral osteoarthritis (10). Standard treatment for PFP, according to various guidelines, includes patient education and exercise therapy (11–14). Strength exercises targeting the quadriceps and hip abductors have proven effective in several studies (15–21). However, even with evidence-based treatments, 40% to 57% of patients experience insufficient long-term effects (22,23), highlighting the need for improved therapeutic strategies. Low compliance due to time and location constraints of clinic-based exercise therapy may contribute to this lack of effectiveness (24). Psychological factors such as anxiety, depression, catastrophizing, and fear of movement are associated with pain and physical function in PFP patients and negatively impact recovery processes like rehabilitation training, as suggested by Maclachlan's systematic review (25). To address these factors, Selhorst et al. conducted a randomized controlled trial with adolescent PFP patients, comparing rehabilitation training alone to rehabilitation combined with stepwise cognitive invervention. The group receiving multidisciplinary intervention showed significant improvements in pain and functional levels (26). Similarly, Bagheri et al. found that young female athletes participating in a mindfulness program alongside exercise exhibited better outcomes in pain severity, knee function, subjective treatment effects, and catastrophizing compared to those who only engaged in exercise (27). Despite these findings, research on psychological interventions in PFP patients remains limited (26–30), and no studies have combined CBT, which has proven efficacy in chronic pain (31,32), with exercise therapy in PFP patients. App-based therapy can overcome time and location constraints of face-to-face treatment, thereby improving patient compliance (33,34). EverEx has developed a multidisciplinary treatment app ‘ MORA Cure PFP ’ for PFP patients that includes self-rehabilitation exercise therapy, which automatically adjusts based on the patient's status, and CBT for chronic pain. MORA Cure PFP is classified as a software as a medical device (SaMD), that can only be used after diagnosis and prescription by a physician and is prior to regulatory approval. An exploratory clinical trial involving 40 patients, conducted from November 2022 to October 2023 (ClinicalTrials.gov., NCT05614583) demonstrated efficacy and safety comparable to real-world treatment (35). Objectives {7} This confirmatory clinical trial aims to evaluate the safety and efficacy of MORA Cure PFP by comparing it with conventional treatment in PFP patients. For specific objectives, see Table 1 . Trial design {8} This clinical trial is a confirmatory medical device clinical trial and is a two-arm, 1:1 randomized, open-label, multi-centered superiority study. Participants who meet the inclusion/exclusion criteria will be randomly assigned to the treatment group and the control group. Treatment group will be given the digital therapeutic app, and control group will receive exercise education and self-exercise materials. Participant flow diagram according to the Consolidated Standards of Reporting Trials (CONSORT), is presented in Figure 1 . METHODS: PARTICIPANTS, INTERVENTIONS and OUTCOMES Study setting {9} This clinical trial will be conducted at both academic hospitals and community hospitals (for the list of sites, see https://clinicaltrials.gov/study/NCT06260865 ) located in South Korea. After being diagnosed and receiving the guidance on the intervention at the hospital, participants will perform the treatment themselves on a daily basis. Eligibility criteria {10} To be included in this study, patients must meet the following criteria: experiencing pain around or behind the patella (kneecap) in unilateral or bilateral knee joints for over 3 months (15,16,36); pain during squatting movements (13,15–17,19,36–39); pain in two or more of the following activities/tests—prolonged sitting, cycling, running, climbing stairs, kneeling, patellar compression test, tenderness around the patella test (13,15–17,19,36–39); voluntary decision to participate with signed informed consent. Exclusion criteria are as follows: knee osteoarthritis exceeding Kellgren-Lawrence (K-L) grade 2 on X-ray (36); traumatic event causing fractures or dislocations around the knee within the past 3 months (15,19); knee surgery within the past 3 months (16,17,37,38); patellar tendinitis diagnosed by imaging within the past 3 months (37); current use of narcotic analgesics for pain control (16,39); anticipated use of prohibited medications/treatments within 16 weeks of screening; pregnancy; current or recent (within 3 months) participation in another clinical trial; and any other factors deemed unsuitable by the investigator (36). Who will take informed consent? {26a} Before participating in the clinical trial procedures, participants will voluntarily complete and sign an informed consent form. The consent form will be paper-based, and a licensed physician will explain its contents, giving the participant sufficient time to make an informed decision. The consent of the research participants must be obtained in accordance with the ethical principles and standards outlined in the Declaration of Helsinki. All consent forms used will be those approved by the IRB, and a copy of the signed consent form will be provided to the participant. If the consent form is amended, the changes will be explained, and the consent process will be repeated. Additional consent provision for collection and use of participant data and biological specimens {26b} Not applicable, this trial does not collect biological specimens. INTERVENTIONS Explanation for the choice of comparators {6b} To evaluate the safety and efficacy of MORA Cure PFP, the treatment group was assigned to use the app. The control group was set as the real-world at best treatment. Standard treatment for PFP, according to various guidelines, includes patient education and exercise therapy (11–14). Therefore, the control group was defined as those who receive in-person exercise education by healthcare professionals, follow the provided paper-based materials to perform self-exercise, and record their exercise progress. Intervention description {11a} After confirming eligibility based on the inclusion/exclusion criteria, the target knee (left or right) for evaluation will be selected. If only one knee meets the criteria for PFP, that knee will be selected. If both knees qualify, the knee with greater pain will be chosen. All subsequent evaluations will be conducted on the knee selected as the target knee for assessment. The investigational medical device ‘MORA Cure PFP’ used in this study will be applied only to participants assigned to the treatment group. MORA Cure PFP consists of a web platform for healthcare professionals and a mobile application for patients. The investigator prescribes treatment through the healthcare web platform, and participants install the application on their mobile phones to begin therapy. At baseline, the investigator will randomize and enroll participants. For those assigned to the treatment group, the investigator will register them on the healthcare web platform and prescribe the device. Upon prescription, an installation code for the patient app will appear on the web platform. Participants will then follow the installation manual to install the app, agree to the terms of service, complete registration, and start the plan, with the Day 1 program beginning on the same day. The device provides an 8-week program of rehabilitative exercise and cognitive behavioral therapy (CBT) for PFP (Fig. 2). After the initial 8-week treatment period, participants can retain access to the device for up to 12 weeks. For participants in the control group, a healthcare professional with experience in musculoskeletal disease treatment will conduct self-exercise education according to the paper-based self-guided exercise material. The exercise education will last for at least 15 minutes, and participants will be instructed to record the time spent on self-exercise in the patient diaries distributed at baseline. At each subsequent visit, participants will be asked to bring their ongoing diaries, and whenever feasible, the diaries will be collected to monitor their progress. Strategies to improve adherence to interventions {11c} To enhance adherence, participants are provided with education on the importance of treatment after group allocation. The experimental group receives instructions on using the application, while the control group is taught self-exercise using dedicated materials. Each participant is required to perform daily self-treatment and log their activities, including exercise completion and duration. For the experimental group, the application automatically tracks and records exercise times, ensuring consistent monitoring. In the control group, participants manually log their exercise in a paper diary. During each visit, the investigator collects the diaries and monitors progress, offering support and feedback to encourage continued adherence. Participant timeline {13} Participants in this clinical trial will complete 4 to 5 outpatient visits: V1 (Screening), V2 (Baseline), V3 (In-treatment), V4 (Post-treatment), and V5 (Follow-up). V2 must occur within 4 weeks of V1, and may be conducted on the same day as V1. V3 is scheduled 4 weeks after V2, with an allowable range of 3 to 5 weeks. V4 is set for 8 weeks after V2, with a window of 8 to 9 weeks, and V5 is scheduled 12 weeks after V2, with an allowable range of 12 to 13 weeks. See Table 2 for the specific schedule of assessments for each visit. For Visit 3, participants may not need to visit the medical institution in person. In this case, certain checks, such as prior medication, concomitant medication, and adverse event assessments, may be omitted. Pain intensity assessment and the Kujala evaluation will be conducted by sending a survey link to the participant, who will complete it while in contact with the clinical trial site representative over the phone. Outcomes {12} The primary efficacy outcome of this trial is usual pain intensity score (VAS, 100 scale) at 8 weeks (V4). For secondary outcomes, see Table 1 . Through interviews, demographic information, medical history, surgical history, and prior/concomitant medications will be collected. Physical examination will include measurements of height, weight, and a patella examination. A knee X-ray will be taken to assign a K-L grade (40), which is used to assess exclusion criteria for osteoarthritis. The usual and worst pain intensity scores assess the average and peak knee pain experienced over the past week, respectively. Participants mark their pain level on a visual analogue scale from 0 to 100, with values recorded and rounded to the nearest whole number (41). To assess knee function, participants complete the anterior knee pain scale (Kujala score), 13-item self-report questionnaire (42), with a total score calculated from the responses. Quality of life is assessed via the EQ-5D-5L (43) questionnaire, recording the sum of scores across five questions and today's health status score. Depression severity is evaluated using the Patient Health Questionnaire-9 (PHQ-9) (44), with a total score from nine questions, while pain catastrophizing is assessed using the Pain Catastrophizing Scale (PCS) (45), totaling scores from 13 questions. Participants also rate their perceived recovery level on a 0 to 6 scale (46). All pain and questionnaire assessments are conducted as electronic patient-reported outcomes (ePRO). Participants use digital tools provided at the site, with data automatically transferred to the electronic case report form (eCRF). For visit 3, if conducted as a televisit, participants may complete the assessments remotely. Sample size {14} The primary efficacy variable of this clinical trial is the intensity of usual pain over the past week at 8 weeks post-treatment initiation, aiming to assess whether the experimental group shows superior improvement compared to the control group. The hypothesis for the superiority test on the primary efficacy variable is as follows: \(\:{H}_{0}:\:{\mu\:}_{t}={\mu\:}_{c}\:\:\:\:vs.\:\:\:\:\:{H}_{1}:\:{\mu\:}_{t}\ne\:{\mu\:}_{c}\) , where \(\:{\mu\:}_{t}\) represents the usual pain intensity at 8 weeks for the experimental group, and \(\:{{\mu\:}}_{\text{c}}\) represents the same for the control group. The sample size was calculated based on prior study of MORA Cure PFP (ClinicalTrials.gov., NCT05614583). In the exploratory clinical trial, the usual pain over the past week of full analysis set at 8 weeks post-treatment was 2.31 ± 1.49 for the experimental group and 3.18 ± 2.43 for the control group (35). The calculated effect size (Cohen's d) is as follows: \(\:d=\frac{{m}_{t}-{m}_{c}}{\sqrt{\left({s}_{t}^{2}+{s}_{c}^{2}\right)/2}}=\frac{2.31-3.18}{\sqrt{\left({1.49}^{2}+{2.43}^{2}\right)/2}}=\:-0.428\) , where \(\:{m}_{t}\) ​ is mean of the experimental group, \(\:{m}_{c}\) is mean of the control group, \(\:{s}_{t}\) is standard deviation of the experimental group, \(\:{s}_{c}\) is standard deviation of the control group (47). Values were used up to the second decimal place, and the effect size was calculated without rounding. Using an effect size of -0.428, a Type I error of 0.05, and a power of 0.8, the formula for calculating the sample size per group is: \(\:n=\frac{2{\left({z}_{1-\alpha\:/2}+{z}_{1-\beta\:}\right)}^{2}}{{\left(d\right)}^{2}}=\frac{2{\left(1.960+0.842\right)}^{2}}{{\left(0.428\right)}^{2}}=86\) , where \(\:n\) is required sample size per group (rounded up to the nearest whole number), \(\:{\alpha\:}\) is Type I error, \(\:{\beta\:}\) is Type II error (1 - power), and \(\:d\) is effect size (47). Considering a typical dropout rate of 10–30% for clinical trials involving digital services (48), a 20% dropout rate was assumed for this study. Adjusting for this dropout rate, the required sample size per group is calculated as: \(\:{n}^{{\prime\:}}=86\times\:\frac{1}{1-r}=107.5\) , where r is the dropout rate (0.2). Thus, the target sample size is set at 216 participants in total, with 108 per group (Fig. 1). Recruitment {15} Participant recruitment will be handled by the institution. The investigator may invite patients under their care to participate, or participants may be recruited through in-hospital posters or an internet page. In these cases, participants must visit the institution to complete the informed consent form and undergo an eligibility check. All recruitment methods will be implemented only after obtaining IRB approval. Criteria for discontinuing or modifying allocated interventions {11b} Participants will be withdrawn from the trial if they: receive unapproved medication, procedures, or treatments that could impact trial outcomes; fail to meet inclusion/exclusion criteria post-enrollment; are lost to follow-up; experience adverse events requiring withdrawal as determined by the investigator; request to discontinue (withdrawal of consent); or if the investigator deems their continued participation unsuitable for any other reason. If a participant misses a visit, the investigator must make every effort to contact them, encourage attendance, confirm their well-being, and document the reason for absence. Withdrawn participants will be included in efficacy and safety evaluations unless a valid reason for exclusion exists. Modifications to the intervention are not allowed in this trial. Relevant concomitant care permitted or prohibited during the trial {11d} During the clinical trial, participants may use acetaminophen 650 mg as a rescue medication if they experience intolerable pain. The investigator may prescribe this at visits. Participants already on pain medication before the trial are encouraged to switch to the rescue medication but may continue their existing one at the investigator's discretion. From baseline (visit 2) to follow-up (visit 5), participants should ideally avoid pain medications within 24 hours before each visit. The following are prohibited from visit 1 to visit 5: intra-articular or knee injections (e.g., corticosteroids), arthroscopic surgery, corrective osteotomy, knee replacement, or any unapproved procedures or surgeries, opioid analgesics for pain, topical knee ointments or patches, unapproved joint pain medications or treatments, and high-impact physical activities. Provision for post-trial care {30d} After completing or withdrawing from the clinical trial, participants may resume regular medical care as before. If an adverse device effect arises, they may be compensated for medical expenses per the compensation policy until the issue is resolved. The sponsor will secure IRB approval for the insurance policy covering such compensation. Additionally, if there is any suspicion of an adverse event after a participant’s trial completion or withdrawal, the investigator must assess and provide further medical care as needed. ASSIGNMENT of INTERVENTIONS: ALLOCATION Sequence generation {16a} Only participants who meet the inclusion/exclusion criteria will be randomly assigned to either the experimental or control group in a 1:1 ratio. The method used for this assignment is computer-generated block randomization. To ensure independence, a third-party institution will be entrusted with generating the randomization list. Stratification will not be performed. Concealment mechanism {16b} To conceal the randomization list, neither the sponsor nor the delegated CRO will have access to the list. The sequence will be generated within the third-party institution, and it will be directly built into the eCRF system. The results of this process will be encrypted and will not be identifiable. Implementation {16c} Random assignment will be conducted through