Effectiveness and safety of the hyaluronic acid INNORYOS 2.2% in patients with early to advanced knee osteoarthritis. A prospective non-interventional randomized clinical trial.

Effectiveness and safety of the hyaluronic acid INNORYOS 2.2% in patients with early to advanced knee osteoarthritis. A prospective non-interventional randomized clinical trial. | 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 Effectiveness and safety of the hyaluronic acid INNORYOS 2.2% in patients with early to advanced knee osteoarthritis. A prospective non-interventional randomized clinical trial. Lola Hofweber, Simon von Stengel, Jörg Nürnberger, Wolfgang Kemmler This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4363034/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Introduction : We determined the effectiveness and safety of INNORYOS 2.2% hyaluronic acid (HA) containing 15mg of niacinamide on knee pain, stiffness and function in people with knee OA compared with an established agent. Further study objectives were to monitor side effects during the study period. Methods : The 26-week prospective non-interventional open clinical trial tested on non-inferiority of INNORYOS 2.2% compared to an established HA product (Synvisc 0.8%, 2.0 ml). Briefly, 90 people with knee OA (Kellgren-Lawrence grade I to III), 40–85 years old, were allocated randomly to the two groups. HA injections were carried out at baseline and after 1 and 2 weeks. ANCOVA that adjusted for baseline differences was applied to determine between group differences (i.e. “effects”) after 26 weeks. Results : None of the 90 participants (65.0 ± 10.5 years, BMI: 30.2 ± 5.5 kg/m 2 ) quit the study or was lost to follow-up. In summary WOMAC pain score (p = .26) and function score (p = .49) did not differ significantly between the groups, but data significant better effect after INNORYOS 2.2% were observed for WOMAC stiffness subscale (p = .009). In detail, changes from baseline to 26-week FU average 43.6% (29.1%) for “pain”, 25.9% (0%) for “stiffness” and 37% (27.6%) for “function” subscale in the INNORYOS (Synvisc) group. No adverse effects were observed or reported by the participants. As determined by personal interviews and recorded in the questionnaires no changes of co-medication with impact on the study outcomes were observed. Conclusion : We did not determine significantly lower effects compared with the established product. In contrast, INNORYOS 2.2% tendentially revealed more favourable effect on all WOMAC categories (significant for “stiffness”). Thus, the present study provided further evidence for the effectiveness and safety of INNORYOS 2.2% in patients with early to advanced knee osteoarthritis. Orthopedics knee osteoarthritis hyaluronic acid INNORYOS 2.2% niacinamide Figures Figure 1 Figure 2 1. Introduction Osteoarthritis (OA) is a chronic, degenerative, and progressive disease of the joint ( 1 ). Its prevalence has increased due to aging populations, rising rates of obesity and increased incidence of injuries. In 2019 an increase of 113% of affected people since 1990 was determined ( 2 ). The knee is the most commonly affected joint, with a prevalence of 365 million cases ( 3 ). As 73% of individuals with osteoarthritis are over 55 years old ( 2 ), and the risk of operative complications increases with age ( 4 ), the development of effective conservative treatments remains crucial. Additionally, the Osteoarthritis Research Society International (OARSI) recommends a conservative approach over surgical management ( 5 ). Several studies have demonstrated the efficacy and safety of hyaluronic acid (HA) preparations for intra-articular injection ( 6 – 11 ). To potentially enhance their efficacy in alleviating pain, joint stiffness, and improving mobility, HApreparations can be combined with other inflammation-modulating agents. Niacinamide, an amide of nicotinic acid, possesses anti-inflammatory properties and may positively influence degenerative processes in arthritic joints ( 12 ). As the efficacy of oral niacinamide intake has already been investigated and shown to have promising properties in pain relief and side effects ( 12 – 14 ), this study aimed to test the efficacy and safety of intraarticular injection of HAin combination with niacinamide for the knee. The investigational product, INNORYOS 2.2%, containing 15 mg of niacinamide, was compared with the standard preparation Synvisc in terms of pain relief, improvement of joint stiffness, and mobility. Primary hypothesis: The average effect of INNORYOS 2.2% on Western Ontario and McMaster Universities Osteoarthritis Index (total WOMAC score) is not inferior to the control group provided with the standard agent (Synvisc 0.8%, 2.0 ml). Secondary hypothesis: (a) Average positive change of at least 50% in WOMAC “pain” ( 6 ), “stiffness” and “function” subscales after INNORYOS 2.2% injection from baseline to final follow-up assessment (26 weeks). (b) Positive treatment effects 1 on total WOMAC Score from baseline to final follow-up assessment (26 weeks) after INNORYOS 2.2% treatment in at least 75% of the participants (c) Positive treatment effects 1 on WOMAC “pain” subscale two weeks after the first (baseline) INNORYOS 2.2% injection Further study aims were monitoring of co-medication and adverse effects during the study period. 2. Methods The present study is a prospective non-interventional open clinical trial with two study arms conducted in a parallel group design. Briefly, the study aimed to determine the effectiveness and safety of INNORYOS 2.2% (ALBOMED, Germany) on knee osteoarthritis in adults 40–85 years old. The study was initiated, planned and conducted by ALBOMED GmbH (Schwarzenbruck, Germany) in close cooperation with the Orthopedics and Trauma Surgery Öttingen (Germany) and the Institute of Radiology, University Hospital Erlangen, Germany. The present study started in November 2021 and was conducted over 26 weeks. The ethics committee of the Bayerische Landesärztekammer approved the trial that fully complies with the Helsinki Declaration “Ethical Principles for Medical Research Involving Human Subjects” ( 15 ). After receiving detailed information, all study participants gave their written informed consent. 2.1 Participants Potential study participants were selected by the Orthopedics and Trauma Surgery Öttingen (Germany) applying the following eligibility criteria: 2.1.1 Inclusion criteria: Patients who fulfill the clinical criteria of the American College of Rheumatology for joint osteoarthritis and are considered suitable for viscosupplementation by the examiner (Jürgen Nürnberger) Primary joint osteoarthritis Age between 40 and 85 years Kellgren-Lawrence grade (KL) I to III on standing anteroposterior view ( 16 ) 2.1.2 Exclusion criteria Trauma or surgery to the affected knee in the last 6 months Viscosupplement treatment on the affected knee within the last 6 months Injection with steroidal preparations on the affected knee within the last 3 months Strong inflammation of the affected joint Skin irritation or infection at the injection site Known hypersensitivity to hyaluronic acid or other product components Known autoimmune disease or other relevant abnormal physiological condition Congenital or drug-induced blood clotting disorders, for example due to hemophilia or the use of anticoagulants such as Marcumar (Phenprocoumon) or Coumadin (Warfarin) Pregnancy or breastfeeding According to the sample size calculation, in summary 90 persons were selected and included in this prospective non-interventional open clinical trial (Fig. 1 ) 2.2 Blinding The blinding strategy focused on outcome assessors and the statistician who were kept unaware of the participants’ group status (INNORYOS or control group (CG)) and were not allowed to ask, either. 2.3 Intervention The participants were randomly assigned to one of the two groups by drawing lots. Both the intervention group and the control group were provided with a HAagent injected in their osteoarthritic knee at baseline and after 1 and 2 weeks (visit 1, 2 and 3), respectively. While the intervention group was treated with INNORYOS 2.2%, the CGwas given the hyaluronic acid compound Synvisc. Follow-up visits were scheduled after 14 and 26 weeks (visit 4 and 5) (Table 1 ). Table 1 Brief Overview on INNORYOS 2.2% trial Week baseline 1 2 14 26 Visit number 1 2 3 4 5 Injection X X X --- --- Outcome assessments X X X X X Adverse effects --- X X X X Confounders X X X X X 2.3.1 INNORYOS The INNORYOS study arm was provided with INNORYOS 2.2%, 2.0 ml ("ALBOMED GmbH (Schwarzenbruck, Germany)). The product is certified by HTCert (Certificate No: 2385C03210501). The injectable, colorless, and resorbable hydrogel was used in a dosage form of 2 ml packed in 2.25 ml sterile syringe, containing 2.2% sodium hyaluronate, for direct joint injection (Table 2 ). 2 ml INNORYOS contains 15 mg of niacinamide. The selection of the injection technique was determined by the administering physician based on the specific anatomical considerations of the patient and their pain sensitivity. The main active ingredient, linear hyaluronic acid obtained from bacterial fermentation, is known to alleviate the typical symptoms of cartilage degradation, such as pain, stiffness and movement restrictions ( 10 , 17 – 19 ). The compound contains niacinamide, which has no drug-relevant function but serves to support the main function by inhibiting the degeneration of the hyaluronate chain molecules ( 14 ). Niacinamide is an important biomolecule that is involved in the redox reactions of metabolism. As a component of the coenzymes NAD + and NADP + , it has antioxidant and anti-inflammatory properties which lead to a reduction of free radicals in the joint and therefore decreases oxidative stress ( 12 ). Table 2 INNORYOS 2.2% datasheet Concentration 2.2% Hyaluronic acid + 1.5% Niacinamide Molecular weight 1.2–2.2 MDa Viscosity 370 000 Volume 2.0 ml Forms of therapy 1 to 5 injections Storage 2–25°C Shelf life 42 month 2.3.2 Control group The control group received an established osteoarthritis product (Synvisc 0.8%, 2.0 ml). The positive effects and safety of Synvisc 0.8%, 2.0 ml have been tested in several studies ( 20 – 26 ). The sodium hyaluronate contained (hylan G-F 20) is a high molecular weight, cross-linked derivate of hyaluronan (Table 3 ). Unlike the sodium hyaluronate used in the comparison product INNORYOS 2.2%, Hylan G-F 20 is not of bacterial but of animal origin (rooster comb) ( 25 ). The treatment procedure is equivalent to the test product above. Table 3 Composition of INNORYOS 2.2% and Synvisc INNORYOS 2.2% Synvisc Sodium hyaluronate 22.000 8.000 (hylan G-F 20) Niacinamide 15.000 - Sodium Chloride 6.000 8.500 Disodium hydrogen phosphate 2 H 2 O 0.563 0.160 Sodium dihydrogen phosphate 2 H 2 O 0.045 0.040 Injection water in 1 ml in 1 ml 2.4 Outcomes 2.4.1 Primary study outcome: Changes in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score from baseline (visit 1) to 26 week-follow-up (FU)(Visit 5) 2.4.2 Secondary study outcomes Changes inWOMAC category “pain” from baseline to 26 week-follow-up (FU) Changes inWOMAC category “stiffness” from baseline to 26 week-follow-up (FU) Changes inWOMAC category “function” from baseline to 26 week-follow-up (FU) Changes inWOMAC category “pain” from baseline to 2 week follow-up (Visit 3) Adverse effects during the study period 2.4.3 Explanatory outcomes Changes in co-medication during the study period 2.5 Assessments 2.5.1 Baseline assessment During the initial examination of the patients, anthropometric data were recorded and a clinical examination and radiological assessment of the osteoarthritis were also carried out. In addition, treatment/medication, physical activity and diet were asked about as part of the anamnesis. 2.5.2 Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) We applied the “Likert (scale)” version (WOMAK LK3 series) of the WOMAC Index that is a self-administered questionnaire predominately applied in the area of hip and knee osteoarthritis consisting of 24 items divided into 3 categories. Category A determines “pain” (5 items) during walking, using stairs, in bed, sitting or lying, and while standing upright. Category B focuses on “stiffness” after first awaking and later in the day. Category C determines physical function (17 items) while using stairs, rising from sitting, standing, bending, walking, getting in / out of a car, shopping, putting on / taking off socks, rising from bed, lying in bed, getting in / out of bath, sitting, getting on / off toilet, heavy domestic duties, light domestic duties. In the present project, we consistently focus on knee osteoarthritis. The surveys were conducted as personal interviews during the visits; outcome assessors read out the WOMAC questions to the participants and made the entries. 2.5.2 Adverse effects An adverse event was defined as any adverse medical event, unanticipated illness or injury, or any adverse clinical sign, including an abnormal laboratory finding, in subjects, users or other persons in a clinical trial, whether related to the investigational product or not. Severe adverse effects were defines as (a) death or (b) a serious deterioration in health resulting in (b1) life-threatening illness or injury, (b2) permanent impairment of a bodily structure or function, (b3) hospitalization or prolongation of the patient's hospital stay, (b4) need for medical or surgical intervention to prevent (b1) or (b2), (b5) chronic illness and finally (b6) fetal distress, fetal death or congenital physical or mental impairment or birth defect. 