Ultra-early Gamma Knife stereotactic radiosurgery for trigeminal neuralgia (URGEnt-TN): Feasibility and potential benefit: study protocol for a single-centre, two-arm, parallel group design, pragmatic, noninferiority, phase II, randomized controlled trial with intention-to-treat analysis for pre-refractory GK-SRS in classical or idiopathic TN

Ultra-early Gamma Knife stereotactic radiosurgery for trigeminal neuralgia (URGEnt-TN): Feasibility and potential benefit: study protocol for a single-centre, two-arm, parallel group design, pragmatic, noninferiority, phase II, randomized controlled trial with intention-to-treat analysis for pre-refractory GK-SRS in classical or idiopathic TN | 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 Ultra-early Gamma Knife stereotactic radiosurgery for trigeminal neuralgia (URGEnt-TN): Feasibility and potential benefit: study protocol for a single-centre, two-arm, parallel group design, pragmatic, noninferiority, phase II, randomized controlled trial with intention-to-treat analysis for pre-refractory GK-SRS in classical or idiopathic TN Amanda Lussoso, Samir Patel, Wasif Hussain, Michael Knash, Gregory Bowden, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7341323/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 04 Dec, 2025 Read the published version in Trials → Version 1 posted 5 You are reading this latest preprint version Abstract Background: Trigeminal neuralgia (TN) is a chronic, often debilitating neuropathic facial pain condition. First-line treatment is medical therapy, with carbamazepine being the gold standard. Surgery, including stereotactic radiosurgery in particular with Gamma Knife (GK-SRS), is usually considered when medical management fails, which occurs in > 50% of participants. While surgery can provide long-term relief, prolonged disease duration before intervention is linked to a reduced response rate. A highly precise type of radiation therapy, GK-SRS is a non-invasive management option in TN, with a low risk of serious complications and fewer bothersome side effects compared to medical therapy. Evidence supports the safety and efficacy of GK-SRS in medically-refractory TN, with published data suggesting that earlier intervention (within 3 years of pain onset) leads to improved long-term outcomes. However, the safety and efficacy of ultra-early GK-SRS—administered soon after TN diagnosis and before medical refractoriness—have not been examined. We hypothesize that ultra-early GK-SRS will yield superior long-term pain relief compared to ongoing medical management while also having a lower incidence of treatment-related adverse events. Methods: We will perform a single-centre, two-arm, randomized, controlled, parallel-group design, pragmatic, noninferiority, phase II trial of ultra-early GK-SRS for TN in participants who will be treated before they have developed a medically-refractory state and within 2 years of diagnosed TN per study neurologist. Eighty participants will be randomized 1:1 to either GK-SRS (intervention arm) or ongoing medical management (non-intervention/control arm). Crossover from the non-intervention/control arm to the intervention arm will be permitted. An intention-to-treat analysis will be conducted. The primary outcome will be the proportion of participants with satisfactory pain control at 2 years by the Barrow Neurological Institute Facial Pain Scale. Discussion: This trial aims to test ultra-early GK-SRS as a first-line option in TN, based on a sound rationale for offering GK-SRS prior to failure of medical therapy. If validated, ultra-early GK-SRS will represent a paradigm shift in TN management leading to improved long-term pain control free from adverse medication-related side effects. Trial Registration: This clinical trial has been registered with ClinicalTrials.gov under the identifier number NCT06949436. Registered on April 28, 2025. Trigeminal neuralgia Gamma Knife stereotactic radiosurgery surgery ultra-early surgery Figures Figure 1 Figure 2 Administrative information Note: the numbers in curly brackets in this protocol refer to SPIRIT checklist item numbers. The order of the items has been modified to group similar items (see http://www.equator-network.org/reporting-guidelines/spirit-2013-statement-defining-standard-protocol-items-for-clinical-trials/). Title {1} Ultra-early Gamma Knife stereotactic radiosurgery for trigeminal neuralgia: Feasibility and potential benefit URGEnt-TN Trial registration {2a and 2b}. Trial registry: ClinicalTrials.gov ClinicalTrials.gov ID: NCT06949436 Trial registration date: April 28, 2025 Protocol version {3} SRS-0301 Funding {4} This trial is currently unfunded. Author details {5a} Amanda Lussoso (1), Samir Patel (2), Wasif Hussain (3), Michael Knash(3), Matt Wheatley (4), Gregory Bowden (4), Ngoc Khanh Vu (5), Tejas Sankar (4) 1 -Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, Canada 2 -Division of Radiation Oncology, Department of Oncology, University of Alberta, Edmonton, AB, Canada 3 -Division of Neurology, University of Alberta, Edmonton, AB, Canada 4 - Division of Neurosurgery, University of