an interactive web response system (IWRS) incorporated into eCRF. The pre-generated randomization list will be embedded into the program. ASSIGNMENT of INTERVENTIONS: BLINDING Who will be blinded {17a} This clinical trial is open-label; therefore, blinding is not applicable. Procedure for unblinding if needed {17b} This clinical trial is open-label; therefore, blinding is not applicable. DATA COLLECTION AND MANAGEMENT Plans for assessment and collection of outcomes {18a} Source documents refer to all original records of clinical findings, observations, or other activities essential for the evaluation and replication of the clinical trial. Examples include, but are not limited to: medical records, clinical findings, knee X-rays for K-L grade evaluation, participant diaries for recording treatment compliance, and patient-reported outcomes collected via electronic devices (pain intensity, Kujala scale, EQ-5D-5L, PHQ-9, PCS, and overall perceived level of recovery). For the treatment group, compliance data from the application can also serve as source data. Data collection and recording are performed by the investigator under the supervision of the principal investigator, electronic CRF as the primary method of data collection. The investigator must ensure the accuracy, completeness, legibility, and timeliness of the data included in the case reports and other records. Data recorded in the CRF must be consistent with the source documents; any discrepancies or omissions must be accompanied by an explanation. Changes to electronic CRFs must be traceable through an audit trail system. Plans to promote participant retention and complete follow-up {18b} Participants will receive 50,000 won (equivalent to 26 US dollars) per visit as transportation reimbursement. If Visit 1 and Visit 2 are conducted simultaneously, participants will receive double the amount, and the same amount will be provided for Visit 3, even if it is an electronic visit. At each visit, the investigator will check and monitor the treatment progress (automated data from the app for the treatment group, patient diaries for the control group). The application includes a notification feature that allows reminders to be sent at the patient's preferred time, and personalized messages are sent based on exercise compliance to help motivate the patient. Data management {19} All clinical trial sites and investigators must ensure participant confidentiality and maintain accurate, legible, and timely records in compliance with regulations. The sponsor and regulatory authorities must be granted access to review records for monitoring, audits, and inspections. When using eCRF, authorized investigators enter data and automated systems detect discrepancies, issuing queries for corrections or confirmations. If IWRS or ePROs are used, data integration with the eCRF may occur. The sponsor reviews the eCRFs for completeness and may issue queries for discrepancies or missing data, which the investigator must address. After the trial, protocol violations are determined, and once data integrity is confirmed, a database lock (DB lock) is performed, and a copy of the participant database is sent to the investigator. Statistical analyses take place post-DB lock. The investigator and trial site must retain essential documents according to regulatory standards, with the sponsor specifying the retention period. If further retention is unnecessary, the sponsor must inform the investigator and the clinical trial site in writing. Confidentiality {27} The investigator must ensure the anonymity of study participants, avoiding any identification of participants' names in documents submitted to the sponsor. Signed consent forms, source documents, and participant logs must be kept confidential and stored securely. All personal information collected through the investigational device follows personal information processing policy, and participants shall consent before installing the app. Data collection systems in this trial comply with US code of federal regulation Chap. 21, part 11 and local regulations. All data transmissions are encrypted, and access is controlled through individual user IDs and passwords, with only authorized and trained personnel permitted access. Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33} Not applicable as no biological samples are to be collected. STATISTICAL METHODS Definition of analysis sets In this clinical trial, data will be analyzed using three sets: the full analysis set (FAS), the per protocol set (PPS), and the safety set. The FAS, aligned with the intention-to-treat (ITT) principle, will be the primary analysis set for efficacy evaluations, with additional analyses using the PPS. If discrepancies arise between the two, the outcomes will be presented and investigated. Safety evaluations will use the safety set. The FAS includes participants who meet all of the following: have post-randomization primary efficacy data, records of applying the investigational device (test group) or performing self-exercise (control group), and were not improperly enrolled due to inclusion/exclusion violations. The PPS is a subset of the FAS, including those who completed the trial without major protocol violations, did not withdraw prematurely, and had an overall compliance rate of 50% or higher. The safety set includes all randomized participants with records of using the investigational device or performing self-exercise. Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c} For the analysis of the FAS, missing values occurring after treatment that are used for primary and secondary efficacy evaluation variables will be imputed using the last observation carried forward (LOCF) method. However, when imputing missing values, results prior to the administration of the investigational medical device will not be substituted for post-administration results. Other data will be analyzed as collected (available data) without imputation. For the analysis of the PPS, missing values will not be imputed and will be analyzed as collected. Statistical methods for demographic and other baseline characteristics The full analysis set (FAS) will be analyzed for demographic information, medication history, treatment history, and past/current medical history of participants. Categorical data (e.g., gender) will be presented as frequency and percentage within the safety population, while continuous data (e.g., age) will be summarized using descriptive statistics, including mean, standard deviation, median, minimum, and maximum values. Results will be reported separately for the experimental and control groups. Group comparisons will use a two-sample t-test for continuous variables (or Wilcoxon’s rank-sum test if normality is not met) and Pearson’s chi-square test for categorical variables (or Fisher’s exact test if more than 20% of cells have expected counts below 5). Past and current medical history will be standardized using the latest the Medical Dictionary for Regulatory Activities (MedDRA) version, classified by system organ class (SOC) and preferred term (PT), with frequencies and percentages reported per group. Medication and treatment history will be standardized by the latest anatomical therapeutic chemical (ATC) classification, reported by level 1 (anatomical main group) and level 2 (therapeutic subgroup), and analyzed by Pearson’s chi-square test (or Fisher’s exact test where appropriate). Statistical methods for primary and secondary outcomes {20a} For the definition of efficacy evaluation variables, see Table 1 . Descriptive statistics (mean, standard deviation, median, minimum, maximum) will be presented for both experimental and control groups. Group differences will be analyzed using ANCOVA with baseline values as covariates, providing adjusted means (least square means), p-values, and 95% confidence intervals. Statistical tests will be two-sided with a significance level of 0.05, and results will include clinical interpretation. Safety analysis will be conducted on the safety set. Adverse events (AEs) will be standardized by SOC and PT using the latest MedDRA version. Treatment-emergent adverse events (TEAEs) will be recorded as a single event per participant if they share the same SOC and PT, with severity classified by the highest severity reported, and causal relationship classified by the stronger link to the investigational device. Analysis will focus on TEAEs, including counts and percentages for TEAEs, knee-related TEAEs, adverse device effects (ADEs), and serious adverse events (SAEs). Percentage differences will be tested using Pearson’s chi-square test or Fisher’s exact test, if appropriate. Interim analyses {21b} There are no interim analyses planned. Methods or additional analyses (e.g. Subgroup analyses) {20b} To determine whether the results of the primary efficacy evaluation differ according to subgroups of study participants, a subgroup analysis will be performed. The subgroup analysis will compare participants with a usual pain intensity score over the past week at visit 2 of 50 points or higher to those with a score of 49 points or lower. Plans to give access to the full protocol, participant-level data and statistical code {31c} There are no plans to give access to the full protocol, participant-level data and statistical code. OVERSIGHT AND MONITORING Composition of the coordinating centre and trial steering committee {5d} The investigators will hold investigator meetings as needed, led by two experienced orthopedic surgeons who have been assigned the role of coordinating investigators. Information regarding the protocol and the device must be provided to the investigators prior to the start of the trial, and formal acceptance must be obtained. Before the trial begins, the sponsor will visit each site for a site initiation visit (SIV), where the research team will be briefed on the trial, and the final operational details will be confirmed. If necessary, a site feasibility meeting may be conducted prior to the SIV meeting. The sponsor and CRO will hold monthly meetings to review the progress of the study and discuss any issues that arose during routine monitoring visits. If necessary, additional QC visits, individual investigator meetings, or investigator group meetings may be scheduled to address specific concerns or ensure the smooth continuation of the trial. Composition of the data monitoring committee, its role and reporting structure {21a} This study does not include a data monitoring committee (DMC). The decision to exclude a DMC is based on the fact that the study involves minimal risk to participants, and the investigational medical device has already demonstrated a favorable safety profile in prior studies. Additionally, the study design allows for close monitoring by the investigators and sponsor through regular site visits and data reviews, ensuring that participant safety and data integrity are adequately maintained without the need for an independent monitoring committee. Adverse event reporting and harms {22} All adverse events that occur or worsen after obtaining the subject's consent will be collected, except for those who fail the screening. Pre-existing signs or symptoms at the time of consent are recorded in the medical history section of the CRF. AEs should be monitored until symptoms resolve and the condition stabilizes, and progress reports may be required by the sponsor. The investigator should provide a clear diagnosis, or otherwise record symptoms/signs. Appropriate examinations and treatments must be administered for all AEs. If an AE makes it difficult to continue the trial, the subject may drop out or the trial may be discontinued, with the best treatment provided for safety. The CRF must record whether the AE is treatment-emergent (TEAE), the onset and end dates, severity, causal relationship with the investigational device, actions taken, and outcome. Serious adverse events (SAEs), serious adverse device effects, and unexpected adverse device effects must be reported to the IRB and regulatory authorities within the required timeframes. Specific AEs, such as worsening knee pain, cramps, dizziness, changes in mood or thought patterns, and any other significant AEs, must be documented and shared with the sponsor within 24 hours. Frequency and plans for auditing trial conduct {23} Before the clinical trial begins, the sponsor and investigator review the protocol and CRFs during a site initiation visit or investigator meeting. Monitoring is conducted by the sponsor or their representative, who regularly visits the site to verify the completeness of source documents, the accuracy of case records, adherence to Good Clinical Practice (GCP) and the protocol, participant enrollment, and the management of investigational devices and supplies. Monitors discuss findings with key investigators and ensure that source documents and CRFs are consistent, especially regarding consent, inclusion/exclusion criteria, and SAEs. The investigator must retain all source documents, including signed consent forms, and ensure data traceability. Monitoring follows the sponsor's procedures, with results reported to the sponsor. Audits are performed by the sponsor, while the MFDS conducts inspections. If notified of an MFDS inspection, the investigator must inform the sponsor promptly. Plans for communicating important protocol amendments to relevant parties (e.g. Trial participants, ethical committees) {25} When changes to the approved clinical trial protocol are needed, approval must be obtained from the IRB and MFDS. The sponsor and investigator must document their agreement to follow the protocol, including any amendments, with signatures and dates. The investigator cannot deviate from the protocol without prior approval from the sponsor, IRB, and MFDS, except in cases where immediate action is required to protect participants. In such emergencies, the investigator must report the changes, along with reasons, to the sponsor, IRB, and MFDS as soon as possible to obtain retroactive approval. Dissemination plans {31a} Regardless of the study results, whether positive or not, the sponsor and investigators has the right to publish or present any data collected or generated from the clinical trial. If the investigators wish to present or publish the study results externally, it must first provide the sponsor with an opportunity to review the manuscript or any other disclosure materials in advance to prevent the inadvertent release of confidential information or inventions, and obtain approval before publication or disclosure. DISCUSSION This clinical trial is a double-arm randomized controlled trial aimed at evaluating the safety and efficacy of the digital therapeutic app for PFP (MORA Cure PFP). The app used in the trial includes guideline-based exercise therapy and CBT, designed to facilitate high levels of patient interaction and features suitable for self-guided use, which are expected to improve treatment compliance. The intervention in this study will provide a new method for the rehabilitation of patients with PFP. In recent years, digital therapeutics have gained significant attention. Digital therapeutic devices are primarily applied to chronic conditions such as diabetes or psychiatric disorders, and useful in correcting lifestyle and behavioral habits. Recently, digital therapeutics targeting musculoskeletal diseases have been under development, and results from a clinical trial for one targeting fibromyalgia have been published (49). From a regulatory perspective, digital therapeutics are classified as software as a medical device (SaMD) (50). SaMD refers to software that qualifies as a medical device on its own, as opposed to hardware-based medical devices. Digital therapeutics are specifically designated as treatment-focused SaMDs, which require objective demonstration of therapeutic effectiveness to gain regulatory approval. Prospective clinical trials serve not only as an objective process for regulatory approval by observing therapeutic effects but also as valuable data for subsequent health technology assessments and insurance reimbursement listings. Therefore, when designing clinical trials for digital therapeutics, considerations should include not only medical aspects but also regulatory approval and insurance listing perspectives for medical devices. In designing clinical trials for digital therapeutics, specific considerations are essential. For instance, some trials use a “sham device,” a simplified app lacking therapeutic features, as the control group (51). However, this trial aims to demonstrate the app’s superiority over the at-best treatment (treatment-as-usual). Therefore, the control group will receive in-person exercise education with materials and resources for self-guided exercise without app use. The inclusion/exclusion criteria should accurately represent the indication. In this trial, PFP guidelines (11–14) are used to select participants with chronic patella-related pain lasting over three months and confirm objective pain elicited through movement or physical exams. Given that PFP is often diagnosed by exclusion (11–14), patients with conditions such as osteoarthritis, fractures, dislocations, surgical history, or patellar tendinitis are excluded. Additionally, patients requiring high-potency drugs like narcotic analgesics are beyond the app’s intended use and are excluded. The required participant number is designed based on the app’s feasibility trial (35), offering a more objective basis than calculations based on non-app studies. As the name implies, PFP is characterized primarily by pain, so the primary endpoint is the usual pain level at eight weeks, with expectations that the app group will report lower pain levels than the control group. A representative