2.5.3 Co-medication Co-medication and in particular pain-modulating medication was recorded during each of the visits in order to determine changes in medication that might affect our study outcomes. 2.6 Sample size calculation Due to the focus of the directed primary hypothesis on “non-inferiority of effects”, the sample size was calculated using the one-tailed Student's t-test. An effect size of 0.57 ( 27 ), a statistical significance level of 0.05 and the discriminatory power of 0.8 were applied to calculate the sample size of this clinical trial. The calculation resulted in a sample size of 41 participants/group, however anticipating missing values and a loss of follow up of 10%, 90 participants were ultimately included and allocated to two equal groups of 45 participants each. 2.7 Statistical analysis We applied the Intention to treat (ITT) principle that included all participants randomly assigned to the study arms (INNORYOS 2.2%vs. CG) regardless of their loss to follow-up. Due to the very low number of missing values (n = 1), we simply applied the last observation carried forward method for imputation. Normal distribution was checked graphically (gg-plots, residual plots). We applied 1-tailed-tests, and Mann-Whitney test (when applicable); significance was accepted at p < 0.05. ANCOVA that adjusted for baseline differences was applied to determine between group differences (i.e. “effects”) after 26 weeks (primary outcome). Absolute treatment effects were transposed to percentage changes from baseline to 1, 2, 14 and 26-week FU (i.e. visit 2–5). Simple frequency accounts were applied to address secondary outcomes. Differences in distribution of categorical variables (Table 4 ) were analyzed by Pearson chi-square tests using two tailed tests. 3. Results Baseline characteristics of the two groups were displayed in Table 4 . In summary, significant differences were observed for Kellgren-Lawrence Grade, use of analgesics, NSAID, knee swelling and stiffness with consistently higher degrees of complaints and corresponding more pronounced use of pharmacologic therapy in the control group. Table 4 Baseline characteristics of the study groups (number; mean value± standard deviation, 2-tailed p-value) Variable INNORYOS 2.2% (n = 45) Control (n = 45) p Women/Men [n] 21 / 23 22 / 23 0.833 Age in total [years] 66.6 ± 11.00 63.5 ± 10.00 0.080 BMI in total [kg/m 2 ] 30.6 ± 5.1 29.7 ± 6.0 0.444 Physical activity [VAS 1–10] 05.96 ± 1.40 06.12 ± 1.48 0.595 Knee OA unilateral / bilateral [n] 26 / 19 28 / 17 0.667 Joint space narrowing [n] 45 45 ----- Osteophytes [n] 12 7 0.197 Cyst formation [n] 15 17 0.660 Subchondral sclerosis [n] 26 32 0.186 Kellgren Lawrence Grade [n] Grade 1 Grade 2 Grade 3 18 14 13 6 17 22 0.014 Analgetics [n] 22 36 0.002 Sysadoa [n] 0 0 ----- Physiotherapy [n] 0 0 ----- Injection steroidal agents [n] 1 1 1.00 Injection viscosupplements [n] 1 0 0.315 Knee inspection: pain [n] 45 44 0.915 Knee inspection: swelling [n] 22 42 0.001 Knee inspection: effusion [n] 10 16 0.163 Knee inspection: stiffness [n] 6 20 0.001 Pain when walking [VAS 1–10] 5.20 ± 2.19 5.06 ± 12.28 0.778 3.1 Lost to follow-up, compliance None of the 90 participants quit the study or were lost to follow-up. Consequently, all participants (n = 45 intervention group, n = 45 CG) were analyzed. In one case (CG), one item of the WOMAC stiffness category (…”later on the day”) was not completed by the participant and was imputed by the method described above (Fig. 1 ). 3.2 Primary study outcome Figure 2 displays mean value along with 95% confidence interval for percentage changes in total WOMAC score of the INNORYOS 2.2% and control groups. So far, independently of the date of the FU-assessment a significant inferiority (p > of INNORYOS 2.2% versus the control treatment with Synvisc 0.8%, 2.0 ml has not been observed (Fig. 2 ). (place Fig. 2 “Changes of the total WOMAC-score in the INNORYOS 2.2% and CG during the study” about here). Applying ANCOVA that focuses on changes from baseline to 26-week FU and adjusted for baseline differences, no significant inferiority of INNORYOS 2.2% versus the control treatment can be observed for total WOMAC score (p = .290). In detail, WOMAC pain (p = .26) and function (p = .49) scores did not differ significantly between the groups. However, significantly more favorable data after INNORYOS 2.2% were observed for WOMAC stiffness subcategory (p = .009). In summary, we thus confirmed the primary hypothesis that the average effect of INNORYOS 2.2%, 2.0 ml) on WOMAC total score Index is not inferior to the control group provided with the standard agent (Synvisc 0.8%, 2.0ml). 3.3 Secondary study outcome Hypothesis 2a : In summary, the hypotheses of average positive changes of at least 50% in WOMAC “pain”, “stiffness” and “function” subscale after INNORYOS 2.2% injection from baseline to final follow-up assessment have to be rejected for all WOMAC categories. In detail, changes from baseline to 26 week FU average 43.6% for WOMAC “pain”, 25.9% for WOMAC “stiffness” and 37% for WOMAC “function” score. Although not addressed by the hypotheses, average changes among the control group were consistently tendentially lower for all WOMAC categories (i.e. “pain”: 29.1%; “stiffness”: 0%, function 27.6%). Hypothesis 2b : With respect to the response rate at final FU (26 weeks), we observed positive treatment effects on total WOMAC score in 86.7% of the participants of the INNORYOS 2.2% group. Thus, hypothesis 2b can be confirmed. Hypothesis 2c : Response rate for the first two weeks (visit 3) after initial INNORYOS 2.2% injection averaged 77.8% and thus slightly exceeded the 75% threshold of positive response rate required by hypothesis 2c. 3.4 Adverse effects during the study period No adverse effects were observed or reported by the participants. 3.5 Confounding effects As determined by personal interviews and recorded in the questionnaires, no changes of co-medication with impact on the study outcomes addressed here were observed. 4. Discussion This investigation sought to establish the significant non-inferiority of the test compound INNORYOS 2.2% in contrast to the standard agent Synvisc for managing knee osteoarthritis in individuals aged 40 to 85 years. Synvisc 0.8%, 2.0 ml is one of the most commonly used hyaluronan preparations. It is a high-quality cross-linked HA product whose positive effects have been proven in several studies ( 20 – 26 ). A systematic review has shown that cross-linked HA has a significantly greater therapeutic effect (p = .003) compared to non-cross-linked HA ( 28 ). The cross links improve the physical properties of HA by increasing the molecular size, slowing down enzymatic degradation and increasing the retention time in the joint ( 29 ). However, INNORYOS 2.2% is a high molecular weight HA to which properties similar to those of cross-linked HA are attributed. We assume that INNORYOS 2.2% has the same performance as Synvisc 0.8%, 2.0 ml - unlike non-cross-linked low molecular weight HA ( 4 ). Thus we formulated the primary hypothesis of non-inferiority with respect to changes in total WOMAC score. The primary hypothesis could be accepted, as it was demonstrated that the average performance, provided with INNORYOS 2.2%, incorporating 1.5% niacinamide, was not inferior to the average performance within the comparison group treated with Synvisc 0.8%, 2.0 ml. With respect to the secondary hypothesis, INNORYOS 2.2% did not achieve the desired treatment outcome of a 50% improvement on the WOMAC “pain”, “stiffness” and “function” subscales at the final follow-up visit at week 26 compared to baseline. The 50% improvement benchmark was predicated on a meta-analysis indicating that "HA improves pain by approximately 40–50% compared with baseline levels" ( 6 ). It is worth mentioning that INNORYOS 2.2% tendentially outperformed the comparative product in all categories. However, statistical significance was only observed for the subscale “stiffness”. Beside the performance, the tolerability and safety of the test compound were examined through the monitoring of potential adverse events, none of which occurred. INNORYOS 2.2% consists of hyaluronic acid derived from bacterial fermentation. It therefore does not contain any animal material. Synvisc is a cross-linked HA derived from rooster comb. It is reported that patients using biological fermentation-derived HA had fewer cases of acute flare-ups at the injection site than those using avian-derived HA products ( 30 ). However, on the basis of our study data no comparative safety conclusions can be drawn, as no adverse events occurred in either group. In various contemporary meta-analyses, research emphasis is increasingly gravitating towards alternative conservative treatment modalities such as platelet-rich-plasma (PRP), bone marrow aspirate concentrate, and others ( 9 , 31 – 33 ). These studies indicate a growing superiority of these therapeutic agents, albeit confirming the efficacy of HA as well. Several meta-analyses have been published examining the efficacy of PRP compared to HA. In summary, the studies came to the conclusion that PRP is superior to HA in terms of the total WOMAC score over a study period of one year ( 34 – 36 ). When looking at a subgroup analysis with high molecular weight and cross-linked hyaluronic acid (HA), no statistically significant difference was found between the use of PRP and this type of HA ( 35 ). In contrast to low molecular weight, non-cross-linked HA, PRP does not appear to be superior compared to high molecular weight and cross-linked HA. INNORYOS 2.2% is a high molecular weight HA which contains 15 mg of niacinamide, an amide of nicotinic acid, which possesses anti-inflammatory properties and may positively influence degenerative processes in arthritic joints ( 12 ). Thus, INNORYOS 2.2% represents a potent and safe option which can be used in isolation or possibly in combination with other new procedures. Recent investigations suggest that a combination of platelet-rich plasma and HA can exert a particularly favorable influence on degenerative processes in the knee joint ( 37 , 38 ). Consequently, the significance of hyaluronic acid therapy is unlikely to wane in the future. Interestingly, a meta-analysis showed that the combination of PRP and HA injections was safer than isolated PRP injections when assessing the incidence of adverse events, which makes the combination an interesting treatment option ( 39 ). It will remain advantageous to formulate the most efficacious HA preparation to afford patients the optimal treatment, be it through monotherapy or combination therapy. While this study illustrates the non-inferiority of INNORYOS 2.2% compared to Synvisc, Porcello et al. evaluated several HA products, including those aforementioned, with respect to rheological, lubricative, adhesive, and stability attributes ( 40 ). The results showed that INNORYOS 2.2% “presented the best overall functional behaviour in the retained experimental settings (high adhesivity and lubricity and substantial resistance to oxidative degradation)” ( 40 ) thus surpassing the comparator product Synvisc. Both hyaluronic acid preparations are accessible as a triple application, the customary method in Germany. However, the single application appears to be no less effective than this regimen ( 41 ). As the efficacy of hyaluronic acid injections for osteoarthritis in various joints, such as the hip ( 42 – 46 ) or shoulder ( 47 , 48 ) is currently under investigation with promising outcomes, it can be inferred that INNORYOS 2.2% has an effect on other joints. It must be mentioned as a strength that in fact all participants completed the treatment. A key factor in this was certainly the free provision of treatment to a collective with high levels of suffering. In addition, the rapid onset of a positive effect after the first injection motivated many participants to complete the treatment. Some limitations of our trial should be noted. Of importance, baseline values for Kellgren-Lawrence score differ significant between the groups with higher levels of advanced KL-grade in the CG. However, the prevalence of the single different radiological OA characteristics recorded in the questionnaire (joint space narrowing, osteophytes, cyst formation, subchondral sclerosis) did not differ significantly between the groups. There is some evidence that a higher degree of irreversible changes observed at higher KL-levels might conflict with the treatment effects in the control group ( 49 , 50 ). In parallel, significant differences on baseline use of analgesics (Table 4 ) with significantly higher use in the CG might confound our finding. However, considering that no within or between group changes of medication intake were recorded during the study period, we feel that the impact of differences remains negligible. 5. Conclusion This study showed that INNORYOS 2.2%, a hyaluronic acid preparation containing niacinamide, is significantly non-inferior to the standard preparation Synvisc in the treatment of knee osteoarthritis. While both products exhibited positive effects on pain, mobility, and joint stiffness, the efficacy across all domains was tendentially higher in the group receiving INNORYOS 2.2%, with significant results for “stiffness”. To more precisely address the anti-inflammatory effects presumably induced by niacinamide in the knee, future investigations should record dedicated inflammatory markers. Additionally, a larger cohort and statistical tests for the significant superiority of INNORYOS 2.2% over other hyaluronic acid preparations are warranted. Declarations Funding This work was supported by the ALBOMED, Germany. Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Kemmler reports financial support, article publishing charges, and equipment, drugs, or supplies were provided by ALBOMED, Germany. Wolfgang Kemmler reports a relationship with ALBOMED, Germany that includes: funding grants and non-financial support. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. CRediT authorship contribution statement Lola Hofweber : Data curation, Methodology, Writing - original draft, Writing - review & editing. Simon von Stengel : Data curation, Resources, Supervision, Visualization, Writing-original draft, Writing-Reviewing & Editing. Jörg Nürnberger: Conceptualization, Funding acquisition, Project administration, Data curation, Supervision, Investigation, Writing - review & editing. Wolfgang Kemmler: Funding acquisition, Project administration, Formal analysis, Methodology, Writing - original draft, Writing- Reviewing and Editing. References Clynes MA, Jameson KA, Edwards MH, Cooper C, Dennison EM (2019) Impact of osteoarthritis on activities of daily living: does joint site matter? Aging Clin Exp Res 31(8):1049–1056. https://doi.org/10.1007/s40520-019-01163-0 Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet (2020) ;396(10258):1204-22. https://doi.org/10.1016/s0140-6736(20)30925-9 Long H, Liu Q, Yin H, Wang K, Diao N, Zhang Y et al (2022) Prevalence Trends of Site-Specific Osteoarthritis From 1990 to 2019: Findings From the Global Burden of Disease Study 2019. Arthritis Rheumatol 74(7):1172–1183. https://doi.org/10.1002/art.42089 Lin HS, Watts JN, Peel NM, Hubbard RE (2016) Frailty and post-operative outcomes in older surgical patients: a systematic review. BMC Geriatr 16(1):157. https://doi.org/10.1186/s12877-016-0329-8 Zhang W, Moskowitz RW, Nuki G, Abramson S, Altman RD, Arden N et al (2008) OARSI recommendations for the management of hip and knee osteoarthritis, Part II: OARSI evidence-based, expert consensus guidelines. Osteoarthritis Cartilage 16(2):137–162. https://doi.org/10.1016/j.joca.2007.12.013 Colen S, van den Bekerom MP, Mulier M, Haverkamp D (2012) Hyaluronic acid in the treatment of knee osteoarthritis: a systematic review and meta-analysis with emphasis on the efficacy of different products. BioDrugs 26(4):257–268. https://doi.org/10.2165/11632580-000000000-00000 He WW, Kuang MJ, Zhao J, Sun L, Lu B, Wang Y et al (2017) Efficacy and safety of intraarticular hyaluronic acid and corticosteroid for knee osteoarthritis: A meta-analysis. Int J Surg 39:95–103. https://doi.org/10.1016/j.ijsu.2017.01.087 Petrella RJ, Petrella M (2006) A prospective, randomized, double-blind, placebo controlled study to evaluate the efficacy of intraarticular hyaluronic acid for osteoarthritis of the knee. J Rheumatol 33(5):951–956 Singh H, Knapik DM, Polce EM, Eikani CK, Bjornstad AH, Gursoy S et al (2022) Relative Efficacy of Intra-articular Injections in the Treatment of Knee Osteoarthritis: A Systematic Review and Network Meta-analysis. Am J Sports Med 50(11):3140–3148. https://doi.org/10.1177/03635465211029659 Wang CT, Lin J, Chang CJ, Lin YT, Hou SM (2004) Therapeutic effects of hyaluronic acid on osteoarthritis of the knee. A meta-analysis of randomized controlled trials. J Bone Joint Surg Am 86(3):538–545. https://doi.org/10.2106/00004623-200403000-00012 Webb D, Naidoo P (2018) Viscosupplementation for knee osteoarthritis: a focus on Hylan G-F 20. Orthop Res Rev 10:73–81. https://doi.org/10.2147/orr.S174649 Bains P, Kaur M, Kaur J, Sharma S, Nicotinamide (2018) Mechanism of action and indications in dermatology. Indian J Dermatol Venereol Leprol 84(2):234–237. https://doi.org/10.4103/ijdvl.IJDVL_286_17 Jonas WB, Rapoza CP, Blair WF (1996) The effect of niacinamide on osteoarthritis: a pilot study. Inflamm Res 45(7):330–334. https://doi.org/10.1007/bf02252945 McCarty MF, Russell AL (1999) Niacinamide therapy for osteoarthritis–does it inhibit nitric oxide synthase induction by interleukin 1 in chondrocytes? Med Hypotheses 53(4):350–360. https://doi.org/10.1054/mehy.1998.0792 World Medical A (2013) World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA 310(20):2191–2194. https://doi.org/10.1001/jama.2013.281053 Kellgren JH, Lawrence JS (1957) Radiological assessment of osteo-arthrosis. Ann Rheum Dis 16(4):494–502. https://doi.org/10.1136/ard.16.4.494 Miller LE, Block JE (2013) US-Approved Intra-Articular Hyaluronic Acid Injections are Safe and Effective in Patients with Knee Osteoarthritis: Systematic Review and Meta-Analysis of Randomized, Saline-Controlled Trials. Clin Med Insights Arthritis Musculoskelet Disord 6:57–63. https://doi.org/10.4137/cmamd.S12743 Richette P, Chevalier X, Ea HK, Eymard F, Henrotin Y, Ornetti P et al (2015) Hyaluronan for knee osteoarthritis: an updated meta-analysis of trials with low risk of bias. RMD Open 1(1):e000071. https://doi.org/10.1136/rmdopen-2015-000071 Bellamy N, Campbell J, Robinson V, Gee T, Bourne R, Wells G (2006) Viscosupplementation for the treatment of osteoarthritis of the knee. Cochrane Database Syst Rev 2006(2):Cd005321. https://doi.org/10.1002/14651858.CD005321.pub2 Tammachote N, Kanitnate S, Yakumpor T, Panichkul P, Intra-Articular (2016) Single-Shot Hylan G-F 20 Hyaluronic Acid Injection Compared with Corticosteroid in Knee Osteoarthritis: A Double-Blind, Randomized Controlled Trial. J Bone Joint Surg Am 98(11):885–892. https://doi.org/10.2106/JBJS.15.00544 Zhao H, Liu H, Liang X, Li Y, Wang J, Liu C, Hylan (2016) G-F 20 Versus Low Molecular Weight Hyaluronic Acids for Knee Osteoarthritis: A Meta-Analysis. BioDrugs 30(5):387–396. https://doi.org/10.1007/s40259-016-0186-1 Maheu E, Avouac B, Dreiser RL, Bardin T (2019) A single intra-articular injection of 2.0% non-chemically modified sodium hyaluronate vs 0.8% hylan G-F 20 in the treatment of symptomatic knee osteoarthritis: A 6-month, multicenter, randomized, controlled non-inferiority trial. PLoS ONE 14(12):e0226007. https://doi.org/10.1371/journal.pone.0226007 Cortet B, Lombion S, Naissant B, Vidovic E, Bruyere O (2021) Non-Inferiority of a Single Injection of Sodium Hyaluronate Plus Sorbitol to Hylan G-F20: A 6-Month Randomized Controlled Trial. Adv Ther 38(5):2271–2283. https://doi.org/10.1007/s12325-021-01648-3 Bettonville M, Leon M, Margaux J, Urbin-Choffray D, Theunissen E, Besse-Hammer T et al (2021) Safety and efficacy of a single intra-articular injection of a novel enhanced protein solution (JTA-004) compared to hylan G-F 20 in symptomatic knee osteoarthritis: a randomized, double-blind, controlled phase II/III study. BMC Musculoskelet Disord 22(1):888. https://doi.org/10.1186/s12891-021-04750-3 Ke Y, Jiang W, Xu Y, Chen Y, Zhang Q, Xue Q et al (2021) Efficacy and safety of a single intra-articular injection of 6 ml Hylan G-F 20 compared to placebo in Chinese patients with symptomatic knee osteoarthritis: C-SOUND study, a 26-week multicenter double-blind randomized placebo-controlled trial in China. BMC Musculoskelet Disord 22(1):428. https://doi.org/10.1186/s12891-021-04252-2 De Lucia O, Jerosch J, Yoon S, Sayre T, Ngai W, Filippou G (2021) One-year efficacy and safety of single or one to three weekly injections of hylan G-F 20 for knee osteoarthritis: a systematic literature review and meta-analysis. Clin Rheumatol 40(6):2133–2142. https://doi.org/10.1007/s10067-020-05477-7 Hummer CD, Angst F, Ngai W, Whittington C, Yoon SS, Duarte L et al (2020) High molecular weight Intraarticular hyaluronic acid for the treatment of knee osteoarthritis: a network meta-analysis. BMC Musculoskelet Disord 21(1):702. https://doi.org/10.1186/s12891-020-03729-w Jevsevar D, Donnelly P, Brown GA, Cummins DS (2015) Viscosupplementation for Osteoarthritis of the Knee: A Systematic Review of the Evidence. J Bone Joint Surg Am 97(24):2047–2060. https://doi.org/10.2106/jbjs.N.00743 Lindqvist U, Tolmachev V, Kairemo K, Aström G, Jonsson E, Lundqvist H (2002) Elimination of stabilised hyaluronan from the knee joint in healthy men. Clin Pharmacokinet 41(8):603–613. https://doi.org/10.2165/00003088-200241080-00004 Altman RD, Bedi A, Karlsson J, Sancheti P, Schemitsch E (2016) Product Differences in Intra-articular Hyaluronic Acids for Osteoarthritis of the Knee. Am J Sports Med 44(8):2158–2165. https://doi.org/10.1177/0363546515609599 Anil U, Markus DH, Hurley ET, Manjunath AK, Alaia MJ, Campbell KA et al (2021) The efficacy of intra-articular injections in the treatment of knee osteoarthritis: A network meta-analysis of randomized controlled trials. Knee 32:173–182. https://doi.org/10.1016/j.knee.2021.08.008 Belk JW, Lim JJ, Keeter C, McCulloch PC, Houck DA, McCarty EC et al (2023) Patients With Knee Osteoarthritis Who Receive Platelet-Rich Plasma or Bone Marrow Aspirate Concentrate Injections Have Better Outcomes Than Patients Who Receive Hyaluronic Acid: Systematic Review and Meta-analysis. Arthroscopy 39(7):1714–1734. https://doi.org/10.1016/j.arthro.2023.03.001 Kim JH, Park YB, Ha CW (2023) Are leukocyte-poor or multiple injections of platelet-rich plasma more effective than hyaluronic acid for knee osteoarthritis? A systematic review and meta-analysis of randomized controlled trials. Arch Orthop Trauma Surg 143(7):3879–3897. https://doi.org/10.1007/s00402-022-04637-5 Tan J, Chen H, Zhao L, Huang W (2021) Platelet-Rich Plasma Versus Hyaluronic Acid in the Treatment of Knee Osteoarthritis: A Meta-analysis of 26 Randomized Controlled Trials. Arthroscopy 37(1):309–325. https://doi.org/10.1016/j.arthro.2020.07.011 Tang JZ, Nie MJ, Zhao JZ, Zhang GC, Zhang Q, Wang B (2020) Platelet-rich plasma versus hyaluronic acid in the treatment of knee osteoarthritis: a meta-analysis. J Orthop Surg Res 15(1):403. https://doi.org/10.1186/s13018-020-01919-9 Belk JW, Kraeutler MJ, Houck DA, Goodrich JA, Dragoo JL, McCarty EC (2021) Platelet-Rich Plasma Versus Hyaluronic Acid for Knee Osteoarthritis: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Am J Sports Med 49(1):249–260. https://doi.org/10.1177/0363546520909397 Zhao J, Huang H, Liang G, Zeng LF, Yang W, Liu J (2020) Effects and safety of the combination of platelet-rich plasma (PRP) and hyaluronic acid (HA) in the treatment of knee osteoarthritis: a systematic review and meta-analysis. BMC Musculoskelet Disord 21(1):224. https://doi.org/10.1186/s12891-020-03262-w Karasavvidis T, Totlis T, Gilat R, Cole BJ (2021) Platelet-Rich Plasma Combined With Hyaluronic Acid Improves Pain and Function Compared With Hyaluronic Acid Alone in Knee Osteoarthritis: A Systematic Review and Meta-analysis. Arthroscopy 37(4):1277–87e1. https://doi.org/10.1016/j.arthro.2020.11.052 Zhang Q, Liu T, Gu Y, Gao Y, Ni J (2022) Efficacy and safety of platelet-rich plasma combined with hyaluronic acid versus platelet-rich plasma alone for knee osteoarthritis: a systematic review and meta-analysis. J Orthop Surg Res 17(1):499. https://doi.org/10.1186/s13018-022-03398-6 Porcello A, Hadjab F, Ajouaou M, Philippe V, Martin R, Abdel-Sayed P et al (2023) Ex Vivo Functional Benchmarking of Hyaluronan-Based Osteoarthritis Viscosupplement Products: Comprehensive Assessment of Rheological, Lubricative, Adhesive, and Stability Attributes. Gels 9(10). https://doi.org/10.3390/gels9100808 Suppan VKL, Tew MM, Wong BC, Chan HK, Chew YW, Tan CS et al (2020) One-year follow-up of efficacy and cost of repeated doses versus single larger dose of intra-articular hyaluronic acid for knee osteoarthritis. J Orthop Surg (Hong Kong) 28(1):2309499019895029. https://doi.org/10.1177/2309499019895029 Belk JW, Houck DA, Littlefield CP, Kraeutler MJ, Potyk AG, Mei-Dan O et al (2022) Platelet-Rich Plasma Versus Hyaluronic Acid for Hip Osteoarthritis Yields Similarly Beneficial Short-Term Clinical Outcomes: A Systematic Review and Meta-analysis of Level I and II Randomized Controlled Trials. Arthroscopy 38(6):2035–2046. https://doi.org/10.1016/j.arthro.2021.11.005 Brander V, Skrepnik N, Petrella RJ, Jiang GL, Accomando B, Vardanyan A (2019) Evaluating the use of intra-articular injections as a treatment for painful hip osteoarthritis: a randomized, double-blind, multicenter, parallel-group study comparing a single 6-mL injection of hylan G-F 20 with saline. Osteoarthritis Cartilage 27(1):59–70. https://doi.org/10.1016/j.joca.2018.08.018 Nouri F, Babaee M, Peydayesh P, Esmaily H, Raeissadat SA (2022) Comparison between the effects of ultrasound guided intra-articular injections of platelet-rich plasma (PRP), high molecular weight hyaluronic acid, and their combination in hip osteoarthritis: a randomized clinical trial. BMC Musculoskelet Disord 23(1):856. https://doi.org/10.1186/s12891-022-05787-8 Sambe HG, Yasir M, Man RK, Gogikar A, Nanda A, Janga LSN et al (2023) Comparing Intra-articular Platelet-Rich Plasma With Hyaluronic Acid for the Treatment of Hip Osteoarthritis: A Systematic Review and Meta-Analysis. Cureus 15(10):e47919. https://doi.org/10.7759/cureus.47919 Villanova-López MM, Núñez-Núñez M, Fernández-Prieto D, González-López C, García-Donaire J, Pérez-Pérez A et al (2020) Randomized, double-blind, controlled trial, phase III, to evaluate the use of platelet-rich plasma versus hyaluronic acid in hip coxarthrosis. Rev Esp Cir Ortop Traumatol (Engl Ed) 64(2):134–142. https://doi.org/10.1016/j.recot.2019.09.008 Familiari F, Ammendolia A, Rupp MC, Russo R, Pujia A, Montalcini T et al (2023) Efficacy of intra-articular injections of hyaluronic acid in patients with glenohumeral joint osteoarthritis: A systematic review and meta-analysis. J Orthop Res 41(11):2345–2358. https://doi.org/10.1002/jor.25648 Zhang B, Thayaparan A, Horner N, Bedi A, Alolabi B, Khan M (2019) Outcomes of hyaluronic acid injections for glenohumeral osteoarthritis: a systematic review and meta-analysis. J Shoulder Elb Surg 28(3):596–606. https://doi.org/10.1016/j.jse.2018.09.011 