Alberta, Edmonton, AB, Canada 5- Real World Evidence Unit, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada Name and contact information for the trial sponsor {5b} Not applicable. This trial is unsponsored. Role of sponsor {5c} Not applicable. This trial is unsponsored. Introduction Background and rationale {6a} Trigeminal neuralgia (TN) is a chronic, often severely debilitating, neuropathic facial pain condition characterized by “recurrent unilateral brief electric shock-like pains, abrupt in onset and termination, limited to the distribution of one or more divisions of the trigeminal nerve (cranial nerve five - CNV) and triggered by innocuous stimuli” [ 1 ]. TN has an approximate global incidence of 12 cases per 100,000 and a female predominance of 3:2 [ 2 , 3 ], and occurs predominantly in the sixth decade of life, peaking around 70 years [ 4 – 6 ]. The severe lancinating pain of TN is triggered by common somatosensory stimuli experienced in everyday life, such as chewing, speaking, brushing teeth, temperature changes, or tactile pressure to the face; pain attacks may also occur entirely spontaneously [ 7 ]. Given the severity of TN, prompt pain management is critically important. In general, pharmaceutical therapy is the first-line treatment, with carbamazepine (CBZ) being the gold standard. However, CBZ is associated with a high incidence of adverse effects (40%-66%) [ 8 ], including somnolence, dizziness, double vision, rash, nausea, headache, vomiting, tremor, ataxia, disturbed sleep, mood changes, lack of concentration, memory loss, and hyponatremia [ 9 – 12 ]. In rare circumstances, severe adverse effects can occur, including myelosuppression, hepatotoxicity, lymphadenopathy, systemic lupus erythematosus, elevated liver enzymes, hematologic dyscrasias, thrombocytopenia, aplastic anaemia [ 10 ], and dosages reaching toxic levels [ 5 ]. In addition, the presence of the HLA-B*15:02 allele found almost exclusively in Asian genealogy warrants genetic testing for participants with Asian lineage to determine their potential risk of CBZ-induced Stevens-Johnson syndrome and toxic epidermal necrolysis that may be life-threatening [ 13 ]. Oxcarbazepine (OXC) is an enantiomer of CBZ associated with fewer side effects, contraindications, and overall better tolerability [ 5 , 10 , 14 ]; however, similar to CBZ, it can cause sedation, dizziness, poor concentration, diplopia, nausea, headache, somnolence, ataxia, and thrombocytopenia, typically experienced to a lesser degree [ 10 – 12 , 15 ]. Of note, the incidence of hyponatremia is dose-dependent and of particular concern [ 10 ], so OXC use needs to be monitored carefully to avoid electrolyte imbalance. A large retrospective study examining the natural history of classical TN demonstrated robust initial responsiveness of 98% for CBZ and 94% for OXC. However, following means of 8.6 (CBZ) and 13 (OXC) months, a significant proportion of participants (27% CBZ, 18% OXC) developed intolerability and required subsequent dosage reduction to inadequate levels for appropriate pain management [ 10 ]. Other quantitative examinations of the frequency of adverse effects and overall tolerability of CBZ and OXC for neuralgiform pain, have found that dosage increases sufficient for pain management subsequently increase adverse cognitive effects [ 11 ]. More specifically, a standard one-unit dosage increase, the dosage necessary to generate a pharmacologically significant effect, results in a 50% increase in the likelihood of worsening side effects and eventual incapacity to reach therapeutic dosage for adequate pain suppression [ 11 ]. Taylor et al. [ 16 ] examined CBZ treatment for classical TN over a 16-year period, and found a significant decline in efficacy by year four, with an overall 44% failure rate necessitating alternative treatment. Despite the favourable tolerability of OXC, a long-term cohort study comparing OXC and surgical management of intractable TN found that effectiveness was short-term, subsequently necessitating surgical intervention as a rescue therapy [ 15 ]. According to the American Academy of Neurology (AAN) and the European Federation of Neurological Societies (EFNS) guidelines on TN management, when medical therapy becomes ineffective due to poor pain control or intolerability, referral for surgery is the next reasonable step [ 17 ]. Current surgical options in TN include microvascular decompression (MVD), percutaneous rhizotomy (PR), and Gamma Knife stereotactic radiosurgery (GK-SRS), and are typically reserved for participants deemed “ medically refractory ” [ 18 ]. However, there is no consensus as to the number of failed medical treatments required before surgical referral. Although some guidelines state that up to three groups of medications be trialed [ 18 ], some experts suggest that participants failing first-line medical therapy are unlikely to respond to other medications and should be referred for surgery earlier [ 15 , 17 ]. Furthermore, pain becomes increasingly intractable with disease duration [ 15 ], and there is evidence that participants refractory to medical therapy prefer earlier