digital therapeutic for knee-related conditions is Mawendo (manufactured by Mawendo GmbH, Germany). In Germany, digital therapeutics are covered under the category of Digitale Gesundheitsanwendungen (DiGA) by public health insurance (Gesetzliche Krankenversicherung, GKV), and Mawendo accounts for approximately one-quarter of the total reimbursement within the DiGA category (52). A randomized controlled trial involving 259 participants showed statistically significant therapeutic superiority of Mawendo over standard physiotherapy (53). Its primary outcomes are functional improvement, as measured by knee injury and osteoarthritis outcome score-activities of daily living subscale (KOOS-ADL), and pain reduction, assessed using VAS. While Mawendo’s typical treatment period spans 12 weeks, this study will include an 8-week treatment phase followed by a 4-week extra curriculum. An additional difference of this study is its inclusion of psychological measures, evaluating depression and pain catastrophizing levels. Limitations There are several limitations in this trial. First, for the treatment group, the placebo effect of the “app” itself, rather than the therapeutic program, may be considered. However, given that app-based therapy inherently increases interaction and compliance, this should be seen as a contributing factor to the treatment rather than a placebo. Additionally, when evaluating the device—especially in value-based health technology assessments—comparison with the current at-best therapy is more appropriate. Second, the assessment tools used in this trial, including pain measured with the VAS scale and various questionnaires, lack objectivity. However, given that the evaluation is not based on objective lab values but on assessments of the symptoms, some subjectivity in evaluation is inevitable. Furthermore, since there are no direct comparison targets such as ‘exercise-only’ or ‘CBT-only’ apps, it is challenging to clarify which specific component plays a primary role. Finally, blinding was not feasible in the design of the study's experimental and control groups, which may be vulnerable to bias. CONCLUSION The digital therapeutic app for PFP offers a structured progressive exercise program and CBT designed for chronic pain, with the goal of enhancing compliance and treatment effectiveness. This trial will evaluate the safety and efficacy of the digital therapeutic app compared to an active control (treatment as usual). ABBREVIATIONS ADE Adverse Device Effect AE Adverse Event ATC Anatomical Therapeutic Chemical CBT Cognitive Behavioral Therapy CRF Case Report Form CRO Contract Research Organization DB Database eCRF Electronic Case Report Form ePRO Electronic Patient Reported Outcome FAS Full Analysis Set GCP Good Clinical Practice ITT Intention-to-Treat IRB Institutional Review Board LOCF Last Observation Carried Forward MedDRA The Medical Dictionary for Regulatory Activities MFDS Ministry of Food and Drug Safety PCS Pain Catastrophizing Scale PFP Patellofemoral pain PHQ-9 Patient Health Questionnaire-9 PP Per Protocol PPS Per Protocol Set PT Preferred Term SAE Serious Adverse Event S aMD Software as a Medical Device SOC System Organ Class TEAE Treatment-emergent Adverse Event VAS Visual Analogue Scale Declarations TRIAL STATUS The current protocol version is revision 3, dated 20 th March 2024. Participant recruitment began on 26 th April 2024 and is expected to be finished by the end of December 2024. Acknowledgements We would like to acknowledge all investigation sites staffs, especially principal investigators (Drs. Man Soo Kim, Sang-Hak Lee, Moon-Jong Chang, Dong Jin Ryu, Jong Min Kim, Seong-Hwan Kim, Jae Young Park, and Gyu Seong Jeong) for their ongoing support in this project. We would like to acknowledge the regulatory affairs managers for their perspective on clinical trial design related to device approval and insurance listing. We also extend our gratitude to the product team for their efforts in the development of the medical device. This research was supported by the SmartTech Clinical Research Center (SCRC), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: RS-2023-KH142023). Authors’ contributions {31b} All authors collaboratively conceived and designed the study. JHP and CL contributed their expertise in rehabilitative exercise, while CY, JGK, CBC provided expertise as an orthopedic surgeon. CC offered insights in CBT for chronic pain. THP contributed statistical methodology and conducted sample size calculations. THP prepared and drafted the study protocol and the initial manuscript. All authors provided substantial feedback and participated in revising the manuscript. Funding {4} The trial was sponsored by EverEx Inc. and partially funded by the Ministry of Health & Welfare, Republic of Korea (grant number: RS-2023-KH142023). The study sponsor designed the study, drafted the protocol, conducted review and acceptance from the investigators, obtained approvals from the MFDS and IRBs, and executed funding contracts with the study sites. The sponsor have assigned the CROs to perform study monitoring, data management, and statistical analysis. Availability of data and materials {29} All intangible and tangible products resulting from the conduct of this study, including all reports, data, attached documents, work outcomes, and intellectual property, shall be owned by the sponsor. This provision is ensured through a documented agreement among the sponsor, investigator, and site, established before the commencement of the clinical trial. Ethics approval and consent to participate {24} Ethical approval was granted by the following IRBs: Institutional Review Board, The Catholic University of Korea, Seoul St. Mary’s Hospital (No. KC24DDDS0561, approval date: 25 th October 2024), Institutional Review Board, Kyung Hee University Hospital at Gandong (KHNMC 2024-03035, 8 th April 2024), Seoul National University Bundang Hospital Instituional Review Board (E-2409-924-402, 22 th August 2024), Seoul Metropolitan Government-Seoul National University Boramae Medical Center Institutional Review Board (30-2024-32, 20 th May 2024), Institutional Review Board, MyongJi Hospital (2024-08-018, 28 th August 2024), Inha University Hospital Institutional Review Board (INHAUH 2024-03-016, 24 th May 2024), Asan Medical Center Institutional Review Board (2024-0762, 13 th June 2024), Chung-Ang University Hospital Institutional Review Board (2403-005-592, 19 th April 2024), Institutional Review Board, CHA Bundang Medical Center, CHA University (2024-03-006-003, 22 th April 2024), Institutional Review Board, Hanyang University Guri Hospital (2024-02-022-002, 1th April 2024). 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Objectives and efficacy endpoints of the trial Objectives Endpoints Primary To compare usual pain level at 8 weeks between treatment and control group Usual pain intensity over the past 1 week at the 8-week (V4) Secondary To compare the following between treatment control group: Worst pain level at 8-week Knee function at 8-week Quality of life at 8-week Health status at 8-week Depression level at 8-week Pain catastrophizing level at 8-week Overall perceived recovery level at 8-week Usual pain at 12-week Worst pain level at 12-week Knee function at 12-week Quality of life at 12-week Health status at 12-week Depression level at 12-week Pain catastrophizing level at 12-week Overall perceived recovery level at 12-week Usual pain level at 4-week Worst pain level at 4-week Knee function at 4-week Change in usual pain level at 8-week compared to baseline Change in worst pain level at 8-week compared to baseline Change in knee function at 8-week compared to baseline Change in quality of life at 8-week compared to baseline Change in health status at 8-week compared to baseline Change in depression level at 8-week compared to baseline Change in pain catastrophizing level at 8-week compared to baseline Change in usual pain level at 12-week compared to baseline Change in worst pain level at 12-week compared to baseline Change in knee function at 12-week compared to baseline Change in quality of life at 12-week compared to baseline Change in health status at 12-week compared to baseline Change in depression level at 12-week compared to baseline Change in pain catastrophizing level at 12-week compared to baseline Change in usual pain level at 4-week compared to baseline Change in worst pain level at 4-week compared to baseline Change in knee function at 4-week compared to baseline Worst pain intensity over the past 1 week at 8-week (V4) Kujala questionnaire total score at 8-week (V4) EQ-5D-5L questionnaire total score at 8-week (V4) EQ-5D-5L questionnaire health status score at 8-week (V4) PHQ-9 questionnaire total score at 8-week (V4) PCS questionnaire total score at 8-week (V4) Overall perceived recovery score at 8-week (V4) Usual pain intensity over the past 1 week at 12-week (V5) Worst pain intensity over the past 1 week at 12-week (V5) Kujala questionnaire total score at 12-week (V5) EQ-5D-5L questionnaire total score at 12-week (V5) EQ-5D-5L questionnaire health status score at 12-week (V5) PHQ-9 questionnaire total score at 12-week (V5) PCS questionnaire total score at 12-week (V5) Overall perceived recovery score at 12-week (V5) Usual pain intensity over the past 1 week at 4-week (V2) Worst pain intensity over the past 1 week at 4-week (V2) Kujala questionnaire total score at 4-week (V2) [Usual pain intensity over the past 1 week at the 8-week (V4)] – [Usual pain intensity over the past 1 week at the baseline (V2)] [Worst pain intensity over the past 1 week at the 8-week (V4)] – [Worst pain intensity over the past 1 week at the baseline (V2)] [Kujala questionnaire total score at the 8-week (V4)] – [Kujala questionnaire total score at the baseline (V2)] [EQ-5D-5L questionnaire total score at the 8-week (V4)] – [EQ-5D-5L questionnaire total score at the baseline (V2)] [EQ-5D-5L questionnaire health status score at the 8-week (V4)] – [EQ-5D-5L questionnaire health status score at the baseline (V2)] [PHQ-9 questionnaire total score at the 8-week (V4)] – [PHQ-9 questionnaire total score at the baseline (V2)] [PCS questionnaire total score at the 8-week (V4)] – [PCS questionnaire total score at the baseline (V2)] [Usual pain intensity over the past 1 week at the 12-week (V5)] – [Usual pain intensity over the past 1 week at the baseline (V2)] [Worst pain intensity over the past 1 week at the 12-week (V5)] – [Worst pain intensity over the past 1 week at the baseline (V2)] [Kujala questionnaire total score at the 12-week (V5)] – [Kujala questionnaire total score at the baseline (V2)] [EQ-5D-5L questionnaire total score at the 12-week (V5)] – [EQ-5D-5L questionnaire total score at the baseline (V2)] [EQ-5D-5L questionnaire health status score at the 12-week (V5)] – [EQ-5D-5L questionnaire health status score at the baseline (V2)] [PHQ-9 questionnaire total score at the 12-week (V5)] – [PHQ-9 questionnaire total score at the baseline (V2)] [PCS questionnaire total score at the 12-week (V5)] – [PCS questionnaire total score at the baseline (V2)] [Usual pain intensity over the past 1 week at the 4-week (V3)] – [Usual pain intensity over the past 1 week at the baseline (V2)] [Worst pain intensity over the past 1 week at the 4-week (V3)] – [Worst pain intensity over the past 1 week at the baseline (V2)] [Kujala questionnaire total score at the 4-week (V3)] – [Kujala questionnaire total score at the baseline (V2)] Table 2. Assessment schedule by visit Schedule Screening (V1) Baseline (V2) 1 In-treatment (V3) 2,3 Post-treatment (V4) 4 Follow-up (V5) 5 -4 weeks ~ 0-week 0-week 3-week ~ 5-week 8-week ~ 9 week 12-week~13week Informed consent X Screening number assignment X Demographics X Medical history X Height and weight measurement X Physical examination X X X 3 X X Concomitant/previous medication history X X X 3 X X Knee X-ray Imaging and K-L grading X 6 Inclusion/exclusion criteria review X X Selection of target knee (L/R) X Randomization and assignment of registration number X Pain intensity assessment X X X X Kujala questionnaire X X X X EQ-5D-5L questionnaire X X X PHQ-9 questionnaire X X X PCS questionnaire X X X Overall perceived recovery score assessment X X Disease education X Investigational device prescription and app installation (treatment group only) X Education on self-exercise (control group only) X Self-exercise patient diary distribution (control group only) X Self-exercise patient diary return (control group only) X 7 X 7 X Adverse event review X X 3 X X Investigational device app deletion (treatment gropu only) X V2 must be conducted within 4 weeks of V1, and V1 and V2 can take place on the same day. V3 is conducted 4 weeks after V2, with a permissible variation of one week before or after (3 to 5 weeks). For V3, a visit to the medical institution may not be required. In this case, previous and concomitant medication reviews, as well as adverse event reviews, may be omitted. Pain intensity and Kujala assessments can be remotely collected by sending a link through a phone call. V4 is conducted 8 weeks after V2, with a permissible delay of one week (8 to 9 weeks). V5 is conducted 12 weeks after V2, with a permissible delay of one week (12 to 13 weeks). If an X-ray taken within 3 months is available for K-L grade evaluation, this may be omitted. For V3 and V4, the self-exercise log should be reviewed, and completed logs should be collected. Figures 1 and 2 Figures 1 and 2 are not available with this version. Cite Share Download PDF Status: Published Journal Publication published 01 Sep, 2025 Read the published version in Trials → Version 1 posted Reviewers agreed at journal 12 May, 2025 Reviewers invited by journal 09 May, 2025 Editor assigned by journal 24 Feb, 2025 First submitted to journal 21 Feb, 2025 Editorial decision: Minor revision 17 Feb, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5465840","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":419905803,"identity":"b6f8af11-5d25-4e73-9c8c-80f23fe0c329","order_by":0,"name":"Tae Hyun Park","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1ElEQVRIiWNgGAWjYBACPgYGZmYQg5+9AUgaWBDWwgbTItlzAKRFggQtBjcSQBQxWiRyjI0L/tjkGdx8fnXDjwIJBv727gSCWpJntqUVS97OKbvZA3SYxJmzGwhqOczbcDix73ZO2g0eoBYDiVwitPD8OZzYcPNM2s0/xGpJ5mE7nDjhBvux28TZwvOs2Ji3LS1xZk8O220ZAwkegn7hZ0/eLM3zxyaxn/34s5tv/tjI8bf34tfCIJAAY/EYgEn8ysHWHICx2B8QVj0KRsEoGAUjEgAANjdEawX763kAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0003-3783-7691","institution":"EverEx","correspondingAuthor":true,"prefix":"","firstName":"Tae","middleName":"Hyun","lastName":"Park","suffix":""},{"id":419905804,"identity":"faafe469-efb3-4b2c-a4f6-c17eb0add1f5","order_by":1,"name":"Chan Yoon","email":"","orcid":"","institution":"EverEx","correspondingAuthor":false,"prefix":"","firstName":"Chan","middleName":"","lastName":"Yoon","suffix":""},{"id":419905805,"identity":"f2c9baa6-04e2-4b92-bdb5-3c09340ddfb2","order_by":2,"name":"Jae Hyeon Park","email":"","orcid":"","institution":"Hanyang University College of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Jae","middleName":"Hyeon","lastName":"Park","suffix":""},{"id":419905806,"identity":"c6aa4ff2-30fc-433d-8b76-77780da3fa6d","order_by":3,"name":"Sanghee Lee","email":"","orcid":"","institution":"EverEx","correspondingAuthor":false,"prefix":"","firstName":"Sanghee","middleName":"","lastName":"Lee","suffix":""},{"id":419905807,"identity":"77290a26-26de-4e18-a6ff-26147db938a6","order_by":4,"name":"Chi-hyun Choi","email":"","orcid":"https://orcid.org/0000-0003-2120-1111","institution":"EverEx","correspondingAuthor":false,"prefix":"","firstName":"Chi-hyun","middleName":"","lastName":"Choi","suffix":""},{"id":419905808,"identity":"9204e0d3-5b72-43d1-bb32-e36efe85b723","order_by":5,"name":"Chong Bum Chang","email":"","orcid":"","institution":"Seoul National University Bundang Hospital","correspondingAuthor":false,"prefix":"","firstName":"Chong","middleName":"Bum","lastName":"Chang","suffix":""},{"id":419905809,"identity":"58d58036-219f-40d5-9182-3fa66974e26b","order_by":6,"name":"Jin Goo Kim","email":"","orcid":"","institution":"Myongji Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jin","middleName":"Goo","lastName":"Kim","suffix":""}],"badges":[],"createdAt":"2024-11-16 12:33:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5465840/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5465840/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13063-025-09030-2","type":"published","date":"2025-09-01T15:57:48+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":90828032,"identity":"93ae7fd1-478e-4e57-b90c-8358d80d4816","added_by":"auto","created_at":"2025-09-08 16:05:12","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1950698,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5465840/v1/33d9d85f-4cf0-4924-a867-afc728963c5e.pdf"}],"financialInterests":"","formattedTitle":"Study protocol for a prospective, randomized controlled confirmatory clinical investigation to evaluate the safety and efficacy of a multidisciplinary digital therapeutics in patients with patellofemoral pain syndrome","fulltext":[{"header":"ADMINISTRATIVE INFORMATION","content":"\u003cp\u003eNote: the numbers in curly brackets in this protocol refer to SPIRIT checklist item numbers. The order of the items has been modified to group similar items (see http://www.equator-network.org/reporting-guidelines/ spirit-2013-statement-defining-standard-protocolitems-for-clinical-trials/).