Toh EM, Prasad PS, Teanby D (2002) Correlating the efficacy of knee viscosupplementation with osteoarthritic changes on roentgenological examination. Knee 9(4):321–330. https://doi.org/10.1016/s0968-0160(02)00040-6 Altman RD, Farrokhyar F, Fierlinger A, Niazi F, Rosen J (2016) Analysis for Prognostic Factors from a Database for the Intra-Articular Hyaluronic Acid (Euflexxa) Treatment for Osteoarthritis of the Knee. Cartilage 7(3):229–237. https://doi.org/10.1177/1947603515620890 Footnotes R = relative treatment development, n = number of questions, x i = value given in question i on the respective control date, y i = value given in question i on the first treatment date before the injection Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 1 posted 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-4363034","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":298307864,"identity":"1a2bbf35-ccad-44d9-a313-6baa18a8b6a5","order_by":0,"name":"Lola Hofweber","email":"","orcid":"","institution":"Institute of Radiology, University Hospital Erlangen, Germany","correspondingAuthor":false,"prefix":"","firstName":"Lola","middleName":"","lastName":"Hofweber","suffix":""},{"id":298307865,"identity":"0dbd3ebe-08e2-4f99-b014-29d80999229b","order_by":1,"name":"Simon von Stengel","email":"","orcid":"https://orcid.org/0009-0007-6172-5848","institution":"Institute of Radiology, University Hospital Erlangen, Germany","correspondingAuthor":false,"prefix":"","firstName":"Simon","middleName":"","lastName":"von Stengel","suffix":""},{"id":298309556,"identity":"db0cb0ed-ac74-4b6a-953e-018b75a925bf","order_by":2,"name":"Jörg Nürnberger","email":"","orcid":"","institution":"Practice of Orhopedics and Trauma Surgery, Öttingen, Germany","correspondingAuthor":false,"prefix":"","firstName":"Jörg","middleName":"","lastName":"Nürnberger","suffix":""},{"id":298309557,"identity":"867dabc2-5a5d-4dec-b1f2-b76abb6783d0","order_by":3,"name":"Wolfgang Kemmler","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABCElEQVRIiWNgGAWjYFAC5oYPYJoHRBQwMPAzHwAy2PBpYWycgdBiwMAg2ZZAqhaDYwS0GBxvbGz8UnPHroHn8NFNNwxs8o2PMT+TYCizwa3lzMHGZpljz5IbeNvSbucYpFluO8ZmJsFwLg2nFrMbie2PJdgOJzPw85gBtRw2MLvfYCbB2HYYn5bGZol/IC3834Ba/hsYt7F/A2r5j1dL48e2w3YMvD1sQC0HDAzYeEC2HMCpxR7kF8a+wwlsPMdADks2kDjGU2yRcC4ZpxbJ9uaDjT++Hbbn50l+djunws6Av419440PZXY4tYAAMzBKEttQhBLwagBG5g+gAwmoGQWjYBSMgpEMAKxhWQKYmW3wAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0003-3515-0669","institution":"Institute of Medical Physics, Friedrich-Alexander-University of Erlangen, Nürnberg, Germany","correspondingAuthor":true,"prefix":"","firstName":"Wolfgang","middleName":"","lastName":"Kemmler","suffix":""}],"badges":[],"createdAt":"2024-05-03 09:04:49","currentVersionCode":1,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":true,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-4363034/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4363034/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":56025772,"identity":"95b41aae-8af3-43dc-a108-44b4d3a5106c","added_by":"auto","created_at":"2024-05-07 17:00:51","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":447040,"visible":true,"origin":"","legend":"\u003cp\u003eParticipants flow through the study.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4363034/v1/126d91f28e4b6ff31539b2bb.jpeg"},{"id":56025771,"identity":"5db2a4d3-4b98-4368-873b-b4c27b58151e","added_by":"auto","created_at":"2024-05-07 17:00:51","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":211637,"visible":true,"origin":"","legend":"\u003cp\u003eChanges of the total WOMAC-score in the INNORYOS 2.2% and control group during the study.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4363034/v1/8f396f5696a47f1c309070b4.png"},{"id":56025786,"identity":"a6bcee35-6c05-4444-ae86-a59c121b8bfd","added_by":"auto","created_at":"2024-05-07 17:00:56","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1034768,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4363034/v1/bfdbd19e-8790-4486-a129-35823947f5c5.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eEffectiveness and safety of the hyaluronic acid INNORYOS 2.2% in patients with early to advanced knee osteoarthritis. A prospective non-interventional randomized clinical trial.\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eOsteoarthritis (OA) is a chronic, degenerative, and progressive disease of the joint (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Its prevalence has increased due to aging populations, rising rates of obesity and increased incidence of injuries. In 2019 an increase of 113% of affected people since 1990 was determined (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). The knee is the most commonly affected joint, with a prevalence of 365\u0026nbsp;million cases (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). As 73% of individuals with osteoarthritis are over 55 years old (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e), and the risk of operative complications increases with age (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e), the development of effective conservative treatments remains crucial. Additionally, the Osteoarthritis Research Society International (OARSI) recommends a conservative approach over surgical management (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eSeveral studies have demonstrated the efficacy and safety of hyaluronic acid (HA) preparations for intra-articular injection (\u003cspan additionalcitationids=\"CR7 CR8 CR9 CR10\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). To potentially enhance their efficacy in alleviating pain, joint stiffness, and improving mobility, HApreparations can be combined with other inflammation-modulating agents. Niacinamide, an amide of nicotinic acid, possesses anti-inflammatory properties and may positively influence degenerative processes in arthritic joints (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). As the efficacy of oral niacinamide intake has already been investigated and shown to have promising properties in pain relief and side effects (\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e), this study aimed to test the efficacy and safety of intraarticular injection of HAin combination with niacinamide for the knee. The investigational product, INNORYOS 2.2%, containing 15 mg of niacinamide, was compared with the standard preparation Synvisc in terms of pain relief, improvement of joint stiffness, and mobility.\u003c/p\u003e \u003cp\u003ePrimary hypothesis: The average effect of INNORYOS 2.2% on Western Ontario and McMaster Universities Osteoarthritis Index (total WOMAC score) is not inferior to the control group provided with the standard agent (Synvisc 0.8%, 2.0 ml).\u003c/p\u003e \u003cp\u003eSecondary hypothesis: (a) Average positive change of at least 50% in WOMAC \u0026ldquo;pain\u0026rdquo; (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e), \u0026ldquo;stiffness\u0026rdquo; and \u0026ldquo;function\u0026rdquo; subscales after INNORYOS 2.2% injection from baseline to final follow-up assessment (26 weeks). (b) Positive treatment effects\u003ca class=\"FNLink\" href=\"#Fn1\" id=\"#FNLinkFn1\"\u003e1\u003c/a\u003e on total WOMAC Score from baseline to final follow-up assessment (26 weeks) after INNORYOS 2.2% treatment in at least 75% of the participants (c) Positive treatment effects\u003csup\u003e1\u003c/sup\u003e on WOMAC \u0026ldquo;pain\u0026rdquo; subscale two weeks after the first (baseline) INNORYOS 2.2% injection\u003c/p\u003e \u003cp\u003eFurther study aims were monitoring of co-medication and adverse effects during the study period.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cp\u003eThe present study is a prospective non-interventional open clinical trial with two study arms conducted in a parallel group design. Briefly, the study aimed to determine the effectiveness and safety of INNORYOS 2.2% (ALBOMED, Germany) on knee osteoarthritis in adults 40\u0026ndash;85 years old. The study was initiated, planned and conducted by ALBOMED GmbH (Schwarzenbruck, Germany) in close cooperation with the Orthopedics and Trauma Surgery \u0026Ouml;ttingen (Germany) and the Institute of Radiology, University Hospital Erlangen, Germany. The present study started in November 2021 and was conducted over 26 weeks. The ethics committee of the Bayerische Landes\u0026auml;rztekammer approved the trial that fully complies with the Helsinki Declaration \u0026ldquo;Ethical Principles for Medical Research Involving Human Subjects\u0026rdquo; (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). After receiving detailed information, all study participants gave their written informed consent.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Participants\u003c/h2\u003e \u003cp\u003ePotential study participants were selected by the Orthopedics and Trauma Surgery \u0026Ouml;ttingen (Germany) applying the following eligibility criteria:\u003c/p\u003e \u003cdiv id=\"Sec4\" class=\"Section3\"\u003e \u003ch2\u003e2.1.1 Inclusion criteria:\u003c/h2\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003ePatients who fulfill the clinical criteria of the American College of Rheumatology for joint osteoarthritis and are considered suitable for viscosupplementation by the examiner (J\u0026uuml;rgen N\u0026uuml;rnberger)\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003ePrimary joint osteoarthritis\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eAge between 40 and 85 years\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eKellgren-Lawrence grade (KL) I to III on standing anteroposterior view (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e)\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section3\"\u003e \u003ch2\u003e2.1.2 Exclusion criteria\u003c/h2\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eTrauma or surgery to the affected knee in the last 6 months\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eViscosupplement treatment on the affected knee within the last 6 months\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eInjection with steroidal preparations on the affected knee within the last 3 months\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eStrong inflammation of the affected joint\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eSkin irritation or infection at the injection site\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eKnown hypersensitivity to hyaluronic acid or other product components\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eKnown autoimmune disease or other relevant abnormal physiological condition\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eCongenital or drug-induced blood clotting disorders, for example due to hemophilia or the use of anticoagulants such as Marcumar (Phenprocoumon) or Coumadin (Warfarin)\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003ePregnancy or breastfeeding\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eAccording to the sample size calculation, in summary 90 persons were selected and included in this prospective non-interventional open clinical trial (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Blinding\u003c/h2\u003e \u003cp\u003eThe blinding strategy focused on outcome assessors and the statistician who were kept unaware of the participants\u0026rsquo; group status (INNORYOS or control group (CG)) and were not allowed to ask, either.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Intervention\u003c/h2\u003e \u003cp\u003eThe participants were randomly assigned to one of the two groups by drawing lots. Both the intervention group and the control group were provided with a HAagent injected in their osteoarthritic knee at baseline and after 1 and 2 weeks (visit 1, 2 and 3), respectively. While the intervention group was treated with INNORYOS 2.2%, the CGwas given the hyaluronic acid compound Synvisc. Follow-up visits were scheduled after 14 and 26 weeks (visit 4 and 5) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBrief Overview on INNORYOS 2.2% trial\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeek\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ebaseline\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVisit number\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInjection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOutcome assessments\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdverse effects\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e---\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConfounders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section3\"\u003e \u003ch2\u003e2.3.1 INNORYOS\u003c/h2\u003e \u003cp\u003eThe INNORYOS study arm was provided with INNORYOS 2.2%, 2.0 ml (\"ALBOMED GmbH (Schwarzenbruck, Germany)). The product is certified by HTCert (Certificate No: 2385C03210501). The injectable, colorless, and resorbable hydrogel was used in a dosage form of 2 ml packed in 2.25 ml sterile syringe, containing 2.2% sodium hyaluronate, for direct joint injection (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). 2 ml INNORYOS contains 15 mg of niacinamide. The selection of the injection technique was determined by the administering physician based on the specific anatomical considerations of the patient and their pain sensitivity.