surgery [ 19 ]. Accordingly, there is a need for further evaluation of the potential benefits of early surgery. Developed in 1951, GK-SRS uses radioactive cobalt-60 isotope sources to produce converging radiation beams intersecting a target volume and was ultimately adapted for treating TN[ 20 ]. The least invasive neurosurgical approach to TN, GK-SRS is entirely non-invasive other than the use of stereotactic headframe immobilization [ 21 ]. In a single session, GK-SRS delivers a highly concentrated dose of ionizing radiation to a precise treatment target along the trigeminal nerve (typically the mid-cisternal segment at 70–90 Gy) with minimal irradiation of surrounding normal healthy tissues beyond the treatment margins [ 22 ], and no need to stop anticoagulation in participants requiring it [ 23 ]. Tuleasca et al. [ 3 ] summarized evidence in support of GK-SRS across 45 studies (5687 participants), by way of a systematic review and meta-analysis reporting freedom from pain (FFP), time to pain relief (TTPR), recurrence rates, time to recurrence, and presence of hypesthesia or other complications. Mean FFP outcome with or without medication adjustment was 84.8% and mean FFP outcome without the need for medication entirely was 53.1%, with TTPR ranging from 15–78 days. Mean pain recurrence rate was 24.6%, occurring between 7.5–20.4 months. Additionally, the maintenance of pain relief at 7 and 10 years was noteworthy in five studies, ranging between 22% and 59.7% (7 years) and 30% and 45.3% (10 years). Incidence of facial sensory dysfunction (i.e., hypesthesia) is the most significant complication of GK-SRS (21.7%), occurring between 6 to 36 months. However, the development of bothersome or very bothersome hypesthesia occurred in only a tiny proportion of participants (0%-17.3% mean = 3.1%). Other rare side effects included dry eye, deafferentation pain, and keratitis. In 27/45 GK-SRS studies, there were no reported side effects at all [ 3 ]. In addition, post GK-SRS associated malignancies are rare, with a cumulative incidence of 0.00045% over 10 years [ 24 ]. It is pertinent to consider that the number needed to harm (NNH) for the most significant complication of GK-SRS (hypesthesia) is approximately 4.7 [ 25 ], compared to approximately 2.6 for at least one adverse effect of CBZ[ 8 ]. There remains a notable gap in the literature exploring very early GK-SRS. Of particular importance, of the 45 studies reviewed by Tuleasca et al. [ 3 ], only one retrospective study analyzed GK-SRS when used exclusively as the primary surgical treatment in TN [ 26 ]. Mousavi et al. [ 26 ] reported initial pain relief in 88% of participants, with earlier GK-SRS treatment within 3 years of pain onset resulting in earlier pain relief (median 1 week) compared to 6 weeks for participants with TN > 3 years. Longer duration of adequate pain control was also seen in a larger percentage of participants whose pain history was < 3 years (1 year 93%, 10 years 73%) compared to participants with a longer pre-operative pain history (1 year 63%, 10 years 28%). Moreover, a longer interval of pain relief without medication (89% at 3 years) was seen in a greater proportion of participants with a history of pain 3-year history of pain (52% at 3 years). Participants with a history of pain for > 3 years prior to GK-SRS had an 8% likelihood of being pain-free without medication by year 5 and 0% at year 10, compared to 73% and 40%, respectively in participants with pain < 3 years [ 26 ]. In line with these data, a recent international multicenter study proposed consideration of earlier radiosurgery (within 4 years of diagnosis), finding a shorter interval to pain relief and significant decreases in medication utilization for participants treated within this time-frame [ 27 ]. Taken together, these findings point to the potential of early GK-SRS to provide faster and more durable medication-free pain relief with a very low rate of adverse side effects. What is not known is whether ultra-early intervention with GK-SRS—before the actual development of medical-refractoriness (however that is defined)—may alter the natural progression of TN, avoiding the need for long term high-dose medical therapy with its associated side effects. In this study, we aim to evaluate the feasibility and potential benefit of GK-SRS as an ultra-early treatment option for TN. We hypothesize that ultra-early GK-SRS will: (1) provide more durable pain relief compared to ongoing best medical management (2) reduce or eliminate the need for high-dose medical therapy (3) have a lower rate of adverse effects compared to best medical management Objectives {7} To assess the efficacy of ultra-early (i.e., prior to medical-refractoriness) GK-SRS as a treatment for TN compared to standard best medical management. Trial design {8} This is a single-centre, two-arm, parallel group design, pragmatic, noninferiority, phase II, randomized controlled trial of ultra-early GK-SRS for TN in participants treated prior to developing a medically-refractory state and within 2 years of diagnosed TN per study neurologist. Two parallel cohorts will be