\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 160px;\"\u003e\n \u003cp\u003eTitle {1}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 441px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStudy protocol for a prospective, randomized controlled confirmatory clinical trial to evaluate the safety and efficacy of a multidisciplinary digital therapeutics in patients with patellofemo\u003c/strong\u003e\u003cstrong\u003eral pain\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 160px;\"\u003e\n \u003cp\u003eTrial registration {2a and 2b}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 441px;\"\u003e\n \u003cp\u003eClinicalTrials.gov., NCT06260865, registered 15th February 2024 (https://clinicaltrials.gov/study/NCT06260865)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 160px;\"\u003e\n \u003cp\u003eProtocol version {3}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 441px;\"\u003e\n \u003cp\u003eThe current protocol version is revision 3, dated 20\u003csup\u003eth\u003c/sup\u003e March 2024.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 160px;\"\u003e\n \u003cp\u003eFunding {4}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 441px;\"\u003e\n \u003cp\u003eThis study is funded by EverEx Inc., Seoul, Korea and partially funded by the Ministry of Health \u0026amp; Welfare, Republic of Korea (grant number: RS-2023-KH142023). EverEx is a manufacturer of the digital therapeutic app (medical device) and sponsor of this trial.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 160px;\"\u003e\n \u003cp\u003eAuthor details {5a}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 441px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTae Hyun Park\u003c/strong\u003e\u003csup\u003e1\u003c/sup\u003e\u003cstrong\u003e, MD; Chan Yoon\u003c/strong\u003e\u003csup\u003e1\u003c/sup\u003e\u003cstrong\u003e, MD; Jae Hyeon Park\u003c/strong\u003e\u003csup\u003e2\u003c/sup\u003e\u003cstrong\u003e, MD; Sanghee Lee\u003c/strong\u003e\u003csup\u003e1\u003c/sup\u003e\u003cstrong\u003e, MD; Chi-hyun Choi\u003c/strong\u003e\u003csup\u003e1*\u003c/sup\u003e, MD; Chong Bum Chang\u003csup\u003e3*\u003c/sup\u003e, MD; Jin Goo Kim\u003csup\u003e4\u003c/sup\u003e, MD\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e1\u003c/sup\u003eEverEx Inc., Seoul, Korea\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e2\u003c/sup\u003eDepartment of Rehabilitation Medicine, Hanyang University College of Medicine\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e3\u003c/sup\u003eDepartment of Orthopaedic Surgery, Seoul National University Bundang Hospital\u003c/p\u003e\n \u003cp\u003e\u003csup\u003e4\u003c/sup\u003eDepartment of Orthopaedic Surgery, Hanyang University Myongji Hospital\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 160px;\"\u003e\n \u003cp\u003eName and contact information for the trial sponsor {5b}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 441px;\"\u003e\n \u003cp\u003eEverEx Inc., 29-7 Seoripul-gil, Seocho-gu, Seoul, Korea\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 160px;\"\u003e\n \u003cp\u003eRole of sponsor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 441px;\"\u003e\n \u003cp\u003eThe study sponsor designed the study, drafted the protocol, conducted review and acceptance from the investigators, obtained approvals from the ministry of food and drug safety (MFDS) and institutional review boards (IRB), and executed funding contracts with the study sites. The sponsor has assigned the contract research organizations (CRO) to perform study monitoring, data management, and statistical analysis. Regarding publication, the sponsor and investigators will jointly publish under mutual agreement. The sponsor plans to apply for device approval from the MFDS based on the clinical trial data.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"INTRODUCTION","content":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e \u003cstrong\u003eand rationale {6a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatellofemoral pain (PFP) is a common condition with a prevalence ranging from 3% to 40%\u0026nbsp;(1), accounting for 25% of knee pain originating from running\u0026nbsp;(2)\u0026nbsp;and 7% to 10% of all medical consultations\u0026nbsp;(3,4). It is more prevalent in females and affects individuals from their teens to their 50s\u0026nbsp;(1,3). The pathophysiology of PFP remains unclear\u0026nbsp;(5), and various non-surgical and surgical treatments have been attempted\u0026nbsp;(6,7). Without proper diagnosis and treatment, PFP does not improve spontaneously\u0026nbsp;(8); over 50% of patients may experience persistent pain for more than two years\u0026nbsp;(9), potentially leading to the progression of patellofemoral osteoarthritis\u0026nbsp;(10).\u003c/p\u003e\n\u003cp\u003eStandard treatment for PFP, according to various guidelines, includes patient education and exercise therapy\u0026nbsp;(11–14). Strength exercises targeting the quadriceps and hip abductors have proven effective in several studies\u0026nbsp;(15–21). However, even with evidence-based treatments, 40% to 57% of patients experience insufficient long-term effects\u0026nbsp;(22,23), highlighting the need for improved therapeutic strategies. Low compliance due to time and location constraints of clinic-based exercise therapy may contribute to this lack of effectiveness\u0026nbsp;(24).\u003c/p\u003e\n\u003cp\u003ePsychological factors such as anxiety, depression, catastrophizing, and fear of movement are associated with pain and physical function in PFP patients and negatively impact recovery processes like rehabilitation training, as suggested by Maclachlan's systematic review\u0026nbsp;(25). To address these factors, Selhorst et al. conducted a randomized controlled trial with adolescent PFP patients, comparing rehabilitation training alone to rehabilitation combined with stepwise cognitive invervention. The group receiving multidisciplinary intervention showed significant improvements in pain and functional levels\u0026nbsp;(26). Similarly, Bagheri et al. found that young female athletes participating in a mindfulness program alongside exercise exhibited better outcomes in pain severity, knee function, subjective treatment effects, and catastrophizing compared to those who only engaged in exercise\u0026nbsp;(27). Despite these findings, research on psychological interventions in PFP patients remains limited\u0026nbsp;(26–30), and no studies have combined CBT, which has proven efficacy in chronic pain\u0026nbsp;(31,32), with exercise therapy in PFP patients.\u003c/p\u003e\n\u003cp\u003eApp-based therapy can overcome time and location constraints of face-to-face treatment, thereby improving patient compliance\u0026nbsp;(33,34). EverEx has developed a multidisciplinary treatment app ‘\u003cstrong\u003eMORA Cure PFP\u003c/strong\u003e’ for PFP patients that includes self-rehabilitation exercise therapy, which automatically adjusts based on the patient's status, and CBT for chronic pain. \u003cstrong\u003e\u0026nbsp;MORA Cure PFP\u003c/strong\u003e is classified as a software as a medical device (SaMD), that can only be used after diagnosis and prescription by a physician and is prior to regulatory approval. An exploratory clinical trial involving 40 patients, conducted from November 2022 to October 2023 (ClinicalTrials.gov., \u0026nbsp;NCT05614583) demonstrated efficacy and safety comparable to real-world treatment\u0026nbsp;(35).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjectives {7}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis confirmatory clinical trial aims to evaluate the safety and efficacy of \u003cstrong\u003eMORA Cure PFP\u003c/strong\u003e by comparing it with conventional treatment in PFP patients. For specific objectives, see \u003cstrong\u003eTable 1\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial design {8}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis clinical trial is a confirmatory medical device clinical trial and is a two-arm, 1:1 randomized, open-label, multi-centered superiority study. Participants who meet the inclusion/exclusion criteria will be randomly assigned to the treatment group and the control group. Treatment group will be given the digital therapeutic app, and control group will receive exercise education and self-exercise materials. Participant flow diagram according to the Consolidated Standards of Reporting Trials (CONSORT), is presented in \u003cstrong\u003eFigure 1\u003c/strong\u003e.\u003c/p\u003e"},{"header":"METHODS: PARTICIPANTS, INTERVENTIONS and OUTCOMES","content":"\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStudy setting {9}\u003c/h2\u003e \u003cp\u003eThis clinical trial will be conducted at both academic hospitals and community hospitals (for the list of sites, see \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://clinicaltrials.gov/study/NCT06260865\u003c/span\u003e\u003cspan address=\"https://clinicaltrials.gov/study/NCT06260865\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) located in South Korea. After being diagnosed and receiving the guidance on the intervention at the hospital, participants will perform the treatment themselves on a daily basis.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eEligibility criteria {10}\u003c/h3\u003e\n\u003cp\u003eTo be included in this study, patients must meet the following criteria: experiencing pain around or behind the patella (kneecap) in unilateral or bilateral knee joints for over 3 months (15,16,36); pain during squatting movements (13,15\u0026ndash;17,19,36\u0026ndash;39); pain in two or more of the following activities/tests\u0026mdash;prolonged sitting, cycling, running, climbing stairs, kneeling, patellar compression test, tenderness around the patella test (13,15\u0026ndash;17,19,36\u0026ndash;39); voluntary decision to participate with signed informed consent.\u003c/p\u003e \u003cp\u003eExclusion criteria are as follows: knee osteoarthritis exceeding Kellgren-Lawrence (K-L) grade 2 on X-ray (36); traumatic event causing fractures or dislocations around the knee within the past 3 months (15,19); knee surgery within the past 3 months (16,17,37,38); patellar tendinitis diagnosed by imaging within the past 3 months (37); current use of narcotic analgesics for pain control (16,39); anticipated use of prohibited medications/treatments within 16 weeks of screening; pregnancy; current or recent (within 3 months) participation in another clinical trial; and any other factors deemed unsuitable by the investigator (36).\u003c/p\u003e\n\u003ch3\u003eWho will take informed consent? {26a}\u003c/h3\u003e\n\u003cp\u003eBefore participating in the clinical trial procedures, participants will voluntarily complete and sign an informed consent form. The consent form will be paper-based, and a licensed physician will explain its contents, giving the participant sufficient time to make an informed decision. The consent of the research participants must be obtained in accordance with the ethical principles and standards outlined in the Declaration of Helsinki. All consent forms used will be those approved by the IRB, and a copy of the signed consent form will be provided to the participant. If the consent form is amended, the changes will be explained, and the consent process will be repeated.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eAdditional consent provision for collection and use of participant data and biological specimens {26b}\u003c/h2\u003e \u003cp\u003eNot applicable, this trial does not collect biological specimens.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eINTERVENTIONS\u003c/h3\u003e\n\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eExplanation for the choice of comparators {6b}\u003c/h2\u003e \u003cp\u003eTo evaluate the safety and efficacy of MORA Cure PFP, the treatment group was assigned to use the app. The control group was set as the real-world at best treatment. Standard treatment for PFP, according to various guidelines, includes patient education and exercise therapy (11\u0026ndash;14). Therefore, the control group was defined as those who receive in-person exercise education by healthcare professionals, follow the provided paper-based materials to perform self-exercise, and record their exercise progress.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eIntervention description {11a}\u003c/h2\u003e \u003cp\u003eAfter confirming eligibility based on the inclusion/exclusion criteria, the target knee (left or right) for evaluation will be selected. If only one knee meets the criteria for PFP, that knee will be selected. If both knees qualify, the knee with greater pain will be chosen. All subsequent evaluations will be conducted on the knee selected as the target knee for assessment.\u003c/p\u003e \u003cp\u003eThe investigational medical device \u0026lsquo;MORA Cure PFP\u0026rsquo; used in this study will be applied only to participants assigned to the treatment group. MORA Cure PFP consists of a web platform for healthcare professionals and a mobile application for patients. The investigator prescribes treatment through the healthcare web platform, and participants install the application on their mobile phones to begin therapy. At baseline, the investigator will randomize and enroll participants. For those assigned to the treatment group, the investigator will register them on the healthcare web platform and prescribe the device. Upon prescription, an installation code for the patient app will appear on the web platform. Participants will then follow the installation manual to install the app, agree to the terms of service, complete registration, and start the plan, with the Day 1 program beginning on the same day. The device provides an 8-week program of rehabilitative exercise and cognitive behavioral therapy (CBT) for PFP (Fig.\u0026nbsp;2). After the initial 8-week treatment period, participants can retain access to the device for up to 12 weeks.\u003c/p\u003e \u003cp\u003eFor participants in the control group, a healthcare professional with experience in musculoskeletal disease treatment will conduct self-exercise education according to the paper-based self-guided exercise material. The exercise education will last for at least 15 minutes, and participants will be instructed to record the time spent on self-exercise in the patient diaries distributed at baseline. At each subsequent visit, participants will be asked to bring their ongoing diaries, and whenever feasible, the diaries will be collected to monitor their progress.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eStrategies to improve adherence to interventions {11c}\u003c/h2\u003e \u003cp\u003eTo enhance adherence, participants are provided with education on the importance of treatment after group allocation. The experimental group receives instructions on using the application, while the control group is taught self-exercise using dedicated materials.\u003c/p\u003e \u003cp\u003eEach participant is required to perform daily self-treatment and log their activities, including exercise completion and duration. For the experimental group, the application automatically tracks and records exercise times, ensuring consistent monitoring. In the control group, participants manually log their exercise in a paper diary. During each visit, the investigator collects the diaries and monitors progress, offering support and feedback to encourage continued adherence.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eParticipant timeline {13}\u003c/h2\u003e \u003cp\u003eParticipants in this clinical trial will complete 4 to 5 outpatient visits: V1 (Screening), V2 (Baseline), V3 (In-treatment), V4 (Post-treatment), and V5 (Follow-up). V2 must occur within 4 weeks of V1, and may be conducted on the same day as V1. V3 is scheduled 4 weeks after V2, with an allowable range of 3 to 5 weeks. V4 is set for 8 weeks after V2, with a window of 8 to 9 weeks, and V5 is scheduled 12 weeks after V2, with an allowable range of 12 to 13 weeks. See \u003cb\u003eTable\u0026nbsp;2\u003c/b\u003e for the specific schedule of assessments for each visit. For Visit 3, participants may not need to visit the medical institution in person. In this case, certain checks, such as prior medication, concomitant medication, and adverse event assessments, may be omitted. Pain intensity assessment and the Kujala evaluation will be conducted by sending a survey link to the participant, who will complete it while in contact with the clinical trial site representative over the phone.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eOutcomes {12}\u003c/h2\u003e \u003cp\u003eThe primary efficacy outcome of this trial is usual pain intensity score (VAS, 100 scale) at 8 weeks (V4). For secondary outcomes, see \u003cb\u003eTable\u0026nbsp;1\u003c/b\u003e.\u003c/p\u003e \u003cp\u003eThrough interviews, demographic information, medical history, surgical history, and prior/concomitant medications will be collected. Physical examination will include measurements of height, weight, and a patella examination. A knee X-ray will be taken to assign a K-L grade (40), which is used to assess exclusion criteria for osteoarthritis.\u003c/p\u003e \u003cp\u003eThe usual and worst pain intensity scores assess the average and peak knee pain experienced over the past week, respectively. Participants mark their pain level on a visual analogue scale from 0 to 100, with values recorded and rounded to the nearest whole number (41).\u003c/p\u003e \u003cp\u003eTo assess knee function, participants complete the anterior knee pain scale (Kujala score), 13-item self-report questionnaire (42), with a total score calculated from the responses. Quality of life is assessed via the EQ-5D-5L (43) questionnaire, recording the sum of scores across five questions and today's health status score. Depression severity is evaluated using the Patient Health Questionnaire-9 (PHQ-9) (44), with a total score from nine questions, while pain catastrophizing is assessed using the Pain Catastrophizing Scale (PCS) (45), totaling scores from 13 questions. Participants also rate their perceived recovery level on a 0 to 6 scale (46).