\u003c/p\u003e \u003cp\u003eThe main active ingredient, linear hyaluronic acid obtained from bacterial fermentation, is known to alleviate the typical symptoms of cartilage degradation, such as pain, stiffness and movement restrictions (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). The compound contains niacinamide, which has no drug-relevant function but serves to support the main function by inhibiting the degeneration of the hyaluronate chain molecules (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eNiacinamide is an important biomolecule that is involved in the redox reactions of metabolism. As a component of the coenzymes NAD\u003csup\u003e+\u003c/sup\u003e and NADP\u003csup\u003e+\u003c/sup\u003e, it has antioxidant and anti-inflammatory properties which lead to a reduction of free radicals in the joint and therefore decreases oxidative stress (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eINNORYOS 2.2% datasheet\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConcentration\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e2.2% Hyaluronic acid\u0026thinsp;+\u0026thinsp;1.5% Niacinamide\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eMolecular weight\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.2\u0026ndash;2.2 MDa\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eViscosity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e370 000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eVolume\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.0 ml\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eForms of therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 to 5 injections\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eStorage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u0026ndash;25\u0026deg;C\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eShelf life\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e42 month\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section3\"\u003e \u003ch2\u003e2.3.2 Control group\u003c/h2\u003e \u003cp\u003eThe control group received an established osteoarthritis product (Synvisc 0.8%, 2.0 ml). The positive effects and safety of Synvisc 0.8%, 2.0 ml have been tested in several studies (\u003cspan additionalcitationids=\"CR21 CR22 CR23 CR24 CR25\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe sodium hyaluronate contained (hylan G-F 20) is a high molecular weight, cross-linked derivate of hyaluronan (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Unlike the sodium hyaluronate used in the comparison product INNORYOS 2.2%, Hylan G-F 20 is not of bacterial but of animal origin (rooster comb) (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe treatment procedure is equivalent to the test product above.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComposition of INNORYOS 2.2% and Synvisc\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eINNORYOS 2.2%\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eSynvisc\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eSodium hyaluronate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e8.000 (hylan G-F 20)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eNiacinamide\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eSodium Chloride\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cp\u003e6.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e8.500\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eDisodium hydrogen phosphate 2 H\u003csub\u003e2\u003c/sub\u003eO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cp\u003e0.563\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.160\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eSodium dihydrogen phosphate 2 H\u003csub\u003e2\u003c/sub\u003eO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cp\u003e0.045\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.040\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eInjection water\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cp\u003ein 1 ml\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ein 1 ml\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Outcomes\u003c/h2\u003e \u003cdiv id=\"Sec11\" class=\"Section3\"\u003e \u003ch2\u003e2.4.1 Primary study outcome:\u003c/h2\u003e \u003cp\u003eChanges in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score from baseline (visit 1) to 26 week-follow-up (FU)(Visit 5)\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section3\"\u003e \u003ch2\u003e2.4.2 Secondary study outcomes\u003c/h2\u003e \u003cp\u003eChanges inWOMAC category \u0026ldquo;pain\u0026rdquo; from baseline to 26 week-follow-up (FU)\u003c/p\u003e \u003cp\u003eChanges inWOMAC category \u0026ldquo;stiffness\u0026rdquo; from baseline to 26 week-follow-up (FU)\u003c/p\u003e \u003cp\u003eChanges inWOMAC category \u0026ldquo;function\u0026rdquo; from baseline to 26 week-follow-up (FU)\u003c/p\u003e \u003cp\u003eChanges inWOMAC category \u0026ldquo;pain\u0026rdquo; from baseline to 2 week follow-up (Visit 3)\u003c/p\u003e \u003cp\u003eAdverse effects during the study period\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section3\"\u003e \u003ch2\u003e2.4.3 Explanatory outcomes\u003c/h2\u003e \u003cp\u003eChanges in co-medication during the study period\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003e2.5 Assessments\u003c/h2\u003e \u003cdiv id=\"Sec15\" class=\"Section3\"\u003e \u003ch2\u003e2.5.1 Baseline assessment\u003c/h2\u003e \u003cp\u003eDuring the initial examination of the patients, anthropometric data were recorded and a clinical examination and radiological assessment of the osteoarthritis were also carried out. In addition, treatment/medication, physical activity and diet were asked about as part of the anamnesis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section3\"\u003e \u003ch2\u003e2.5.2 Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)\u003c/h2\u003e \u003cp\u003eWe applied the \u0026ldquo;Likert (scale)\u0026rdquo; version (WOMAK LK3 series) of the WOMAC Index that is a self-administered questionnaire predominately applied in the area of hip and knee osteoarthritis consisting of 24 items divided into 3 categories. Category A determines \u0026ldquo;pain\u0026rdquo; (5 items) during walking, using stairs, in bed, sitting or lying, and while standing upright. Category B focuses on \u0026ldquo;stiffness\u0026rdquo; after first awaking and later in the day. Category C determines physical function (17 items) while using stairs, rising from sitting, standing, bending, walking, getting in / out of a car, shopping, putting on / taking off socks, rising from bed, lying in bed, getting in / out of bath, sitting, getting on / off toilet, heavy domestic duties, light domestic duties. In the present project, we consistently focus on knee osteoarthritis. The surveys were conducted as personal interviews during the visits; outcome assessors read out the WOMAC questions to the participants and made the entries.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section3\"\u003e \u003ch2\u003e2.5.2 Adverse effects\u003c/h2\u003e \u003cp\u003eAn adverse event was defined as any adverse medical event, unanticipated illness or injury, or any adverse clinical sign, including an abnormal laboratory finding, in subjects, users or other persons in a clinical trial, whether related to the investigational product or not. Severe adverse effects were defines as (a) death or (b) a serious deterioration in health resulting in (b1) life-threatening illness or injury, (b2) permanent impairment of a bodily structure or function, (b3) hospitalization or prolongation of the patient's hospital stay, (b4) need for medical or surgical intervention to prevent (b1) or (b2), (b5) chronic illness and finally (b6) fetal distress, fetal death or congenital physical or mental impairment or birth defect.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section3\"\u003e \u003ch2\u003e2.5.3 Co-medication\u003c/h2\u003e \u003cp\u003eCo-medication and in particular pain-modulating medication was recorded during each of the visits in order to determine changes in medication that might affect our study outcomes.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003e2.6 Sample size calculation\u003c/h2\u003e \u003cp\u003eDue to the focus of the directed primary hypothesis on \u0026ldquo;non-inferiority of effects\u0026rdquo;, the sample size was calculated using the one-tailed Student's t-test. An effect size of 0.57 (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e), a statistical significance level of 0.05 and the discriminatory power of 0.8 were applied to calculate the sample size of this clinical trial. The calculation resulted in a sample size of 41 participants/group, however anticipating missing values and a loss of follow up of 10%, 90 participants were ultimately included and allocated to two equal groups of 45 participants each.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003e2.7 Statistical analysis\u003c/h2\u003e \u003cp\u003eWe applied the Intention to treat (ITT) principle that included all participants randomly assigned to the study arms (INNORYOS 2.2%vs. CG) regardless of their loss to follow-up. Due to the very low number of missing values (n\u0026thinsp;=\u0026thinsp;1), we simply applied the last observation carried forward method for imputation. Normal distribution was checked graphically (gg-plots, residual plots). We applied 1-tailed-tests, and Mann-Whitney test (when applicable); significance was accepted at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05. ANCOVA that adjusted for baseline differences was applied to determine between group differences (i.e. \u0026ldquo;effects\u0026rdquo;) after 26 weeks (primary outcome). Absolute treatment effects were transposed to percentage changes from baseline to 1, 2, 14 and 26-week FU (i.e. visit 2\u0026ndash;5). Simple frequency accounts were applied to address secondary outcomes. Differences in distribution of categorical variables (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e) were analyzed by Pearson chi-square tests using two tailed tests.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cp\u003eBaseline characteristics of the two groups were displayed in Table \u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. In summary, significant differences were observed for Kellgren-Lawrence Grade, use of analgesics, NSAID, knee swelling and stiffness with consistently higher degrees of complaints and corresponding more pronounced use of pharmacologic therapy in the control group.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics of the study groups (number; mean value\u0026plusmn; standard deviation, 2-tailed p-value)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eINNORYOS 2.2%\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;45)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003eControl\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;45)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWomen/Men [n]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.833\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge in total [years]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e66.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026plusmn;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e63.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026plusmn;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e10.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.080\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI in total [kg/m\u003csup\u003e2\u003c/sup\u003e]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026plusmn;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e29.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026plusmn;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.444\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePhysical activity [VAS 1\u0026ndash;10]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e05.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026plusmn;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e06.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026plusmn;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.595\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKnee OA unilateral / bilateral [n]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.667\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eJoint space narrowing [n]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-----\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOsteophytes [n]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.197\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCyst formation [n]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.660\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSubchondral sclerosis [n]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.186\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKellgren Lawrence Grade [n]\u003c/p\u003e \u003cp\u003eGrade 1\u003c/p\u003e \u003cp\u003eGrade 2\u003c/p\u003e \u003cp\u003eGrade 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18\u003c/p\u003e \u003cp\u003e14\u003c/p\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6\u003c/p\u003e \u003cp\u003e17\u003c/p\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.014\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnalgetics [n]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSysadoa [n]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-----\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePhysiotherapy [n]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-----\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInjection steroidal agents [n]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInjection viscosupplements [n]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.315\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKnee inspection: pain [n]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.915\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKnee inspection: swelling [n]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKnee inspection: effusion [n]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.163\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKnee inspection: stiffness [n]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePain when walking [VAS 1\u0026ndash;10]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026plusmn;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026plusmn;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e12.