studied: 1) participants treated with GK-SRS (intervention arm/treatment group); and 2) participants treated with ongoing best medical management (non-intervention/control group). Crossover will be allowed from the non-intervention arm to the intervention arm. An intention-to-treat analysis will be carried out. Methods: Participants, interventions and outcomes Study setting {9} The primary location of the intervention is the Brown & Scott Families Advanced Imaging and Gamma Knife Centre at the University of Alberta Hospital, Edmonton, Alberta, Canada. Eligibility criteria {10} Inclusion Criteria: Age ≥ 18 years Clinical diagnosis of classical or idiopathic TN [ 1 ], based on clinical history and MRI scan Onset of pain within 2 years prior to enrolment Not deemed medically-refractory (defined as suboptimal pain control despite ≥ 2 medication trials of adequate dose) If currently on medication, on stable dose for at least 3 months Exclusion Criteria: Secondary TN Bilateral TN Any contraindication to GK-SRS Any prior cranial radiation Any prior surgical intervention for TN History of new psychiatric diagnoses within 2 years of study participation, or uncontrolled, concurrent psychiatric illness (e.g., depression with recent suicide attempts) Females who are pregnant or breast-feeding Who will take informed consent? {26a} Investigators will ensure all study aspects are thoroughly discussed with potential participants, including accessing electronic health records (to assess eligibility) and all potential risks and benefits prior to enrolment. Participants will have the opportunity to ask questions at any stage of enrolment. Written informed consent for access to health care records and consent to contact will be obtained by the referring physician. Following the determination of eligibility, written consent will be obtained by a study coordinator or team physician (other than the participant's treating physician) to ensure that there is no undue pressure on potential participants to agree to the study at the time of enrolment. Participants will state their complete understanding of risks, benefits, intervention details, and ability to withdraw their consent at any time without compromising the quality of their treatment. A written informed consent form (ICF) will be obtained for each participant, signed and dated by the participant and the study team member who conducted the informed consent procedure. Additional consent provisions for collection and use of participant data and biological specimens {26b} Not applicable. The process of collecting biological specimens will not be carried out for this research. Interventions Explanation for the choice of comparators {6b} The intervention group receiving GK-SRS will be compared to a non-intervention/control group treated with current standard of care medical therapy. Among these, carbamazepine and oxcarbazepine are the most commonly prescribed due to their established efficacy in managing symptoms of TN. Intervention description {11a} Intervention Arm: GK-SRS treatment will be carried out to the mid-cisternal segment of the trigeminal nerve ipsilateral to the affected side of the face. Under local anaesthesia, a Leksell stereotactic head frame will fixed to the patient’s head to allow for complete cranial immobilization during treatment. The mid-cisternal segment will be treated using a single 4 mm isocenter. A dose of 40 Gy (maximum point dose 80 Gy) will be administered to the 50% isodose line while limiting the brainstem dose to 12 Gy [3]. Non-intervention/Control Arm: Participants allocated to the non-intervention/control arm will continue medical management per the judgment of their treating physician (see 11b). Criteria for discontinuing or modifying allocated interventions {11b} For the GK-SRS intervention arm, the intervention is a single surgical procedure occurring on a single day. It is possible that the treatment may need to be halted prematurely due to patient discomfort or technical issues, though this would be a very rare event. In the event that GK-SRS treatment needs to be stopped prematurely, it will be allowed to be completed at a later date, per usual practice. Two neurologist members of the study team (MWH and MK) with expertise in the medical management of TN will manage medication use in all enrolled participants across both groups. Where appropriate, medication dosage will be modified as necessary, depending on whether the patient's condition improves or worsens. These adjustments will be made at the discretion of the treating neurologist, who will carefully evaluate the patient's response to the treatment and any request for modifications (including weaning off medications). Strategies to improve adherence to interventions {11c} Given GK-SRS is a one-time intervention, “adherence to interventions” applies only to medication management, study visits, and performance surveillance labs in both the intervention arm and the non-intervention/control arm. To improve adherence to the intervention protocol, at each follow-up visit (6, 12, 24 months and 5 years), participants will be asked by the