\u003c/p\u003e \u003cp\u003eAll pain and questionnaire assessments are conducted as electronic patient-reported outcomes (ePRO). Participants use digital tools provided at the site, with data automatically transferred to the electronic case report form (eCRF). For visit 3, if conducted as a televisit, participants may complete the assessments remotely.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eSample size {14}\u003c/h2\u003e \u003cp\u003eThe primary efficacy variable of this clinical trial is the intensity of usual pain over the past week at 8 weeks post-treatment initiation, aiming to assess whether the experimental group shows superior improvement compared to the control group. The hypothesis for the superiority test on the primary efficacy variable is as follows: \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:{H}_{0}:\\:{\\mu\\:}_{t}={\\mu\\:}_{c}\\:\\:\\:\\:vs.\\:\\:\\:\\:\\:{H}_{1}:\\:{\\mu\\:}_{t}\\ne\\:{\\mu\\:}_{c}\\)\u003c/span\u003e\u003c/span\u003e, where \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:{\\mu\\:}_{t}\\)\u003c/span\u003e\u003c/span\u003e represents the usual pain intensity at 8 weeks for the experimental group, and \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:{{\\mu\\:}}_{\\text{c}}\\)\u003c/span\u003e\u003c/span\u003e represents the same for the control group.\u003c/p\u003e \u003cp\u003eThe sample size was calculated based on prior study of MORA Cure PFP (ClinicalTrials.gov., NCT05614583). In the exploratory clinical trial, the usual pain over the past week of full analysis set at 8 weeks post-treatment was 2.31\u0026thinsp;\u0026plusmn;\u0026thinsp;1.49 for the experimental group and 3.18\u0026thinsp;\u0026plusmn;\u0026thinsp;2.43 for the control group (35). The calculated effect size (Cohen's d) is as follows: \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:d=\\frac{{m}_{t}-{m}_{c}}{\\sqrt{\\left({s}_{t}^{2}+{s}_{c}^{2}\\right)/2}}=\\frac{2.31-3.18}{\\sqrt{\\left({1.49}^{2}+{2.43}^{2}\\right)/2}}=\\:-0.428\\)\u003c/span\u003e\u003c/span\u003e, where \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:{m}_{t}\\)\u003c/span\u003e\u003c/span\u003e​ is mean of the experimental group, \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:{m}_{c}\\)\u003c/span\u003e\u003c/span\u003e is mean of the control group, \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:{s}_{t}\\)\u003c/span\u003e\u003c/span\u003e is standard deviation of the experimental group, \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:{s}_{c}\\)\u003c/span\u003e\u003c/span\u003e is standard deviation of the control group (47). Values were used up to the second decimal place, and the effect size was calculated without rounding.\u003c/p\u003e \u003cp\u003eUsing an effect size of -0.428, a Type I error of 0.05, and a power of 0.8, the formula for calculating the sample size per group is: \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:n=\\frac{2{\\left({z}_{1-\\alpha\\:/2}+{z}_{1-\\beta\\:}\\right)}^{2}}{{\\left(d\\right)}^{2}}=\\frac{2{\\left(1.960+0.842\\right)}^{2}}{{\\left(0.428\\right)}^{2}}=86\\)\u003c/span\u003e\u003c/span\u003e, where \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:n\\)\u003c/span\u003e\u003c/span\u003e is required sample size per group (rounded up to the nearest whole number), \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:{\\alpha\\:}\\)\u003c/span\u003e\u003c/span\u003e is Type I error, \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:{\\beta\\:}\\)\u003c/span\u003e\u003c/span\u003e is Type II error (1 - power), and \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:d\\)\u003c/span\u003e\u003c/span\u003e is effect size (47).\u003c/p\u003e \u003cp\u003eConsidering a typical dropout rate of 10\u0026ndash;30% for clinical trials involving digital services (48), a 20% dropout rate was assumed for this study. Adjusting for this dropout rate, the required sample size per group is calculated as: \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:{n}^{{\\prime\\:}}=86\\times\\:\\frac{1}{1-r}=107.5\\)\u003c/span\u003e\u003c/span\u003e, where r is the dropout rate (0.2). Thus, the target sample size is set at 216 participants in total, with 108 per group (Fig.\u0026nbsp;1).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eRecruitment {15}\u003c/h2\u003e \u003cp\u003eParticipant recruitment will be handled by the institution. The investigator may invite patients under their care to participate, or participants may be recruited through in-hospital posters or an internet page. In these cases, participants must visit the institution to complete the informed consent form and undergo an eligibility check. All recruitment methods will be implemented only after obtaining IRB approval.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eCriteria for discontinuing or modifying allocated interventions {11b}\u003c/h2\u003e \u003cp\u003eParticipants will be withdrawn from the trial if they: receive unapproved medication, procedures, or treatments that could impact trial outcomes; fail to meet inclusion/exclusion criteria post-enrollment; are lost to follow-up; experience adverse events requiring withdrawal as determined by the investigator; request to discontinue (withdrawal of consent); or if the investigator deems their continued participation unsuitable for any other reason.\u003c/p\u003e \u003cp\u003eIf a participant misses a visit, the investigator must make every effort to contact them, encourage attendance, confirm their well-being, and document the reason for absence. Withdrawn participants will be included in efficacy and safety evaluations unless a valid reason for exclusion exists. Modifications to the intervention are not allowed in this trial.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eRelevant concomitant care permitted or prohibited during the trial {11d}\u003c/h2\u003e \u003cp\u003eDuring the clinical trial, participants may use acetaminophen 650 mg as a rescue medication if they experience intolerable pain. The investigator may prescribe this at visits. Participants already on pain medication before the trial are encouraged to switch to the rescue medication but may continue their existing one at the investigator's discretion. From baseline (visit 2) to follow-up (visit 5), participants should ideally avoid pain medications within 24 hours before each visit.\u003c/p\u003e \u003cp\u003eThe following are prohibited from visit 1 to visit 5: intra-articular or knee injections (e.g., corticosteroids), arthroscopic surgery, corrective osteotomy, knee replacement, or any unapproved procedures or surgeries, opioid analgesics for pain, topical knee ointments or patches, unapproved joint pain medications or treatments, and high-impact physical activities.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eProvision for post-trial care {30d}\u003c/h2\u003e \u003cp\u003eAfter completing or withdrawing from the clinical trial, participants may resume regular medical care as before. If an adverse device effect arises, they may be compensated for medical expenses per the compensation policy until the issue is resolved. The sponsor will secure IRB approval for the insurance policy covering such compensation. Additionally, if there is any suspicion of an adverse event after a participant\u0026rsquo;s trial completion or withdrawal, the investigator must assess and provide further medical care as needed.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003eASSIGNMENT of INTERVENTIONS: ALLOCATION\u003c/h2\u003e \u003cdiv id=\"Sec21\" class=\"Section3\"\u003e \u003ch2\u003eSequence generation {16a}\u003c/h2\u003e \u003cp\u003eOnly participants who meet the inclusion/exclusion criteria will be randomly assigned to either the experimental or control group in a 1:1 ratio. The method used for this assignment is computer-generated block randomization. To ensure independence, a third-party institution will be entrusted with generating the randomization list. Stratification will not be performed.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec22\" class=\"Section2\"\u003e \u003ch2\u003eConcealment mechanism {16b}\u003c/h2\u003e \u003cp\u003eTo conceal the randomization list, neither the sponsor nor the delegated CRO will have access to the list. The sequence will be generated within the third-party institution, and it will be directly built into the eCRF system. The results of this process will be encrypted and will not be identifiable.\u003c/p\u003e \u003cdiv id=\"Sec23\" class=\"Section3\"\u003e \u003ch2\u003eImplementation {16c}\u003c/h2\u003e \u003cp\u003eRandom assignment will be conducted through an interactive web response system (IWRS) incorporated into eCRF. The pre-generated randomization list will be embedded into the program.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec24\" class=\"Section2\"\u003e \u003ch2\u003eASSIGNMENT of INTERVENTIONS: BLINDING\u003c/h2\u003e \u003cdiv id=\"Sec25\" class=\"Section3\"\u003e \u003ch2\u003eWho will be blinded {17a}\u003c/h2\u003e \u003cp\u003eThis clinical trial is open-label; therefore, blinding is not applicable.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec26\" class=\"Section3\"\u003e \u003ch2\u003eProcedure for unblinding if needed {17b}\u003c/h2\u003e \u003cp\u003eThis clinical trial is open-label; therefore, blinding is not applicable.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec27\" class=\"Section3\"\u003e \u003ch2\u003eDATA COLLECTION AND MANAGEMENT\u003c/h2\u003e \u003cdiv id=\"Sec28\" class=\"Section4\"\u003e \u003ch2\u003ePlans for assessment and collection of outcomes {18a}\u003c/h2\u003e \u003cp\u003eSource documents refer to all original records of clinical findings, observations, or other activities essential for the evaluation and replication of the clinical trial. Examples include, but are not limited to: medical records, clinical findings, knee X-rays for K-L grade evaluation, participant diaries for recording treatment compliance, and patient-reported outcomes collected via electronic devices (pain intensity, Kujala scale, EQ-5D-5L, PHQ-9, PCS, and overall perceived level of recovery). For the treatment group, compliance data from the application can also serve as source data.\u003c/p\u003e \u003cp\u003eData collection and recording are performed by the investigator under the supervision of the principal investigator, electronic CRF as the primary method of data collection. The investigator must ensure the accuracy, completeness, legibility, and timeliness of the data included in the case reports and other records. Data recorded in the CRF must be consistent with the source documents; any discrepancies or omissions must be accompanied by an explanation. Changes to electronic CRFs must be traceable through an audit trail system.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec29\" class=\"Section2\"\u003e \u003ch2\u003ePlans to promote participant retention and complete follow-up {18b}\u003c/h2\u003e \u003cp\u003eParticipants will receive 50,000 won (equivalent to 26 US dollars) per visit as transportation reimbursement. If Visit 1 and Visit 2 are conducted simultaneously, participants will receive double the amount, and the same amount will be provided for Visit 3, even if it is an electronic visit. At each visit, the investigator will check and monitor the treatment progress (automated data from the app for the treatment group, patient diaries for the control group). The application includes a notification feature that allows reminders to be sent at the patient's preferred time, and personalized messages are sent based on exercise compliance to help motivate the patient.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eData management {19}\u003c/h3\u003e\n\u003cp\u003eAll clinical trial sites and investigators must ensure participant confidentiality and maintain accurate, legible, and timely records in compliance with regulations. The sponsor and regulatory authorities must be granted access to review records for monitoring, audits, and inspections. When using eCRF, authorized investigators enter data and automated systems detect discrepancies, issuing queries for corrections or confirmations. If IWRS or ePROs are used, data integration with the eCRF may occur.\u003c/p\u003e \u003cp\u003eThe sponsor reviews the eCRFs for completeness and may issue queries for discrepancies or missing data, which the investigator must address. After the trial, protocol violations are determined, and once data integrity is confirmed, a database lock (DB lock) is performed, and a copy of the participant database is sent to the investigator. Statistical analyses take place post-DB lock.\u003c/p\u003e \u003cp\u003eThe investigator and trial site must retain essential documents according to regulatory standards, with the sponsor specifying the retention period. If further retention is unnecessary, the sponsor must inform the investigator and the clinical trial site in writing.\u003c/p\u003e \u003cdiv id=\"Sec31\" class=\"Section2\"\u003e \u003ch2\u003eConfidentiality {27}\u003c/h2\u003e \u003cp\u003eThe investigator must ensure the anonymity of study participants, avoiding any identification of participants' names in documents submitted to the sponsor. Signed consent forms, source documents, and participant logs must be kept confidential and stored securely. All personal information collected through the investigational device follows personal information processing policy, and participants shall consent before installing the app.\u003c/p\u003e \u003cp\u003eData collection systems in this trial comply with US code of federal regulation Chap.\u0026nbsp;21, part 11 and local regulations. All data transmissions are encrypted, and access is controlled through individual user IDs and passwords, with only authorized and trained personnel permitted access.\u003c/p\u003e \u003cp\u003e \u003cb\u003ePlans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}\u003c/b\u003e \u003c/p\u003e \u003cp\u003eNot applicable as no biological samples are to be collected.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec32\" class=\"Section2\"\u003e \u003ch2\u003eSTATISTICAL METHODS\u003c/h2\u003e \u003cdiv id=\"Sec33\" class=\"Section3\"\u003e \u003ch2\u003eDefinition of analysis sets\u003c/h2\u003e \u003cp\u003eIn this clinical trial, data will be analyzed using three sets: the full analysis set (FAS), the per protocol set (PPS), and the safety set. The FAS, aligned with the intention-to-treat (ITT) principle, will be the primary analysis set for efficacy evaluations, with additional analyses using the PPS. If discrepancies arise between the two, the outcomes will be presented and investigated. Safety evaluations will use the safety set.\u003c/p\u003e \u003cp\u003eThe FAS includes participants who meet all of the following: have post-randomization primary efficacy data, records of applying the investigational device (test group) or performing self-exercise (control group), and were not improperly enrolled due to inclusion/exclusion violations. The PPS is a subset of the FAS, including those who completed the trial without major protocol violations, did not withdraw prematurely, and had an overall compliance rate of 50% or higher. The safety set includes all randomized participants with records of using the investigational device or performing self-exercise.\u003c/p\u003e \u003cp\u003e \u003cb\u003eMethods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}\u003c/b\u003e \u003c/p\u003e \u003cp\u003eFor the analysis of the FAS, missing values occurring after treatment that are used for primary and secondary efficacy evaluation variables will be imputed using the last observation carried forward (LOCF) method. However, when imputing missing values, results prior to the administration of the investigational medical device will not be substituted for post-administration results. Other data will be analyzed as collected (available data) without imputation.\u003c/p\u003e \u003cp\u003eFor the analysis of the PPS, missing values will not be imputed and will be analyzed as collected.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec34\" class=\"Section3\"\u003e \u003ch2\u003eStatistical methods for demographic and other baseline characteristics\u003c/h2\u003e \u003cp\u003eThe full analysis set (FAS) will be analyzed for demographic information, medication history, treatment history, and past/current medical history of participants. Categorical data (e.g., gender) will be presented as frequency and percentage within the safety population, while continuous data (e.g., age) will be summarized using descriptive statistics, including mean, standard deviation, median, minimum, and maximum values. Results will be reported separately for the experimental and control groups. Group comparisons will use a two-sample t-test for continuous variables (or Wilcoxon\u0026rsquo;s rank-sum test if normality is not met) and Pearson\u0026rsquo;s chi-square test for categorical variables (or Fisher\u0026rsquo;s exact test if more than 20% of cells have expected counts below 5).\u003c/p\u003e \u003cp\u003ePast and current medical history will be standardized using the latest the Medical Dictionary for Regulatory Activities (MedDRA) version, classified by system organ class (SOC) and preferred term (PT), with frequencies and percentages reported per group. Medication and treatment history will be standardized by the latest anatomical therapeutic chemical (ATC) classification, reported by level 1 (anatomical main group) and level 2 (therapeutic subgroup), and analyzed by Pearson\u0026rsquo;s chi-square test (or Fisher\u0026rsquo;s exact test where appropriate).