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.778\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec22\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Lost to follow-up, compliance\u003c/h2\u003e \u003cp\u003eNone of the 90 participants quit the study or were lost to follow-up. Consequently, all participants (n\u0026thinsp;=\u0026thinsp;45 intervention group, n\u0026thinsp;=\u0026thinsp;45 CG) were analyzed. In one case (CG), one item of the WOMAC stiffness category (\u0026hellip;\u0026rdquo;later on the day\u0026rdquo;) was not completed by the participant and was imputed by the method described above (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec23\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Primary study outcome\u003c/h2\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e displays mean value along with 95% confidence interval for percentage changes in total WOMAC score of the INNORYOS 2.2% and control groups. So far, independently of the date of the FU-assessment a significant inferiority (p\u0026thinsp;\u0026gt;\u0026thinsp;of INNORYOS 2.2% versus the control treatment with Synvisc 0.8%, 2.0 ml has not been observed (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003e(place\u003c/b\u003e Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e \u003cb\u003e\u0026ldquo;Changes of the total WOMAC-score in the INNORYOS 2.2% and CG during the study\u0026rdquo; about here).\u003c/b\u003e\u003c/p\u003e \u003cp\u003eApplying ANCOVA that focuses on changes from baseline to 26-week FU and adjusted for baseline differences, no significant inferiority of INNORYOS 2.2% versus the control treatment can be observed for total WOMAC score (p\u0026thinsp;=\u0026thinsp;.290). In detail, WOMAC pain (p\u0026thinsp;=\u0026thinsp;.26) and function (p\u0026thinsp;=\u0026thinsp;.49) scores did not differ significantly between the groups. However, significantly more favorable data after INNORYOS 2.2% were observed for WOMAC stiffness subcategory (p\u0026thinsp;=\u0026thinsp;.009).\u003c/p\u003e \u003cp\u003eIn summary, we thus confirmed the primary hypothesis that the average effect of INNORYOS 2.2%, 2.0 ml) on WOMAC total score Index is not inferior to the control group provided with the standard agent (Synvisc 0.8%, 2.0ml).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec24\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Secondary study outcome\u003c/h2\u003e \u003cp\u003e \u003cstrong\u003eHypothesis\u003c/strong\u003e \u003cp\u003e \u003cb\u003e2a\u003c/b\u003e: In summary, the hypotheses of average positive changes of at least 50% in WOMAC \u0026ldquo;pain\u0026rdquo;, \u0026ldquo;stiffness\u0026rdquo; and \u0026ldquo;function\u0026rdquo; subscale after INNORYOS 2.2% injection from baseline to final follow-up assessment have to be rejected for all WOMAC categories. In detail, changes from baseline to 26 week FU average 43.6% for WOMAC \u0026ldquo;pain\u0026rdquo;, 25.9% for WOMAC \u0026ldquo;stiffness\u0026rdquo; and 37% for WOMAC \u0026ldquo;function\u0026rdquo; score. Although not addressed by the hypotheses, average changes among the control group were consistently tendentially lower for all WOMAC categories (i.e. \u0026ldquo;pain\u0026rdquo;: 29.1%; \u0026ldquo;stiffness\u0026rdquo;: 0%, function 27.6%).\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eHypothesis\u003c/strong\u003e \u003cp\u003e \u003cb\u003e2b\u003c/b\u003e: With respect to the response rate at final FU (26 weeks), we observed positive treatment effects on total WOMAC score in 86.7% of the participants of the INNORYOS 2.2% group. Thus, hypothesis 2b can be confirmed.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eHypothesis\u003c/strong\u003e \u003cp\u003e \u003cb\u003e2c\u003c/b\u003e: Response rate for the first two weeks (visit 3) after initial INNORYOS 2.2% injection averaged 77.8% and thus slightly exceeded the 75% threshold of positive response rate required by hypothesis 2c.\u003c/p\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec25\" class=\"Section2\"\u003e \u003ch2\u003e3.4 Adverse effects during the study period\u003c/h2\u003e \u003cp\u003eNo adverse effects were observed or reported by the participants.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec26\" class=\"Section2\"\u003e \u003ch2\u003e3.5 Confounding effects\u003c/h2\u003e \u003cp\u003eAs determined by personal interviews and recorded in the questionnaires, no changes of co-medication with impact on the study outcomes addressed here were observed.\u003c/p\u003e \u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThis investigation sought to establish the significant non-inferiority of the test compound INNORYOS 2.2% in contrast to the standard agent Synvisc for managing knee osteoarthritis in individuals aged 40 to 85 years.\u003c/p\u003e \u003cp\u003eSynvisc 0.8%, 2.0 ml is one of the most commonly used hyaluronan preparations. It is a high-quality cross-linked HA product whose positive effects have been proven in several studies (\u003cspan additionalcitationids=\"CR21 CR22 CR23 CR24 CR25\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). A systematic review has shown that cross-linked HA has a significantly greater therapeutic effect (p\u0026thinsp;=\u0026thinsp;.003) compared to non-cross-linked HA (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). The cross links improve the physical properties of HA by increasing the molecular size, slowing down enzymatic degradation and increasing the retention time in the joint (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eHowever, INNORYOS 2.2% is a high molecular weight HA to which properties similar to those of cross-linked HA are attributed. We assume that INNORYOS 2.2% has the same performance as Synvisc 0.8%, 2.0 ml - unlike non-cross-linked low molecular weight HA (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Thus we formulated the primary hypothesis of non-inferiority with respect to changes in total WOMAC score. The primary hypothesis could be accepted, as it was demonstrated that the average performance, provided with INNORYOS 2.2%, incorporating 1.5% niacinamide, was not inferior to the average performance within the comparison group treated with Synvisc 0.8%, 2.0 ml. With respect to the secondary hypothesis, INNORYOS 2.2% did not achieve the desired treatment outcome of a 50% improvement on the WOMAC \u0026ldquo;pain\u0026rdquo;, \u0026ldquo;stiffness\u0026rdquo; and \u0026ldquo;function\u0026rdquo; subscales at the final follow-up visit at week 26 compared to baseline. The 50% improvement benchmark was predicated on a meta-analysis indicating that \"HA improves pain by approximately 40\u0026ndash;50% compared with baseline levels\" (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). It is worth mentioning that INNORYOS 2.2% tendentially outperformed the comparative product in all categories. However, statistical significance was only observed for the subscale \u0026ldquo;stiffness\u0026rdquo;.\u003c/p\u003e \u003cp\u003eBeside the performance, the tolerability and safety of the test compound were examined through the monitoring of potential adverse events, none of which occurred. INNORYOS 2.2% consists of hyaluronic acid derived from bacterial fermentation. It therefore does not contain any animal material. Synvisc is a cross-linked HA derived from rooster comb. It is reported that patients using biological fermentation-derived HA had fewer cases of acute flare-ups at the injection site than those using avian-derived HA products (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). However, on the basis of our study data no comparative safety conclusions can be drawn, as no adverse events occurred in either group.\u003c/p\u003e \u003cp\u003eIn various contemporary meta-analyses, research emphasis is increasingly gravitating towards alternative conservative treatment modalities such as platelet-rich-plasma (PRP), bone marrow aspirate concentrate, and others (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan additionalcitationids=\"CR32\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e). These studies indicate a growing superiority of these therapeutic agents, albeit confirming the efficacy of HA as well. Several meta-analyses have been published examining the efficacy of PRP compared to HA. In summary, the studies came to the conclusion that PRP is superior to HA in terms of the total WOMAC score over a study period of one year (\u003cspan additionalcitationids=\"CR35\" citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e). When looking at a subgroup analysis with high molecular weight and cross-linked hyaluronic acid (HA), no statistically significant difference was found between the use of PRP and this type of HA (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e). In contrast to low molecular weight, non-cross-linked HA, PRP does not appear to be superior compared to high molecular weight and cross-linked HA.\u003c/p\u003e \u003cp\u003eINNORYOS 2.2% is a high molecular weight HA which contains 15 mg of niacinamide, an amide of nicotinic acid, which possesses anti-inflammatory properties and may positively influence degenerative processes in arthritic joints (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Thus, INNORYOS 2.2% represents a potent and safe option which can be used in isolation or possibly in combination with other new procedures. Recent investigations suggest that a combination of platelet-rich plasma and HA can exert a particularly favorable influence on degenerative processes in the knee joint (\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e). Consequently, the significance of hyaluronic acid therapy is unlikely to wane in the future. Interestingly, a meta-analysis showed that the combination of PRP and HA injections was safer than isolated PRP injections when assessing the incidence of adverse events, which makes the combination an interesting treatment option (\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIt will remain advantageous to formulate the most efficacious HA preparation to afford patients the optimal treatment, be it through monotherapy or combination therapy.\u003c/p\u003e \u003cp\u003eWhile this study illustrates the non-inferiority of INNORYOS 2.2% compared to Synvisc, Porcello et al. evaluated several HA products, including those aforementioned, with respect to rheological, lubricative, adhesive, and stability attributes (\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e). The results showed that INNORYOS 2.2% \u0026ldquo;presented the best overall functional behaviour in the retained experimental settings (high adhesivity and lubricity and substantial resistance to oxidative degradation)\u0026rdquo; (\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e) thus surpassing the comparator product Synvisc.\u003c/p\u003e \u003cp\u003eBoth hyaluronic acid preparations are accessible as a triple application, the customary method in Germany. However, the single application appears to be no less effective than this regimen (\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e). As the efficacy of hyaluronic acid injections for osteoarthritis in various joints, such as the hip (\u003cspan additionalcitationids=\"CR43 CR44 CR45\" citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e) or shoulder (\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e) is currently under investigation with promising outcomes, it can be inferred that INNORYOS 2.2% has an effect on other joints.\u003c/p\u003e \u003cp\u003eIt must be mentioned as a strength that in fact all participants completed the treatment. A key factor in this was certainly the free provision of treatment to a collective with high levels of suffering. In addition, the rapid onset of a positive effect after the first injection motivated many participants to complete the treatment.\u003c/p\u003e \u003cp\u003eSome limitations of our trial should be noted. Of importance, baseline values for Kellgren-Lawrence score differ significant between the groups with higher levels of advanced KL-grade in the CG. However, the prevalence of the single different radiological OA characteristics recorded in the questionnaire (joint space narrowing, osteophytes, cyst formation, subchondral sclerosis) did not differ significantly between the groups. There is some evidence that a higher degree of irreversible changes observed at higher KL-levels might conflict with the treatment effects in the control group (\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e). In parallel, significant differences on baseline use of analgesics (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e) with significantly higher use in the CG might confound our finding. However, considering that no within or between group changes of medication intake were recorded during the study period, we feel that the impact of differences remains negligible.