study team of any changes to their medication, additional surgical procedures, or non-surgical treatments for TN. A medication diary will be requested to improve adherence to medical therapy for both the intervention arm and the non-intervention/control arms. Relevant concomitant care permitted or prohibited during the trial {11d} Participants allocated to the intervention arm will receive ongoing medical management tailored to their specific needs, as determined by the clinical judgment of the treating neurologist. Participants may receive other medications as required. Crossover will be permitted from the non-intervention/control arm to the intervention arm at any time. Provisions for post-trial care {30} In accordance with the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans (TCPS 2), if a participant is harmed as a result of participating in this trial, the research team and the University of Alberta will ensure access to appropriate care and support, including follow-up care where warranted. Post-trial access to care or interventions shown to be beneficial during the study may be provided where feasible and ethically appropriate. At the conclusion of the trial, all enrolled participants will be given the option of continuing ongoing care by the neurologist who managed their medications during the trial. Outcomes {12} The primary endpoint is satisfactory pain control at 2 years after GK-SRS treatment (for intervention arm) or 2 years after enrolment in the non-intervention/control arm, measured using Barrow Neurological Institute Pain Intensity Score (BNI) (satisfactory pain control = BNI I, II, IIIa) [28]. Secondary endpoints include: Worst incidence of treatment-related adverse events by intervention arm. Adverse events will be determined using the International Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 [29] at 6, 12, 24 months, and 5 years after the day of GK-SRS treatment, for participants in the intervention arm and at 6, 12, 24 months, and 5 years after enrolment, for participants in the non-intervention/control arm. Pain medication equivalent dose measured with the Medication Quantification Scale version III (MQS III) [30]. Intervention arm: Baseline visit; GK-SRS treatment visit; follow-up visits 6, 12, 24 months, and 5 years after day of GK-SRS treatment. Non-intervention/control arm: Baseline visit; follow-up visits 6, 12, 24 months, and 5 years after enrolment. Score of BNI I 2 years after the day of GK-SRS treatment. Proportion of participants with satisfactory pain control at long-term: those participants classified as BNI I-IIIa 5 years after day of GK-SRS treatment, or 5 years after enrolment in the non-intervention/control arm. Presence and severity of facial numbness in the intervention arm after GK-SRS treatment measured using the Barrow Neurological Institute Facial Numbness Scale [28] at 6, 12, 24 months, and 5 years after GK-SRS treatment. Number of participants crossing over from non-intervention/control arm to intervention arm during follow up period at 6, 12, 24 months, and 5 years after enrolment. Number of participants in GK-SRS arm referred for repeat surgery at 6, 12, 24 months, and 5 years after GK-SRS treatment. Patient-rated pain severity (0-100) measured with the Visual Analogue Scale (VAS) [31]. Intervention arm: Baseline visit; GK-SRS treatment visit; follow-up visits 6, 12, 24 months, and 5 years after day of GK-SRS treatment. Non-intervention/control arm: Baseline visit; follow-up visits 6, 12, 24 months, and 5 years after enrolment. Brief Pain Inventory-Facial (BPI-Facial) [32] to evaluate three additional pain domains: intensity, interference in general activities, and interference in face-specific activities. Baseline visit; GK-SRS treatment visit; follow-up visits 6, 12, 24 months, and 5 years after day of GK-SRS treatment. Non-intervention/control arm: Baseline visit; follow-up visits 6, 12, 24 months, and 5 years after enrolment. Psychological status measured using the Hospital Anxiety and Depression Scale (HADS) [33] and Pain Catastrophizing Scale (PCS) [34]. Baseline visit; GK-SRS treatment visit; follow-up visits 6, 12, 24 months, and 5 years after day of GK-SRS treatment. Non-intervention/control arm: Baseline visit; follow-up visits 6, 12, 24 months, and 5 years after enrolment. Quality of life measured using the Short Form Health Survey (SF-36 v2) [35]. Baseline visit; follow-up visits 6, 12, 24 months, and 5 years after day of GK-SRS treatment. Non-intervention/control arm: Baseline visit; follow-up visits 6, 12, 24 months, and 5 years after enrolment. Participant timeline {13} Participant timelines are summarized in figures 1 (SPIRIT figure) and 2 (flowchart). Sample size {14} The sample size is estimated based on the primary outcome over 2 years using a non-inferiority design for two proportions, i.e., the proportion of participants with satisfactory pain control at 2 years (BNI I-IIIa). We aim to detect a difference of 10% satisfactory pain control between the 2 groups, i.e., over 2 years the GK-SRS group would have a proportion of satisfactory pain control not lower than the medical