\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e\n\u003ch3\u003eStatistical methods for primary and secondary outcomes {20a}\u003c/h3\u003e\n\u003cp\u003eFor the definition of efficacy evaluation variables, see \u003cb\u003eTable\u0026nbsp;1\u003c/b\u003e. Descriptive statistics (mean, standard deviation, median, minimum, maximum) will be presented for both experimental and control groups. Group differences will be analyzed using ANCOVA with baseline values as covariates, providing adjusted means (least square means), p-values, and 95% confidence intervals. Statistical tests will be two-sided with a significance level of 0.05, and results will include clinical interpretation.\u003c/p\u003e \u003cp\u003eSafety analysis will be conducted on the safety set. Adverse events (AEs) will be standardized by SOC and PT using the latest MedDRA version. Treatment-emergent adverse events (TEAEs) will be recorded as a single event per participant if they share the same SOC and PT, with severity classified by the highest severity reported, and causal relationship classified by the stronger link to the investigational device. Analysis will focus on TEAEs, including counts and percentages for TEAEs, knee-related TEAEs, adverse device effects (ADEs), and serious adverse events (SAEs). Percentage differences will be tested using Pearson\u0026rsquo;s chi-square test or Fisher\u0026rsquo;s exact test, if appropriate.\u003c/p\u003e\n\u003ch3\u003eInterim analyses {21b}\u003c/h3\u003e\n\u003cp\u003eThere are no interim analyses planned.\u003c/p\u003e \u003cdiv id=\"Sec37\" class=\"Section2\"\u003e \u003ch2\u003eMethods or additional analyses (e.g. Subgroup analyses) {20b}\u003c/h2\u003e \u003cp\u003eTo determine whether the results of the primary efficacy evaluation differ according to subgroups of study participants, a subgroup analysis will be performed. The subgroup analysis will compare participants with a usual pain intensity score over the past week at visit 2 of 50 points or higher to those with a score of 49 points or lower.\u003c/p\u003e \u003cdiv id=\"Sec38\" class=\"Section3\"\u003e \u003ch2\u003ePlans to give access to the full protocol, participant-level data and statistical code {31c}\u003c/h2\u003e \u003cp\u003eThere are no plans to give access to the full protocol, participant-level data and statistical code.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec39\" class=\"Section2\"\u003e \u003ch2\u003eOVERSIGHT AND MONITORING\u003c/h2\u003e \u003cdiv id=\"Sec40\" class=\"Section3\"\u003e \u003ch2\u003eComposition of the coordinating centre and trial steering committee {5d}\u003c/h2\u003e \u003cp\u003eThe investigators will hold investigator meetings as needed, led by two experienced orthopedic surgeons who have been assigned the role of coordinating investigators. Information regarding the protocol and the device must be provided to the investigators prior to the start of the trial, and formal acceptance must be obtained. Before the trial begins, the sponsor will visit each site for a site initiation visit (SIV), where the research team will be briefed on the trial, and the final operational details will be confirmed. If necessary, a site feasibility meeting may be conducted prior to the SIV meeting.\u003c/p\u003e \u003cp\u003eThe sponsor and CRO will hold monthly meetings to review the progress of the study and discuss any issues that arose during routine monitoring visits. If necessary, additional QC visits, individual investigator meetings, or investigator group meetings may be scheduled to address specific concerns or ensure the smooth continuation of the trial.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e\n\u003ch3\u003eComposition of the data monitoring committee, its role and reporting structure {21a}\u003c/h3\u003e\n\u003cp\u003eThis study does not include a data monitoring committee (DMC). The decision to exclude a DMC is based on the fact that the study involves minimal risk to participants, and the investigational medical device has already demonstrated a favorable safety profile in prior studies. Additionally, the study design allows for close monitoring by the investigators and sponsor through regular site visits and data reviews, ensuring that participant safety and data integrity are adequately maintained without the need for an independent monitoring committee.\u003c/p\u003e\n\u003ch3\u003eAdverse event reporting and harms {22}\u003c/h3\u003e\n\u003cp\u003eAll adverse events that occur or worsen after obtaining the subject's consent will be collected, except for those who fail the screening. Pre-existing signs or symptoms at the time of consent are recorded in the medical history section of the CRF. AEs should be monitored until symptoms resolve and the condition stabilizes, and progress reports may be required by the sponsor. The investigator should provide a clear diagnosis, or otherwise record symptoms/signs. Appropriate examinations and treatments must be administered for all AEs. If an AE makes it difficult to continue the trial, the subject may drop out or the trial may be discontinued, with the best treatment provided for safety.\u003c/p\u003e \u003cp\u003eThe CRF must record whether the AE is treatment-emergent (TEAE), the onset and end dates, severity, causal relationship with the investigational device, actions taken, and outcome. Serious adverse events (SAEs), serious adverse device effects, and unexpected adverse device effects must be reported to the IRB and regulatory authorities within the required timeframes. Specific AEs, such as worsening knee pain, cramps, dizziness, changes in mood or thought patterns, and any other significant AEs, must be documented and shared with the sponsor within 24 hours.\u003c/p\u003e\n\u003ch3\u003eFrequency and plans for auditing trial conduct {23}\u003c/h3\u003e\n\u003cp\u003eBefore the clinical trial begins, the sponsor and investigator review the protocol and CRFs during a site initiation visit or investigator meeting. Monitoring is conducted by the sponsor or their representative, who regularly visits the site to verify the completeness of source documents, the accuracy of case records, adherence to Good Clinical Practice (GCP) and the protocol, participant enrollment, and the management of investigational devices and supplies. Monitors discuss findings with key investigators and ensure that source documents and CRFs are consistent, especially regarding consent, inclusion/exclusion criteria, and SAEs.\u003c/p\u003e \u003cp\u003eThe investigator must retain all source documents, including signed consent forms, and ensure data traceability. Monitoring follows the sponsor's procedures, with results reported to the sponsor. Audits are performed by the sponsor, while the MFDS conducts inspections. If notified of an MFDS inspection, the investigator must inform the sponsor promptly.\u003c/p\u003e\n\u003ch3\u003ePlans for communicating important protocol amendments to relevant parties (e.g. Trial participants, ethical committees) {25}\u003c/h3\u003e\n\u003cp\u003eWhen changes to the approved clinical trial protocol are needed, approval must be obtained from the IRB and MFDS. The sponsor and investigator must document their agreement to follow the protocol, including any amendments, with signatures and dates. The investigator cannot deviate from the protocol without prior approval from the sponsor, IRB, and MFDS, except in cases where immediate action is required to protect participants. In such emergencies, the investigator must report the changes, along with reasons, to the sponsor, IRB, and MFDS as soon as possible to obtain retroactive approval.\u003c/p\u003e\n\u003ch3\u003eDissemination plans {31a}\u003c/h3\u003e\n\u003cp\u003eRegardless of the study results, whether positive or not, the sponsor and investigators has the right to publish or present any data collected or generated from the clinical trial. If the investigators wish to present or publish the study results externally, it must first provide the sponsor with an opportunity to review the manuscript or any other disclosure materials in advance to prevent the inadvertent release of confidential information or inventions, and obtain approval before publication or disclosure.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThis clinical trial is a double-arm randomized controlled trial aimed at evaluating the safety and efficacy of the digital therapeutic app for PFP (MORA Cure PFP). The app used in the trial includes guideline-based exercise therapy and CBT, designed to facilitate high levels of patient interaction and features suitable for self-guided use, which are expected to improve treatment compliance. The intervention in this study will provide a new method for the rehabilitation of patients with PFP.\u003c/p\u003e \u003cp\u003eIn recent years, digital therapeutics have gained significant attention. Digital therapeutic devices are primarily applied to chronic conditions such as diabetes or psychiatric disorders, and useful in correcting lifestyle and behavioral habits. Recently, digital therapeutics targeting musculoskeletal diseases have been under development, and results from a clinical trial for one targeting fibromyalgia have been published (49).\u003c/p\u003e \u003cp\u003eFrom a regulatory perspective, digital therapeutics are classified as software as a medical device (SaMD) (50). SaMD refers to software that qualifies as a medical device on its own, as opposed to hardware-based medical devices. Digital therapeutics are specifically designated as treatment-focused SaMDs, which require objective demonstration of therapeutic effectiveness to gain regulatory approval. Prospective clinical trials serve not only as an objective process for regulatory approval by observing therapeutic effects but also as valuable data for subsequent health technology assessments and insurance reimbursement listings. Therefore, when designing clinical trials for digital therapeutics, considerations should include not only medical aspects but also regulatory approval and insurance listing perspectives for medical devices.\u003c/p\u003e \u003cp\u003eIn designing clinical trials for digital therapeutics, specific considerations are essential. For instance, some trials use a \u0026ldquo;sham device,\u0026rdquo; a simplified app lacking therapeutic features, as the control group (51). However, this trial aims to demonstrate the app\u0026rsquo;s superiority over the at-best treatment (treatment-as-usual). Therefore, the control group will receive in-person exercise education with materials and resources for self-guided exercise without app use. The inclusion/exclusion criteria should accurately represent the indication. In this trial, PFP guidelines (11\u0026ndash;14) are used to select participants with chronic patella-related pain lasting over three months and confirm objective pain elicited through movement or physical exams. Given that PFP is often diagnosed by exclusion (11\u0026ndash;14), patients with conditions such as osteoarthritis, fractures, dislocations, surgical history, or patellar tendinitis are excluded. Additionally, patients requiring high-potency drugs like narcotic analgesics are beyond the app\u0026rsquo;s intended use and are excluded. The required participant number is designed based on the app\u0026rsquo;s feasibility trial (35), offering a more objective basis than calculations based on non-app studies. As the name implies, PFP is characterized primarily by pain, so the primary endpoint is the usual pain level at eight weeks, with expectations that the app group will report lower pain levels than the control group.\u003c/p\u003e \u003cp\u003eA representative digital therapeutic for knee-related conditions is Mawendo (manufactured by Mawendo GmbH, Germany). In Germany, digital therapeutics are covered under the category of Digitale Gesundheitsanwendungen (DiGA) by public health insurance (Gesetzliche Krankenversicherung, GKV), and Mawendo accounts for approximately one-quarter of the total reimbursement within the DiGA category (52). A randomized controlled trial involving 259 participants showed statistically significant therapeutic superiority of Mawendo over standard physiotherapy (53). Its primary outcomes are functional improvement, as measured by knee injury and osteoarthritis outcome score-activities of daily living subscale (KOOS-ADL), and pain reduction, assessed using VAS. While Mawendo\u0026rsquo;s typical treatment period spans 12 weeks, this study will include an 8-week treatment phase followed by a 4-week extra curriculum. An additional difference of this study is its inclusion of psychological measures, evaluating depression and pain catastrophizing levels.\u003c/p\u003e"},{"header":"Limitations","content":"\u003cp\u003eThere are several limitations in this trial. First, for the treatment group, the placebo effect of the \u0026ldquo;app\u0026rdquo; itself, rather than the therapeutic program, may be considered. However, given that app-based therapy inherently increases interaction and compliance, this should be seen as a contributing factor to the treatment rather than a placebo. Additionally, when evaluating the device\u0026mdash;especially in value-based health technology assessments\u0026mdash;comparison with the current at-best therapy is more appropriate. Second, the assessment tools used in this trial, including pain measured with the VAS scale and various questionnaires, lack objectivity. However, given that the evaluation is not based on objective lab values but on assessments of the symptoms, some subjectivity in evaluation is inevitable. Furthermore, since there are no direct comparison targets such as \u0026lsquo;exercise-only\u0026rsquo; or \u0026lsquo;CBT-only\u0026rsquo; apps, it is challenging to clarify which specific component plays a primary role. Finally, blinding was not feasible in the design of the study's experimental and control groups, which may be vulnerable to bias.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eThe digital therapeutic app for PFP offers a structured progressive exercise program and CBT designed for chronic pain, with the goal of enhancing compliance and treatment effectiveness. This trial will evaluate the safety and efficacy of the digital therapeutic app compared to an active control (treatment as usual).\u003c/p\u003e"},{"header":"ABBREVIATIONS","content":"\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eADE\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAdverse Device Effect\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAE\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAdverse Event\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eATC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAnatomical Therapeutic Chemical\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCBT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCognitive Behavioral Therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCRF\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCase Report Form\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCRO\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eContract Research Organization\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eDB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eDatabase\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eeCRF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eElectronic Case Report Form\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eePRO\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eElectronic Patient Reported Outcome\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eFAS\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eFull Analysis Set\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eGCP\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eGood Clinical Practice\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eITT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eIntention-to-Treat\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eIRB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eInstitutional Review Board\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eLOCF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eLast Observation Carried Forward\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMedDRA\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eThe Medical Dictionary for Regulatory Activities\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMFDS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMinistry of Food and Drug Safety\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePCS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePain Catastrophizing Scale\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePFP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePatellofemoral pain\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePHQ-9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePatient Health Questionnaire-9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePP\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePer Protocol\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePPS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePer Protocol Set\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePT\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePreferred Term\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSAE\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSerious Adverse Event\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eS\u003c/strong\u003e\u003cstrong\u003eaMD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSoftware as a Medical Device\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSOC\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSystem Organ Class\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTEAE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTreatment-emergent Adverse Event\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eVAS\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eVisual Analogue Scale\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eTRIAL STATUS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe current protocol version is revision 3, dated 20\u003csup\u003eth\u003c/sup\u003e March 2024. Participant recruitment began on 26\u003csup\u003eth\u003c/sup\u003e April 2024 and is expected to be finished by the end of December 2024.