\u003c/p\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eThis study showed that INNORYOS 2.2%, a hyaluronic acid preparation containing niacinamide, is significantly non-inferior to the standard preparation Synvisc in the treatment of knee osteoarthritis. While both products exhibited positive effects on pain, mobility, and joint stiffness, the efficacy across all domains was tendentially higher in the group receiving INNORYOS 2.2%, with significant results for \u0026ldquo;stiffness\u0026rdquo;. To more precisely address the anti-inflammatory effects presumably induced by niacinamide in the knee, future investigations should record dedicated inflammatory markers. Additionally, a larger cohort and statistical tests for the significant superiority of INNORYOS 2.2% over other hyaluronic acid preparations are warranted.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the\u0026nbsp;ALBOMED, Germany.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of competing interest \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare the following financial interests/personal relationships which may be considered as potential competing interests:\u003c/p\u003e\n\u003cp\u003eKemmler reports financial support, article publishing charges, and equipment, drugs, or supplies were provided by ALBOMED, Germany. Wolfgang Kemmler reports a relationship with ALBOMED, Germany that includes: funding grants and non-financial support. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCRediT authorship contribution statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLola Hofweber\u003c/strong\u003e: Data curation, Methodology, Writing - original draft, Writing - review \u0026amp; editing. \u003cstrong\u003eSimon von Stengel\u003c/strong\u003e: Data curation, Resources, Supervision, Visualization, Writing-original draft, Writing-Reviewing \u0026amp; Editing.\u003cstrong\u003e\u0026nbsp;J\u0026ouml;rg N\u0026uuml;rnberger:\u003c/strong\u003e Conceptualization,\u0026nbsp;Funding acquisition,\u0026nbsp;Project administration, Data curation, Supervision, Investigation, Writing - review \u0026amp; editing. \u003cstrong\u003eWolfgang Kemmler:\u003c/strong\u003e Funding acquisition, Project administration, Formal analysis, Methodology, Writing - original draft, Writing- Reviewing and Editing.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eClynes MA, Jameson KA, Edwards MH, Cooper C, Dennison EM (2019) Impact of osteoarthritis on activities of daily living: does joint site matter? Aging Clin Exp Res 31(8):1049\u0026ndash;1056. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s40520-019-01163-0\u003c/span\u003e\u003cspan address=\"10.1007/s40520-019-01163-0\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGlobal burden of 369 diseases and injuries in 204 countries and territories, 1990\u0026ndash;2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet (2020) ;396(10258):1204-22. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/s0140-6736(20)30925-9\u003c/span\u003e\u003cspan address=\"10.1016/s0140-6736(20)30925-9\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLong H, Liu Q, Yin H, Wang K, Diao N, Zhang Y et al (2022) Prevalence Trends of Site-Specific Osteoarthritis From 1990 to 2019: Findings From the Global Burden of Disease Study 2019. Arthritis Rheumatol 74(7):1172\u0026ndash;1183. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1002/art.42089\u003c/span\u003e\u003cspan address=\"10.1002/art.42089\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLin HS, Watts JN, Peel NM, Hubbard RE (2016) Frailty and post-operative outcomes in older surgical patients: a systematic review. BMC Geriatr 16(1):157. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1186/s12877-016-0329-8\u003c/span\u003e\u003cspan address=\"10.1186/s12877-016-0329-8\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang W, Moskowitz RW, Nuki G, Abramson S, Altman RD, Arden N et al (2008) OARSI recommendations for the management of hip and knee osteoarthritis, Part II: OARSI evidence-based, expert consensus guidelines. Osteoarthritis Cartilage 16(2):137\u0026ndash;162. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.joca.2007.12.013\u003c/span\u003e\u003cspan address=\"10.1016/j.joca.2007.12.013\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eColen S, van den Bekerom MP, Mulier M, Haverkamp D (2012) Hyaluronic acid in the treatment of knee osteoarthritis: a systematic review and meta-analysis with emphasis on the efficacy of different products. BioDrugs 26(4):257\u0026ndash;268. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.2165/11632580-000000000-00000\u003c/span\u003e\u003cspan address=\"10.2165/11632580-000000000-00000\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHe WW, Kuang MJ, Zhao J, Sun L, Lu B, Wang Y et al (2017) Efficacy and safety of intraarticular hyaluronic acid and corticosteroid for knee osteoarthritis: A meta-analysis. Int J Surg 39:95\u0026ndash;103. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.ijsu.2017.01.087\u003c/span\u003e\u003cspan address=\"10.1016/j.ijsu.2017.01.087\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePetrella RJ, Petrella M (2006) A prospective, randomized, double-blind, placebo controlled study to evaluate the efficacy of intraarticular hyaluronic acid for osteoarthritis of the knee. J Rheumatol 33(5):951\u0026ndash;956\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSingh H, Knapik DM, Polce EM, Eikani CK, Bjornstad AH, Gursoy S et al (2022) Relative Efficacy of Intra-articular Injections in the Treatment of Knee Osteoarthritis: A Systematic Review and Network Meta-analysis. Am J Sports Med 50(11):3140\u0026ndash;3148. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1177/03635465211029659\u003c/span\u003e\u003cspan address=\"10.1177/03635465211029659\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang CT, Lin J, Chang CJ, Lin YT, Hou SM (2004) Therapeutic effects of hyaluronic acid on osteoarthritis of the knee. A meta-analysis of randomized controlled trials. J Bone Joint Surg Am 86(3):538\u0026ndash;545. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.2106/00004623-200403000-00012\u003c/span\u003e\u003cspan address=\"10.2106/00004623-200403000-00012\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWebb D, Naidoo P (2018) Viscosupplementation for knee osteoarthritis: a focus on Hylan G-F 20. Orthop Res Rev 10:73\u0026ndash;81. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.2147/orr.S174649\u003c/span\u003e\u003cspan address=\"10.2147/orr.S174649\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBains P, Kaur M, Kaur J, Sharma S, Nicotinamide (2018) Mechanism of action and indications in dermatology. Indian J Dermatol Venereol Leprol 84(2):234\u0026ndash;237. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.4103/ijdvl.IJDVL_286_17\u003c/span\u003e\u003cspan address=\"10.4103/ijdvl.IJDVL_286_17\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJonas WB, Rapoza CP, Blair WF (1996) The effect of niacinamide on osteoarthritis: a pilot study. Inflamm Res 45(7):330\u0026ndash;334. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/bf02252945\u003c/span\u003e\u003cspan address=\"10.1007/bf02252945\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMcCarty MF, Russell AL (1999) Niacinamide therapy for osteoarthritis\u0026ndash;does it inhibit nitric oxide synthase induction by interleukin 1 in chondrocytes? Med Hypotheses 53(4):350\u0026ndash;360. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1054/mehy.1998.0792\u003c/span\u003e\u003cspan address=\"10.1054/mehy.1998.0792\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWorld Medical A (2013) World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA 310(20):2191\u0026ndash;2194. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1001/jama.2013.281053\u003c/span\u003e\u003cspan address=\"10.1001/jama.2013.281053\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKellgren JH, Lawrence JS (1957) Radiological assessment of osteo-arthrosis. Ann Rheum Dis 16(4):494\u0026ndash;502. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1136/ard.16.4.494\u003c/span\u003e\u003cspan address=\"10.1136/ard.16.4.494\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMiller LE, Block JE (2013) US-Approved Intra-Articular Hyaluronic Acid Injections are Safe and Effective in Patients with Knee Osteoarthritis: Systematic Review and Meta-Analysis of Randomized, Saline-Controlled Trials. Clin Med Insights Arthritis Musculoskelet Disord 6:57\u0026ndash;63. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.4137/cmamd.S12743\u003c/span\u003e\u003cspan address=\"10.4137/cmamd.S12743\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRichette P, Chevalier X, Ea HK, Eymard F, Henrotin Y, Ornetti P et al (2015) Hyaluronan for knee osteoarthritis: an updated meta-analysis of trials with low risk of bias. RMD Open 1(1):e000071. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1136/rmdopen-2015-000071\u003c/span\u003e\u003cspan address=\"10.1136/rmdopen-2015-000071\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBellamy N, Campbell J, Robinson V, Gee T, Bourne R, Wells G (2006) Viscosupplementation for the treatment of osteoarthritis of the knee. Cochrane Database Syst Rev 2006(2):Cd005321. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1002/14651858.CD005321.pub2\u003c/span\u003e\u003cspan address=\"10.1002/14651858.CD005321.pub2\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTammachote N, Kanitnate S, Yakumpor T, Panichkul P, Intra-Articular (2016) Single-Shot Hylan G-F 20 Hyaluronic Acid Injection Compared with Corticosteroid in Knee Osteoarthritis: A Double-Blind, Randomized Controlled Trial. J Bone Joint Surg Am 98(11):885\u0026ndash;892. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.2106/JBJS.15.00544\u003c/span\u003e\u003cspan address=\"10.2106/JBJS.15.00544\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhao H, Liu H, Liang X, Li Y, Wang J, Liu C, Hylan (2016) G-F 20 Versus Low Molecular Weight Hyaluronic Acids for Knee Osteoarthritis: A Meta-Analysis. BioDrugs 30(5):387\u0026ndash;396. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s40259-016-0186-1\u003c/span\u003e\u003cspan address=\"10.1007/s40259-016-0186-1\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMaheu E, Avouac B, Dreiser RL, Bardin T (2019) A single intra-articular injection of 2.0% non-chemically modified sodium hyaluronate vs 0.8% hylan G-F 20 in the treatment of symptomatic knee osteoarthritis: A 6-month, multicenter, randomized, controlled non-inferiority trial. PLoS ONE 14(12):e0226007. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1371/journal.pone.0226007\u003c/span\u003e\u003cspan address=\"10.1371/journal.pone.0226007\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCortet B, Lombion S, Naissant B, Vidovic E, Bruyere O (2021) Non-Inferiority of a Single Injection of Sodium Hyaluronate Plus Sorbitol to Hylan G-F20: A 6-Month Randomized Controlled Trial. Adv Ther 38(5):2271\u0026ndash;2283. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s12325-021-01648-3\u003c/span\u003e\u003cspan address=\"10.1007/s12325-021-01648-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBettonville M, Leon M, Margaux J, Urbin-Choffray D, Theunissen E, Besse-Hammer T et al (2021) Safety and efficacy of a single intra-articular injection of a novel enhanced protein solution (JTA-004) compared to hylan G-F 20 in symptomatic knee osteoarthritis: a randomized, double-blind, controlled phase II/III study. BMC Musculoskelet Disord 22(1):888. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1186/s12891-021-04750-3\u003c/span\u003e\u003cspan address=\"10.1186/s12891-021-04750-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKe Y, Jiang W, Xu Y, Chen Y, Zhang Q, Xue Q et al (2021) Efficacy and safety of a single intra-articular injection of 6 ml Hylan G-F 20 compared to placebo in Chinese patients with symptomatic knee osteoarthritis: C-SOUND study, a 26-week multicenter double-blind randomized placebo-controlled trial in China. BMC Musculoskelet Disord 22(1):428. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1186/s12891-021-04252-2\u003c/span\u003e\u003cspan address=\"10.1186/s12891-021-04252-2\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDe Lucia O, Jerosch J, Yoon S, Sayre T, Ngai W, Filippou G (2021) One-year efficacy and safety of single or one to three weekly injections of hylan G-F 20 for knee osteoarthritis: a systematic literature review and meta-analysis. Clin Rheumatol 40(6):2133\u0026ndash;2142. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s10067-020-05477-7\u003c/span\u003e\u003cspan address=\"10.1007/s10067-020-05477-7\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHummer CD, Angst F, Ngai W, Whittington C, Yoon SS, Duarte L et al (2020) High molecular weight Intraarticular hyaluronic acid for the treatment of knee osteoarthritis: a network meta-analysis. BMC Musculoskelet Disord 21(1):702. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1186/s12891-020-03729-w\u003c/span\u003e\u003cspan address=\"10.1186/s12891-020-03729-w\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJevsevar D, Donnelly P, Brown GA, Cummins DS (2015) Viscosupplementation for Osteoarthritis of the Knee: A Systematic Review of the Evidence. J Bone Joint Surg Am 97(24):2047\u0026ndash;2060. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.2106/jbjs.N.00743\u003c/span\u003e\u003cspan address=\"10.2106/jbjs.N.00743\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLindqvist U, Tolmachev V, Kairemo K, Astr\u0026ouml;m G, Jonsson E, Lundqvist H (2002) Elimination of stabilised hyaluronan from the knee joint in healthy men. Clin Pharmacokinet 41(8):603\u0026ndash;613. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.2165/00003088-200241080-00004\u003c/span\u003e\u003cspan address=\"10.2165/00003088-200241080-00004\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAltman RD, Bedi A, Karlsson J, Sancheti P, Schemitsch E (2016) Product Differences in Intra-articular Hyaluronic Acids for Osteoarthritis of the Knee. Am J Sports Med 44(8):2158\u0026ndash;2165. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1177/0363546515609599\u003c/span\u003e\u003cspan address=\"10.1177/0363546515609599\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAnil U, Markus DH, Hurley ET, Manjunath AK, Alaia MJ, Campbell KA et al (2021) The efficacy of intra-articular injections in the treatment of knee osteoarthritis: A network meta-analysis of randomized controlled trials. Knee 32:173\u0026ndash;182. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.knee.2021.08.008\u003c/span\u003e\u003cspan address=\"10.1016/j.knee.2021.08.008\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBelk JW, Lim JJ, Keeter C, McCulloch PC, Houck DA, McCarty EC et al (2023) Patients With Knee Osteoarthritis Who Receive Platelet-Rich Plasma or Bone Marrow Aspirate Concentrate Injections Have Better Outcomes Than Patients Who Receive Hyaluronic Acid: Systematic Review and Meta-analysis. Arthroscopy 39(7):1714\u0026ndash;1734. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.arthro.2023.03.001\u003c/span\u003e\u003cspan address=\"10.1016/j.arthro.2023.03.001\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKim JH, Park YB, Ha CW (2023) Are leukocyte-poor or multiple injections of platelet-rich plasma more effective than hyaluronic acid for knee osteoarthritis? A systematic review and meta-analysis of randomized controlled trials. Arch Orthop Trauma Surg 143(7):3879\u0026ndash;3897. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s00402-022-04637-5\u003c/span\u003e\u003cspan address=\"10.1007/s00402-022-04637-5\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTan J, Chen H, Zhao L, Huang W (2021) Platelet-Rich Plasma Versus Hyaluronic Acid in the Treatment of Knee Osteoarthritis: A Meta-analysis of 26 Randomized Controlled Trials. Arthroscopy 37(1):309\u0026ndash;325. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.arthro.2020.07.011\u003c/span\u003e\u003cspan address=\"10.1016/j.arthro.2020.07.011\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTang JZ, Nie MJ, Zhao JZ, Zhang GC, Zhang Q, Wang B (2020) Platelet-rich plasma versus hyaluronic acid in the treatment of knee osteoarthritis: a meta-analysis. J Orthop Surg Res 15(1):403. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1186/s13018-020-01919-9\u003c/span\u003e\u003cspan address=\"10.1186/s13018-020-01919-9\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBelk JW, Kraeutler MJ, Houck DA, Goodrich JA, Dragoo JL, McCarty EC (2021) Platelet-Rich Plasma Versus Hyaluronic Acid for Knee Osteoarthritis: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Am J Sports Med 49(1):249\u0026ndash;260. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1177/0363546520909397\u003c/span\u003e\u003cspan address=\"10.1177/0363546520909397\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhao J, Huang H, Liang G, Zeng LF, Yang W, Liu J (2020) Effects and safety of the combination of platelet-rich plasma (PRP) and hyaluronic acid (HA) in the treatment of knee osteoarthritis: a systematic review and meta-analysis. BMC Musculoskelet Disord 21(1):224. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1186/s12891-020-03262-w\u003c/span\u003e\u003cspan address=\"10.1186/s12891-020-03262-w\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKarasavvidis T, Totlis T, Gilat R, Cole BJ (2021) Platelet-Rich Plasma Combined With Hyaluronic Acid Improves Pain and Function Compared With Hyaluronic Acid Alone in Knee Osteoarthritis: A Systematic Review and Meta-analysis. Arthroscopy 37(4):1277\u0026ndash;87e1. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.arthro.2020.11.052\u003c/span\u003e\u003cspan address=\"10.1016/j.arthro.2020.11.052\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang Q, Liu T, Gu Y, Gao Y, Ni J (2022) Efficacy and safety of platelet-rich plasma combined with hyaluronic acid versus platelet-rich plasma alone for knee osteoarthritis: a systematic review and meta-analysis. J Orthop Surg Res 17(1):499. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1186/s13018-022-03398-6\u003c/span\u003e\u003cspan address=\"10.1186/s13018-022-03398-6\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePorcello A, Hadjab F, Ajouaou M, Philippe V, Martin R, Abdel-Sayed P et al (2023) Ex Vivo Functional Benchmarking of Hyaluronan-Based Osteoarthritis Viscosupplement Products: Comprehensive Assessment of Rheological, Lubricative, Adhesive, and Stability Attributes. Gels 9(10). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3390/gels9100808\u003c/span\u003e\u003cspan address=\"10.3390/gels9100808\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSuppan VKL, Tew MM, Wong BC, Chan HK, Chew YW, Tan CS et al (2020) One-year follow-up of efficacy and cost of repeated doses versus single larger dose of intra-articular hyaluronic acid for knee osteoarthritis. J Orthop Surg (Hong Kong) 28(1):2309499019895029. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1177/2309499019895029\u003c/span\u003e\u003cspan address=\"10.1177/2309499019895029\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBelk JW, Houck DA, Littlefield CP, Kraeutler MJ, Potyk AG, Mei-Dan O et al (2022) Platelet-Rich Plasma Versus Hyaluronic Acid for Hip Osteoarthritis Yields Similarly Beneficial Short-Term Clinical Outcomes: A Systematic Review and Meta-analysis of Level I and II Randomized Controlled Trials. Arthroscopy 38(6):2035\u0026ndash;2046. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.arthro.2021.11.005\u003c/span\u003e\u003cspan address=\"10.1016/j.arthro.2021.11.005\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrander V, Skrepnik N, Petrella RJ, Jiang GL, Accomando B, Vardanyan A (2019) Evaluating the use of intra-articular injections as a treatment for painful hip osteoarthritis: a randomized, double-blind, multicenter, parallel-group study comparing a single 6-mL injection of hylan G-F 20 with saline. Osteoarthritis Cartilage 27(1):59\u0026ndash;70. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.joca.2018.08.018\u003c/span\u003e\u003cspan address=\"10.1016/j.joca.2018.08.018\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNouri F, Babaee M, Peydayesh P, Esmaily H, Raeissadat SA (2022) Comparison between the effects of ultrasound guided intra-articular injections of platelet-rich plasma (PRP), high molecular weight hyaluronic acid, and their combination in hip osteoarthritis: a randomized clinical trial. BMC Musculoskelet Disord 23(1):856. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1186/s12891-022-05787-8\u003c/span\u003e\u003cspan address=\"10.1186/s12891-022-05787-8\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSambe HG, Yasir M, Man RK, Gogikar A, Nanda A, Janga LSN et al (2023) Comparing Intra-articular Platelet-Rich Plasma With Hyaluronic Acid for the Treatment of Hip Osteoarthritis: A Systematic Review and Meta-Analysis. Cureus 15(10):e47919. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.7759/cureus.47919\u003c/span\u003e\u003cspan address=\"10.7759/cureus.47919\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVillanova-L\u0026oacute;pez MM, N\u0026uacute;\u0026ntilde;ez-N\u0026uacute;\u0026ntilde;ez M, Fern\u0026aacute;ndez-Prieto D, Gonz\u0026aacute;lez-L\u0026oacute;pez C, Garc\u0026iacute;a-Donaire J, P\u0026eacute;rez-P\u0026eacute;rez A et al (2020) Randomized, double-blind, controlled trial, phase III, to evaluate the use of platelet-rich plasma versus hyaluronic acid in hip coxarthrosis. Rev Esp Cir Ortop Traumatol (Engl Ed) 64(2):134\u0026ndash;142. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.recot.2019.09.008\u003c/span\u003e\u003cspan address=\"10.1016/j.recot.2019.09.008\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFamiliari F, Ammendolia A, Rupp MC, Russo R, Pujia A, Montalcini T et al (2023) Efficacy of intra-articular injections of hyaluronic acid in patients with glenohumeral joint osteoarthritis: A systematic review and meta-analysis. J Orthop Res 41(11):2345\u0026ndash;2358. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1002/jor.25648\u003c/span\u003e\u003cspan address=\"10.1002/jor.25648\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang B, Thayaparan A, Horner N, Bedi A, Alolabi B, Khan M (2019) Outcomes of hyaluronic acid injections for glenohumeral osteoarthritis: a systematic review and meta-analysis. J Shoulder Elb Surg 28(3):596\u0026ndash;606. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.jse.2018.09.011\u003c/span\u003e\u003cspan address=\"10.1016/j.jse.2018.09.011\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eToh EM, Prasad PS, Teanby D (2002) Correlating the efficacy of knee viscosupplementation with osteoarthritic changes on roentgenological examination. Knee 9(4):321\u0026ndash;330. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/s0968-0160(02)00040-6\u003c/span\u003e\u003cspan address=\"10.1016/s0968-0160(02)00040-6\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAltman RD, Farrokhyar F, Fierlinger A, Niazi F, Rosen J (2016) Analysis for Prognostic Factors from a Database for the Intra-Articular Hyaluronic Acid (Euflexxa) Treatment for Osteoarthritis of the Knee. Cartilage 7(3):229\u0026ndash;237. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1177/1947603515620890\u003c/span\u003e\u003cspan address=\"10.1177/1947603515620890\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Footnotes","content":"\u003cp\u003e\u003cimg src=\"data:image/png;base64,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\" width=\"282\" height=\"53\"\u003e\u003c/p\u003e\n\u003cdiv id=\"Par27\" class=\"Para\"\u003eR\u0026thinsp;=\u0026thinsp;relative treatment development, n\u0026thinsp;=\u0026thinsp;number of questions, x\u003csub\u003ei\u003c/sub\u003e = value given in question i on the respective control date, y\u003csub\u003ei\u003c/sub\u003e = value given in question i on the first treatment date before the injection\u003c/div\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Friedrich-Alexander-University Erlangen-Nürnberg","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"knee, osteoarthritis, hyaluronic acid, INNORYOS 2.2%, niacinamide","lastPublishedDoi":"10.21203/rs.3.rs-4363034/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4363034/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eIntroduction\u003c/strong\u003e\u003c/em\u003e: We determined the effectiveness and safety of INNORYOS 2.2% hyaluronic acid (HA) containing 15mg of niacinamide on knee pain, stiffness and function in people with knee OA compared with an established agent. Further study objectives were to monitor side effects during the study period.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/em\u003e: The 26-week prospective non-interventional open clinical trial tested on non-inferiority of INNORYOS 2.2% compared to an established HA product (Synvisc 0.8%, 2.0 ml). Briefly, 90 people with knee OA (Kellgren-Lawrence grade I to III), 40–85 years old, were allocated randomly to the two groups. HA injections were carried out at baseline and after 1 and 2 weeks. ANCOVA that adjusted for baseline differences was applied to determine between group differences (i.e. “effects”) after 26 weeks.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/em\u003e: None of the 90 participants (65.0 ± 10.5 years, BMI: 30.2 ± 5.5 kg/m\u003csup\u003e2\u003c/sup\u003e) quit the study or was lost to follow-up. In summary WOMAC pain score (p = .26) and function score (p = .49) did not differ significantly between the groups, but data significant better effect after INNORYOS 2.2% were observed for WOMAC stiffness subscale (p = .009). In detail, changes from baseline to 26-week FU average 43.6% (29.1%) for “pain”, 25.9% (0%) for “stiffness” and 37% (27.6%) for “function” subscale in the INNORYOS (Synvisc) group.\u003c/p\u003e\n\u003cp\u003eNo adverse effects were observed or reported by the participants. As determined by personal interviews and recorded in the questionnaires no changes of \u003cem\u003eco-medication\u003c/em\u003e with impact on the study outcomes were observed.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/em\u003e: We did not determine significantly lower effects compared with the established product. In contrast, INNORYOS 2.2% tendentially revealed more favourable effect on all WOMAC categories (significant for “stiffness”). Thus, the present study provided further evidence for the effectiveness and safety of INNORYOS 2.2% in patients with early to advanced knee osteoarthritis.\u003c/p\u003e","manuscriptTitle":"Effectiveness and safety of the hyaluronic acid INNORYOS 2.2% in patients with early to advanced knee osteoarthritis. A prospective non-interventional randomized clinical trial.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-07 16:52:46","doi":"10.21203/rs.3.rs-4363034/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2b98957a-ccab-4a71-94fc-081d2eb8d352","owner":[],"postedDate":"May 7th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":31470441,"name":"Orthopedics"}],"tags":[],"updatedAt":"2024-05-07T16:52:46+00:00","versionOfRecord":[],"versionCreatedAt":"2024-05-07 16:52:46","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4363034","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4363034","identity":"rs-4363034","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}