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to acknowledge all investigation sites staffs, especially principal investigators (Drs. Man Soo Kim, Sang-Hak Lee, Moon-Jong Chang, Dong Jin Ryu, Jong Min Kim, Seong-Hwan Kim, Jae Young Park, and Gyu Seong Jeong) for their ongoing support in this project. We would like to acknowledge the regulatory affairs managers for their perspective on clinical trial design related to device approval and insurance listing. We also extend our gratitude to the product team for their efforts in the development of the medical device. This research was supported by the SmartTech Clinical Research Center (SCRC), funded by the Ministry of Health \u0026amp; Welfare, Republic of Korea (grant number: RS-2023-KH142023).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions {31b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors collaboratively conceived and designed the study. JHP and CL contributed their expertise in rehabilitative exercise, while CY, JGK, CBC provided expertise as an orthopedic surgeon. CC offered insights in CBT for chronic pain. THP contributed statistical methodology and conducted sample size calculations. THP prepared and drafted the study protocol and the initial manuscript. All authors provided substantial feedback and participated in revising the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding {4}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe trial was sponsored by EverEx Inc. and partially funded by the Ministry of Health \u0026amp; Welfare, Republic of Korea (grant number: RS-2023-KH142023). The study sponsor designed the study, drafted the protocol, conducted review and acceptance from the investigators, obtained approvals from the MFDS and IRBs, and executed funding contracts with the study sites. The sponsor have assigned the CROs to perform study monitoring, data management, and statistical analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials {29}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll intangible and tangible products resulting from the conduct of this study, including all reports, data, attached documents, work outcomes, and intellectual property, shall be owned by the sponsor. This provision is ensured through a documented agreement among the sponsor, investigator, and site, established before the commencement of the clinical trial.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate {24}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthical approval was granted by the following IRBs: Institutional Review Board, The Catholic University of Korea, Seoul St. Mary\u0026rsquo;s Hospital (No. KC24DDDS0561, approval date: 25\u003csup\u003eth\u003c/sup\u003e October 2024), Institutional Review Board, Kyung Hee University Hospital at Gandong (KHNMC 2024-03035, 8\u003csup\u003eth\u003c/sup\u003e April 2024), Seoul National University Bundang Hospital Instituional Review Board (E-2409-924-402, 22\u003csup\u003eth\u003c/sup\u003e August 2024), Seoul Metropolitan Government-Seoul National University Boramae Medical Center Institutional Review Board (30-2024-32, 20\u003csup\u003eth\u003c/sup\u003e May 2024), Institutional Review Board, MyongJi Hospital (2024-08-018, 28\u003csup\u003eth\u003c/sup\u003e August 2024), Inha University Hospital Institutional Review Board (INHAUH 2024-03-016, 24\u003csup\u003eth\u003c/sup\u003e May 2024), Asan Medical Center Institutional Review Board (2024-0762, 13\u003csup\u003eth\u003c/sup\u003e June 2024), Chung-Ang University Hospital Institutional Review Board (2403-005-592, 19\u003csup\u003eth\u003c/sup\u003e April 2024), Institutional Review Board, CHA Bundang Medical Center, CHA University (2024-03-006-003, 22\u003csup\u003eth\u003c/sup\u003e April 2024), Institutional Review Board, Hanyang University Guri Hospital (2024-02-022-002, 1th April 2024). The Ministry of Food and Drug Safety of Korea has approved the clinical trial and investigation device exemption (1699, 19th March 2024).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication {32}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBefore the start of the clinical trial, the informed consent process included notifying participants that the information collected and the trial results may be published. It was also explained that confidentiality of personal information would be maintained in any publication of the trial results. Participants confirmed their understanding of all details and provided consent of their own free will.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests {28}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTHP, CY, SL, and CC are employees of EverEx Inc., the sponsor of this study, and receive salaries from the company. JHP and CBC serves as an advisor but does not receive compensation from EverEx Inc. \u003cstrong\u003e\u003cbr\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eCallaghan MJ, Selfe J. Has the incidence or prevalence of patellofemoral pain in the general population in the United Kingdom been properly evaluated? Phys Ther Sport. 2007;8(1):37\u0026ndash;43.\u003c/li\u003e\n \u003cli\u003eTaunton JE, Ryan MB, Clement DB, McKenzie DC, Lloyd-Smith DR, Zumbo BD. A retrospective case-control analysis of 2002 running injuries. Br J Sports Med. 2002;36(2):95\u0026ndash;101.\u003c/li\u003e\n \u003cli\u003eGlaviano NR, Kew M, Hart JM, Saliba S. Demographic and epidemiological trends in patellofemoral pain. Int J Sports Phys Ther. 2015;10(3):281.\u003c/li\u003e\n \u003cli\u003eKannus P, Aho H, J\u0026auml;rvinen M, Nttym\u0026auml;ki S. Computerized recording of visits to an outpatient sports clinic. Am J Sports Med. 1987;15(1):79\u0026ndash;85.\u003c/li\u003e\n \u003cli\u003ePowers CM, Witvrouw E, Davis IS, Crossley KM. Evidence-based framework for a pathomechanical model of patellofemoral pain: 2017 patellofemoral pain consensus statement from the 4th International Patellofemoral Pain Research Retreat, Manchester, UK: part 3. Br J Sports Med. 2017;51(24):1713\u0026ndash;23.\u003c/li\u003e\n \u003cli\u003eKettunen JA, Harilainen A, Sandelin J, Schlenzka D, Hietaniemi K, Seitsalo S, et al. Knee arthroscopy and exercise versus exercise only for chronic patellofemoral pain syndrome: 5-year follow-up. Br J Sports Med. 2012;46(4):243\u0026ndash;6.\u003c/li\u003e\n \u003cli\u003eFulkerson JP. Diagnosis and treatment of patients with patellofemoral pain. Am J Sports Med. 2002;30(3):447\u0026ndash;56.\u003c/li\u003e\n \u003cli\u003eSandow MJ, Goodfellow JW. The natural history of anterior knee pain in adolescents. J Bone Joint Surg Br. 1985;67(1):36\u0026ndash;8.\u003c/li\u003e\n \u003cli\u003eRathleff MS, Rathleff CR, Olesen JL, Rasmussen S, Roos EM. Is knee pain during adolescence a self-limiting condition? Prognosis of patellofemoral pain and other types of knee pain. Am J Sports Med. 2016;44(5):1165\u0026ndash;71.\u003c/li\u003e\n \u003cli\u003eCrossley KM. Is patellofemoral osteoarthritis a common sequela of patellofemoral pain? BMJ Publishing Group Ltd and British Association of Sport and Exercise Medicine; 2014.\u003c/li\u003e\n \u003cli\u003eCrossley KM, Middelkoop M van, Callaghan MJ, Collins NJ, Rathleff MS, Barton CJ. 2016 Patellofemoral pain consensus statement from the 4th International Patellofemoral Pain Research Retreat, Manchester. Part 2: recommended physical interventions (exercise, taping, bracing, foot orthoses and combined interventions). Br J Sports Med. 2016 Jul 1;50(14):844\u0026ndash;52.\u003c/li\u003e\n \u003cli\u003eCollins NJ, Barton CJ, Middelkoop M van, Callaghan MJ, Rathleff MS, Vicenzino BT, et al. 2018 Consensus statement on exercise therapy and physical interventions (orthoses, taping and manual therapy) to treat patellofemoral pain: recommendations from the 5th International Patellofemoral Pain Research Retreat, Gold Coast, Australia, 2017. Br J Sports Med. 2018 Sep 1;52(18):1170\u0026ndash;8.\u003c/li\u003e\n \u003cli\u003eWilly RW, Hoglund LT, Barton CJ, Bolgla LA, Scalzitti DA, Logerstedt DS, et al. Patellofemoral pain: clinical practice guidelines linked to the international classification of functioning, disability and health from the academy of orthopaedic physical therapy of the American physical therapy association. J Orthop Sports Phys Ther. 2019;49(9):CPG1\u0026ndash;95.\u003c/li\u003e\n \u003cli\u003eWallis JA, Roddy L, Bottrell J, Parslow S, Taylor NF. A systematic review of clinical practice guidelines for physical therapist management of Patellofemoral pain. Phys Ther. 2021;101(3):pzab021.\u003c/li\u003e\n \u003cli\u003eFukuda TY, Melo WP, Zaffalon BM, Rossetto FM, Magalh\u0026atilde;es E, Bryk FF, et al. Hip posterolateral musculature strengthening in sedentary women with patellofemoral pain syndrome: a randomized controlled clinical trial with 1-year follow-up. J Orthop Sports Phys Ther. 2012;42(10):823\u0026ndash;30.\u003c/li\u003e\n \u003cli\u003eFukuda TY, Rossetto FM, MAGALH\u0026atilde;ES E, Bryk FF, Garcia Lucareli PR, de Almeida Carvalho NA. Short-term effects of hip abductors and lateral rotators strengthening in females with patellofemoral pain syndrome: a randomized controlled clinical trial. J Orthop Sports Phys Ther. 2010;40(11):736\u0026ndash;42.\u003c/li\u003e\n \u003cli\u003eCrossley K, Bennell K, Green S, Cowan S, McConnell J. Physical therapy for patellofemoral pain: a randomized, double-blinded, placebo-controlled trial. Am J Sports Med. 2002;30(6):857\u0026ndash;65.\u003c/li\u003e\n \u003cli\u003eClark DI, Downing N, Mitchell J, Coulson L, Syzpryt EP, Doherty M. Physiotherapy for anterior knee pain: a randomised controlled trial. Ann Rheum Dis. 2000;59(9):700\u0026ndash;4.\u003c/li\u003e\n \u003cli\u003eWitvrouw E, Danneels L, Van Tiggelen D, Willems TM, Cambier D. Open versus closed kinetic chain exercises in patellofemoral pain: a 5-year prospective randomized study. Am J Sports Med. 2004;32(5):1122\u0026ndash;30.\u003c/li\u003e\n \u003cli\u003eHerrington L, Al-Sherhi A. A controlled trial of weight-bearing versus non\u0026mdash;weight-bearing exercises for patellofemoral pain. J Orthop Sports Phys Ther. 2007;37(12):155\u0026ndash;60.\u003c/li\u003e\n \u003cli\u003eDolak KL, Silkman C, McKeon JM, Hosey RG, Lattermann C, Uhl TL. Hip strengthening prior to functional exercises reduces pain sooner than quadriceps strengthening in females with patellofemoral pain syndrome: a randomized clinical trial. J Orthop Sports Phys Ther. 2011;41(8):560\u0026ndash;70.\u003c/li\u003e\n \u003cli\u003eCollins NJ, Bierma-Zeinstra SM, Crossley KM, van Linschoten RL, Vicenzino B, van Middelkoop M. Prognostic factors for patellofemoral pain: a multicentre observational analysis. Br J Sports Med. 2013;47(4):227\u0026ndash;33.\u003c/li\u003e\n \u003cli\u003eLankhorst NE, van Middelkoop M, Crossley KM, Bierma-Zeinstra SMA, Oei EHG, Vicenzino B, et al. Factors that predict a poor outcome 5\u0026ndash;8 years after the diagnosis of patellofemoral pain: a multicentre observational analysis. Br J Sports Med. 2016;50(14):881\u0026ndash;6.\u003c/li\u003e\n \u003cli\u003eJensen R, Hystad T, Baerheim A. Knee function and pain related to psychological variables in patients with long-term patellofemoral pain syndrome. J Orthop Sports Phys Ther. 2005;35(9):594\u0026ndash;600.\u003c/li\u003e\n \u003cli\u003eMaclachlan LR, Collins NJ, Matthews ML, Hodges PW, Vicenzino B. The psychological features of patellofemoral pain: a systematic review. Br J Sports Med. 2017;51(9):732\u0026ndash;42.\u003c/li\u003e\n \u003cli\u003eSelhorst M, Rice W, Jackowski M, Degenhart T, Coffman S. A sequential cognitive and physical approach (SCOPA) for patellofemoral pain: a randomized controlled trial in adolescent patients. Clin Rehabil. 2018;32(12):1624\u0026ndash;35.\u003c/li\u003e\n \u003cli\u003eBagheri S, Naderi A, Mirali S, Calmeiro L, Brewer BW. Adding mindfulness practice to exercise therapy for female recreational runners with patellofemoral pain: A randomized controlled trial. J Athl Train. 2021;56(8):902\u0026ndash;11.\u003c/li\u003e\n \u003cli\u003eKedroff L, Lun ALK, Shimoni D, Bearne LM. Cognitive Behavioural Therapy Informed Physiotherapy for Patellofemoral Pain: A feasibility study. Musculoskeletal Care. 2019;17(4):382\u0026ndash;9.\u003c/li\u003e\n \u003cli\u003eSelhorst M, Hoehn J, Degenhart T, Schmitt L, Fernandez-Fernandez A. Psychologically-informed video reduces maladaptive beliefs in adolescents with patellofemoral pain. Phys Ther Sport. 2020;41:23\u0026ndash;8.\u003c/li\u003e\n \u003cli\u003eSelhorst M, Fernandez-Fernandez A, Schmitt L, Hoehn J. Effect of a Psychologically Informed Intervention to Treat Adolescents With Patellofemoral Pain: A Randomized Controlled Trial. Arch Phys Med Rehabil. 2021;102(7):1267\u0026ndash;73.\u003c/li\u003e\n \u003cli\u003ede C Williams AC, Fisher E, Hearn L, Eccleston C. Psychological therapies for the management of chronic pain (excluding headache) in adults. Cochrane Database Syst Rev. 2020;(8).\u003c/li\u003e\n \u003cli\u003eGarland EL, Brintz CE, Hanley AW, Roseen EJ, Atchley RM, Gaylord SA, et al. Mind-body therapies for opioid-treated pain: a systematic review and meta-analysis. JAMA Intern Med. 2020;180(1):91\u0026ndash;105.\u003c/li\u003e\n \u003cli\u003eHuber S, Priebe JA, Baumann KM, Plidschun A, Schiessl C, T\u0026ouml;lle TR. Treatment of Low Back Pain with a Digital Multidisciplinary Pain Treatment App: Short-Term Results. JMIR Rehabil Assist Technol. 2017 Dec 4;4(2):e11.\u003c/li\u003e\n \u003cli\u003ePriebe JA, Haas KK, Moreno Sanchez LF, Schoefmann K, Utpadel-Fischler DA, Stockert P, et al. Digital Treatment of Back Pain versus Standard of Care: The Cluster-Randomized Controlled Trial, Rise-uP. J Pain Res. 2020 Jul 17;13:1823\u0026ndash;38.\u003c/li\u003e\n \u003cli\u003ePark TH, Yoon C. Clinical investigation report: multidisciplinary digital therapeutics of patellofemoral pain syndrome versus usual care, a randomized controlled pilot study. 2024 Mar. Report No.: E-ETH-01K-CTP-01_CIR.\u003c/li\u003e\n \u003cli\u003eHott A, Brox JI, Pripp AH, Juel NG, Paulsen G, Liavaag S. Effectiveness of isolated hip exercise, knee exercise, or free physical activity for patellofemoral pain: a randomized controlled trial. Am J Sports Med. 2019;47(6):1312\u0026ndash;22.\u003c/li\u003e\n \u003cli\u003eVan Linschoten R, Van Middelkoop M, Berger MY, Heintjes EM, Koopmanschap MA, Verhaar JA, et al. The PEX study\u0026ndash;Exercise therapy for patellofemoral pain syndrome: design of a randomized clinical trial in general practice and sports medicine [ISRCTN83938749]. BMC Musculoskelet Disord. 2006;7(1):1\u0026ndash;6.\u003c/li\u003e\n \u003cli\u003evan Linschoten R, van Middelkoop M, Berger MY, Heintjes EM, Verhaar JA, Willemsen SP, et al. Supervised exercise therapy versus usual care for patellofemoral pain syndrome: an open label randomised controlled trial. Bmj. 2009;339.\u003c/li\u003e\n \u003cli\u003eKannus P, Natri A, Paakkala T, J\u0026Auml;RVINEN M. An outcome study of chronic patellofemoral pain syndrome. Seven-year follow-up of patients in a randomized, controlled trial. JBJS. 1999;81(3):355\u0026ndash;63.\u003c/li\u003e\n \u003cli\u003eKohn MD, Sassoon AA, Fernando ND. Classifications in Brief: Kellgren-Lawrence Classification of Osteoarthritis. Clin Orthop. 2016 Aug;474(8):1886\u0026ndash;93.\u003c/li\u003e\n \u003cli\u003eByrom B, Elash CA, Eremenco S, Bodart S, Muehlhausen W, Platko JV, et al. Measurement Comparability of Electronic and Paper Administration of Visual Analogue Scales: A Review of Published Studies. Ther Innov Regul Sci. 2022 May;56(3):394\u0026ndash;404.\u003c/li\u003e\n \u003cli\u003eKujala UM, Jaakkola LH, Koskinen SK, Taimela S, Hurme M, Nelimarkka O. Scoring of patellofemoral disorders. Arthrosc J Arthrosc Relat Surg Off Publ Arthrosc Assoc N Am Int Arthrosc Assoc. 1993;9(2):159\u0026ndash;63.\u003c/li\u003e\n \u003cli\u003eHerdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, et al. Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res Int J Qual Life Asp Treat Care Rehabil. 2011 Dec;20(10):1727\u0026ndash;36.\u003c/li\u003e\n \u003cli\u003eKroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med. 2001 Sep;16(9):606\u0026ndash;13.\u003c/li\u003e\n \u003cli\u003eSullivan MJL, Bishop SR, Pivik J. The Pain Catastrophizing Scale: Development and validation. Psychol Assess. 1995;7(4):524\u0026ndash;32.\u003c/li\u003e\n \u003cli\u003eJoshi A, Kale S, Chandel S, Pal DK. Likert Scale: Explored and Explained. Br J Appl Sci Technol. 2015 Jan 10;7(4):396\u0026ndash;403.\u003c/li\u003e\n \u003cli\u003eJulious SA. Sample Sizes for Clinical Trials. 2nd ed. New York: Chapman and Hall/CRC; 2023. 420 p.\u003c/li\u003e\n \u003cli\u003eTorous J, Lipschitz J, Ng M, Firth J. Dropout rates in clinical trials of smartphone apps for depressive symptoms: A systematic review and meta-analysis. J Affect Disord. 2020 Feb 15;263:413\u0026ndash;9.\u003c/li\u003e\n \u003cli\u003eGendreau RM, McCracken LM, Williams DA, Luciano JV, Dai Y, Vega N, et al. Self-guided digital behavioural therapy versus active control for fibromyalgia (PROSPER-FM): a phase 3, multicentre, randomised controlled trial. The Lancet. 2024 Jul 27;404(10450):364\u0026ndash;74.\u003c/li\u003e\n \u003cli\u003eWatson A, Chapman R, Shafai G, Maricich YA. FDA regulations and prescription digital therapeutics: Evolving with the technologies they regulate. Front Digit Health. 2023 Apr 17;5:1086219.\u003c/li\u003e\n \u003cli\u003eLutz J, Offidani E, Taraboanta L, Lakhan SE, Campellone TR. Appropriate controls for digital therapeutic clinical trials: A narrative review of control conditions in clinical trials of digital therapeutics (DTx) deploying psychosocial, cognitive, or behavioral content. Front Digit Health [Internet]. 2022 Aug 18 [cited 2024 Oct 28];4. Available from: https://www.frontiersin.org/journals/digital-health/articles/10.3389/fdgth.2022.823977/full\u003c/li\u003e\n \u003cli\u003eSchmidt L, Pawlitzki M, Renard BY, Meuth SG, Masanneck L. The three-year evolution of Germany\u0026rsquo;s Digital Therapeutics reimbursement program and its path forward. NPJ Digit Med. 2024 May 24;7(1):139.\u003c/li\u003e\n \u003cli\u003eMayer T, Koska D, Harsch AK, Maiwald C. Prospektive randomisierte kontrollierte klinische Studie zur Wirksamkeit eines Eigentrainings mit der Digitalen Gesundheitsanwendung \u0026bdquo;Mawendo\u0026ldquo; bei der Behandlung von Krankheiten der Patella (ICD-10-GM M22) [Internet]. 2024 Jul. Report No.: DRKS00023454. Available from: https://drks.de/search/en/trial/DRKS00023454\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1. Objectives and efficacy endpoints of the trial\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eObjectives\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 506px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEndpoints\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePrimary\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eTo compare usual pain level at 8 weeks between treatment and control group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 506px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eUsual pain intensity over the past 1 week at the 8-week (V4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 406px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSecondary\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eTo compare the following between treatment control group:\u003c/p\u003e\n \u003col\u003e\n \u003cli\u003eWorst pain level at 8-week\u003c/li\u003e\n \u003cli\u003eKnee function at 8-week\u003c/li\u003e\n \u003cli\u003eQuality of life at 8-week\u003c/li\u003e\n \u003cli\u003eHealth status at 8-week\u003c/li\u003e\n \u003cli\u003eDepression level at 8-week\u003c/li\u003e\n \u003cli\u003ePain catastrophizing level at 8-week\u003c/li\u003e\n \u003cli\u003eOverall perceived recovery level at 8-week\u003c/li\u003e\n \u003cli\u003eUsual pain at 12-week\u003c/li\u003e\n \u003cli\u003eWorst pain level at 12-week\u003c/li\u003e\n \u003cli\u003eKnee function at 12-week\u003c/li\u003e\n \u003cli\u003eQuality of life at 12-week\u003c/li\u003e\n \u003cli\u003eHealth status at 12-week\u003c/li\u003e\n \u003cli\u003eDepression level at 12-week\u003c/li\u003e\n \u003cli\u003ePain catastrophizing level at 12-week\u003c/li\u003e\n \u003cli\u003eOverall perceived recovery level at 12-week\u003c/li\u003e\n \u003cli\u003eUsual pain level at 4-week\u003c/li\u003e\n \u003cli\u003eWorst pain level at 4-week\u003c/li\u003e\n \u003cli\u003eKnee function at 4-week\u003c/li\u003e\n \u003cli\u003eChange in usual pain level at 8-week compared to baseline\u003c/li\u003e\n \u003cli\u003eChange in worst pain level at 8-week compared to baseline\u003c/li\u003e\n \u003cli\u003eChange in knee function at 8-week compared to baseline\u003c/li\u003e\n \u003cli\u003eChange in quality of life at 8-week compared to baseline\u003c/li\u003e\n \u003cli\u003eChange in health status at 8-week compared to baseline\u003c/li\u003e\n \u003cli\u003eChange in depression level at 8-week compared to baseline\u003c/li\u003e\n \u003cli\u003eChange in pain catastrophizing level at 8-week compared to baseline\u003c/li\u003e\n \u003cli\u003eChange in usual pain level at 12-week compared to baseline\u003c/li\u003e\n \u003cli\u003eChange in worst pain level at 12-week compared to baseline\u003c/li\u003e\n \u003cli\u003eChange in knee function at 12-week compared to baseline\u003c/li\u003e\n \u003cli\u003eChange in quality of life at 12-week compared to baseline\u003c/li\u003e\n \u003cli\u003eChange in health status at 12-week compared to baseline\u003c/li\u003e\n \u003cli\u003eChange in depression level at 12-week compared to baseline\u003c/li\u003e\n \u003cli\u003eChange in pain catastrophizing level at 12-week compared to baseline\u003c/li\u003e\n \u003cli\u003eChange in usual pain level at 4-week compared to baseline\u003c/li\u003e\n \u003cli\u003eChange in worst pain level at 4-week compared to baseline\u003c/li\u003e\n \u003cli\u003eChange in knee function at 4-week compared to baseline\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 506px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003col\u003e\n \u003cli\u003eWorst pain intensity over the past 1 week at 8-week (V4)\u003c/li\u003e\n \u003cli\u003eKujala questionnaire total score at 8-week (V4)\u003c/li\u003e\n \u003cli\u003eEQ-5D-5L questionnaire total score at 8-week (V4)\u003c/li\u003e\n \u003cli\u003eEQ-5D-5L questionnaire health status score at 8-week (V4)\u003c/li\u003e\n \u003cli\u003ePHQ-9 questionnaire total score at 8-week (V4)\u003c/li\u003e\n \u003cli\u003ePCS questionnaire total score at 8-week (V4)\u003c/li\u003e\n \u003cli\u003eOverall perceived recovery score at 8-week (V4)\u003c/li\u003e\n \u003cli\u003eUsual pain intensity over the past 1 week at 12-week (V5)\u003c/li\u003e\n \u003cli\u003eWorst pain intensity over the past 1 week at 12-week (V5)\u003c/li\u003e\n \u003cli\u003eKujala questionnaire total score at 12-week (V5)\u003c/li\u003e\n \u003cli\u003eEQ-5D-5L questionnaire total score at 12-week (V5)\u003c/li\u003e\n \u003cli\u003eEQ-5D-5L questionnaire health status score at 12-week (V5)\u003c/li\u003e\n \u003cli\u003ePHQ-9 questionnaire total score at 12-week (V5)\u003c/li\u003e\n \u003cli\u003ePCS questionnaire total score at 12-week (V5)\u003c/li\u003e\n \u003cli\u003eOverall perceived recovery score at 12-week (V5)\u003c/li\u003e\n \u003cli\u003eUsual pain intensity over the past 1 week at 4-week (V2)\u003c/li\u003e\n \u003cli\u003eWorst pain intensity over the past 1 week at 4-week (V2)\u003c/li\u003e\n \u003cli\u003eKujala questionnaire total score at 4-week (V2)\u003c/li\u003e\n \u003cli\u003e[Usual pain intensity over the past 1 week at the 8-week (V4)] \u0026ndash; [Usual pain intensity over the past 1 week at the baseline (V2)]\u003c/li\u003e\n \u003cli\u003e[Worst pain intensity over the past 1 week at the 8-week (V4)] \u0026ndash; [Worst pain intensity over the past 1 week at the baseline (V2)]\u003c/li\u003e\n \u003cli\u003e[Kujala questionnaire total score at the 8-week (V4)] \u0026ndash; [Kujala questionnaire total score at the baseline (V2)]\u003c/li\u003e\n \u003cli\u003e[EQ-5D-5L questionnaire total score at the 8-week (V4)] \u0026ndash; [EQ-5D-5L questionnaire total score at the baseline (V2)]\u003c/li\u003e\n \u003cli\u003e[EQ-5D-5L questionnaire health status score at the 8-week (V4)] \u0026ndash; [EQ-5D-5L questionnaire health status score at the baseline (V2)]\u003c/li\u003e\n \u003cli\u003e[PHQ-9 questionnaire total score at the 8-week (V4)] \u0026ndash; [PHQ-9 questionnaire total score at the baseline (V2)]\u003c/li\u003e\n \u003cli\u003e[PCS questionnaire total score at the 8-week (V4)] \u0026ndash; [PCS questionnaire total score at the baseline (V2)]\u003c/li\u003e\n \u003cli\u003e[Usual pain intensity over the past 1 week at the 12-week (V5)] \u0026ndash; [Usual pain intensity over the past 1 week at the baseline (V2)]\u003c/li\u003e\n \u003cli\u003e[Worst pain intensity over the past 1 week at the 12-week (V5)] \u0026ndash; [Worst pain intensity over the past 1 week at the baseline (V2)]\u003c/li\u003e\n \u003cli\u003e[Kujala questionnaire total score at the 12-week (V5)] \u0026ndash; [Kujala questionnaire total score at the baseline (V2)]\u003c/li\u003e\n \u003cli\u003e[EQ-5D-5L questionnaire total score at the 12-week (V5)] \u0026ndash; [EQ-5D-5L questionnaire total score at the baseline (V2)]\u003c/li\u003e\n \u003cli\u003e[EQ-5D-5L questionnaire health status score at the 12-week (V5)] \u0026ndash; [EQ-5D-5L questionnaire health status score at the baseline (V2)]\u003c/li\u003e\n \u003cli\u003e[PHQ-9 questionnaire total score at the 12-week (V5)] \u0026ndash; [PHQ-9 questionnaire total score at the baseline (V2)]\u003c/li\u003e\n \u003cli\u003e[PCS questionnaire total score at the 12-week (V5)] \u0026ndash; [PCS questionnaire total score at the baseline (V2)]\u003c/li\u003e\n \u003cli\u003e[Usual pain intensity over the past 1 week at the 4-week (V3)] \u0026ndash; [Usual pain intensity over the past 1 week at the baseline (V2)]\u003c/li\u003e\n \u003cli\u003e[Worst pain intensity over the past 1 week at the 4-week (V3)] \u0026ndash; [Worst pain intensity over the past 1 week at the baseline (V2)]\u003c/li\u003e\n \u003cli\u003e[Kujala questionnaire total score at the 4-week (V3)] \u0026ndash; [Kujala questionnaire total score at the baseline (V2)]\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. Assessment schedule by visit\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"916\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 226px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSchedule\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eScreening\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(V1)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBaseline\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(V2)\u003csup\u003e1\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIn-treatment\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(V3)\u003csup\u003e2,3\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePost-treatment (V4)\u003csup\u003e4\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFollow-up\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(V5)\u003csup\u003e5\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e-4 weeks ~ 0-week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e0-week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e3-week ~ 5-week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e8-week ~ 9 week\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e12-week~13week\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003eInformed consent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003eScreening number assignment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003eDemographics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003eMedical history\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003eHeight and weight measurement\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003ePhysical examination\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003eX\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003eConcomitant/previous medication history\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003eX\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003eKnee X-ray Imaging and K-L grading\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003eX\u003csup\u003e6\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003eInclusion/exclusion criteria review\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003eSelection of target knee (L/R)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003eRandomization and assignment of registration number\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003ePain intensity assessment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003eKujala questionnaire\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003eEQ-5D-5L questionnaire\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003ePHQ-9 questionnaire\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003ePCS questionnaire\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003eOverall perceived recovery score assessment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003eDisease education\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003eInvestigational device prescription and app installation (treatment group only)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003eEducation on self-exercise (control group only)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003eSelf-exercise patient diary distribution (control group only)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003eSelf-exercise patient diary return (control group only)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003eX\u003csup\u003e7\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003eX\u003csup\u003e7\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003eAdverse event review\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003eX\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003eInvestigational device app deletion (treatment gropu only)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 138px;\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\" style=\"width: 916px;\"\u003e\n \u003col\u003e\n \u003cli\u003eV2 must be conducted within 4 weeks of V1, and V1 and V2 can take place on the same day.\u003c/li\u003e\n \u003cli\u003eV3 is conducted 4 weeks after V2, with a permissible variation of one week before or after (3 to 5 weeks).\u003c/li\u003e\n \u003cli\u003eFor V3, a visit to the medical institution may not be required. In this case, previous and concomitant medication reviews, as well as adverse event reviews, may be omitted. Pain intensity and Kujala assessments can be remotely collected by sending a link through a phone call.\u003c/li\u003e\n \u003cli\u003eV4 is conducted 8 weeks after V2, with a permissible delay of one week (8 to 9 weeks).\u003c/li\u003e\n \u003cli\u003eV5 is conducted 12 weeks after V2, with a permissible delay of one week (12 to 13 weeks).\u003c/li\u003e\n \u003cli\u003eIf an X-ray taken within 3 months is available for K-L grade evaluation, this may be omitted.\u003c/li\u003e\n \u003cli\u003eFor V3 and V4, the self-exercise log should be reviewed, and completed logs should be collected.\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Figures 1 and 2","content":"\u003cp\u003eFigures 1 and 2 are not available with this version.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Digital therapeutics (DTx), Patellofemoral pain (PFP), Rehabilitative exercise, Cognitive behavioural therapy (CBT), Software as a medical device (SaMD)","lastPublishedDoi":"10.21203/rs.3.rs-5465840/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5465840/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003ePatellofemoral pain is a prevalent knee condition affecting up to 40% of individuals, especially females aged teens to 50s. Standard treatments, including exercise therapy, often yield insufficient long-term results, partly due to low compliance and psychological factors like depression and catastrophizing of pain. A digital therapeutics ‘\u003cstrong\u003eMORA Cure PFP’\u003c/strong\u003ewhich combine structured progressive exercise and cognitive behavioral therapy via an app, offers a solution to overcome the limitations of conventional treatment for patellofemoral pain patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eTo evaluate the safety and efficacy of \u003cstrong\u003eMORA Cure PFP\u003c/strong\u003e, a two-arm controlled trial will enroll 216 patients diagnosed with patellofemoral pain randomly assigned in a 1:1 ratio to treatment and control groups. The treatment group will use the app, while the control group will perform self-guided exercises using educational materials. This trial aims to determine if the treatment group shows greater reduction in usual pain intensity scores at 8 weeks compared to the control group. Additional assessments include worst pain, knee function, depression, and pain catastrophizing levels.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiscussion: \u003c/strong\u003eKey design elements of the clinical trial, such as control group selection, inclusion/exclusion criteria, number of patients, and primary endpoint, were designed with consideration for not only medical perspectives but also regulatory aspects of software as a medical device, including device approval and health technology assessment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration: \u003c/strong\u003eClinicalTrials.gov., NCT06260865, registered 15th February 2024 (https://clinicaltrials.gov/study/NCT06260865)\u003c/p\u003e","manuscriptTitle":"Study protocol for a prospective, randomized controlled confirmatory clinical investigation to evaluate the safety and efficacy of a multidisciplinary digital therapeutics in patients with patellofemoral pain syndrome","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-03-24 04:00:33","doi":"10.21203/rs.3.rs-5465840/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2025-05-12T15:24:57+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-05-09T16:26:43+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-02-24T06:04:33+00:00","index":"","fulltext":""},{"type":"submitted","content":"Trials","date":"2025-02-21T11:06:47+00:00","index":"","fulltext":""},{"type":"decision","content":"Minor revision","date":"2025-02-17T06:32:35+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b58dc423-8371-4b1d-bc32-37a494015e50","owner":[],"postedDate":"March 24th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-09-08T16:02:51+00:00","versionOfRecord":{"articleIdentity":"rs-5465840","link":"https://doi.org/10.1186/s13063-025-09030-2","journal":{"identity":"trials","isVorOnly":false,"title":"Trials"},"publishedOn":"2025-09-01 15:57:48","publishedOnDateReadable":"September 1st, 2025"},"versionCreatedAt":"2025-03-24 04:00:33","video":"","vorDoi":"10.1186/s13063-025-09030-2","vorDoiUrl":"https://doi.org/10.1186/s13063-025-09030-2","workflowStages":[]},"version":"v1","identity":"rs-5465840","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5465840","identity":"rs-5465840","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}