therapy by 10%. We aim for 80% power and a 0.05 significance level for detecting the aforementioned difference. Using a 35% failure rate for medical therapy over 2 years, a 7% failure rate for GK-SRS at 1 year, and an 11% failure rate at 3 years for GK-SRS [26,37], the required sample size ranges from 32 to 47 participants per group, with 40 being a practical recommendation. Recruitment {15} Outreach is occurring to the local population of referring physicians. The study team includes individuals who are heavily involved in the surgical treatment and medical management of TN and are aware of other practitioners within the catchment area. Study information flyers will be distributed via email (e.g., Alberta College of Family Physicians, Alberta Dental Association, Canadian Headache Society, Trigeminal Neuralgia Association of Canada, and TN facial pain groups) to family physicians, neurologists, dentists/oral pain specialists within the catchment area. The intention of the flyers is to inform potential referring clinicians so that they can identify potentially eligible participants for further evaluation by the study team. Flyers may also be made available via email newsletters and/or social media outlets. Additionally, in-person outreach (flyer distribution) will be carried out in the Urgent Neurology Clinic at the primary institution. Assignment of interventions: allocation Sequence generation {16a} To minimize bias, participants will be allocated by blocked randomization, on a 1:1 basis, to either the non-intervention/control or intervention arm via the National Institute of Health (NIH) Clinical Trial Randomization Tool [38]. Concealment mechanism {16b} To ensure allocation concealment, we will implement the following procedures: A study coordinator or team physician will log into the NIH Clinical Trial Randomization Tool to input participant information. The NIH Clinical Trial Randomization Tool will randomly assign participants to either group in a 1:1 ratio. After inputting all required baseline information, a unique profile for each patient will be generated. Access to these data will be restricted to an authorized third party. Implementation {16c} A study coordinator or team physician will enroll eligible participants. The NIH Clinical Trial Randomization Tool will randomly assign participants to either group in a 1:1 ratio. Per the NIH Clinical Trial Randomization Tool requirements, all essential researchers will not have access to the output. Access to the output sequence will be restricted to a study coordinator who will reveal each successive trial participants allocation, following consent and acceptance into the trial. Assignment of interventions: Blinding Who will be blinded {17a} This trial will, by definition, be non-blinded due to the nature of the head frame application in the intervention arm where participants will be treated with GK-SRS, and by administration of medication and performance surveillance labs for the non-intervention/control group. However, team members (i.e., statistician) will remain blinded to the group assignment of individual participants. Procedure for unblinding if needed {17b} Not applicable. Data collection and management Plans for assessment and collection of outcomes {18a} Efficacy Assessments: Assessment of Pain: At each time point, pain-related outcome variables will be assessed by: (1) pain relief status (BNI I-IIIa = response, BNI IIIb-V = non-response) using the BNI score (I - no pain, no medication; II - occasional pain, no medication required; III - some pain, adequately controlled with medication; IIIa - no pain, continued medication; IIIb - persistent pain, controlled with medication; IV - some pain, not adequately controlled with medications; V - severe pain or no pain relief). (2) patient-rated pain severity (0-100) using the VAS. (3) BPI-Facial to evaluate three additional pain domains: intensity, interference in general activities, and interference in face-specific activities. Assessment of Medication: At each time point, medication-related outcome variables will be quantitatively assessed for drug class, dosage, and detriment (risk) using the MQS III, which provides a single numeric value for all patient’s pain medication profiles. Safety and Other Assessments Assessment of Adverse Events : Adverse events will be assessed, if necessary, using the CTCAE, version 5.0. History and physical examination: A routine neurological examination will be performed by a neurologist on our study team at initial screening, and on an as needed basis during follow-up per standard of care in TN management. Psychological Assessments: At each time point, we will assess psychological status using the HADS and PCS. Both measures are widely used in clinical applications, have strong psychometric properties, low patient burden, and have proven valid and reliable. Other Assessments: (1) Bothersome facial numbness will be assessed using the BNI facial numbness scale ( I= no facial numbness; II= mild facial numbness that is not bothersome; III= somewhat bothersome facial numbness; IV= very bothersome facial numbness). (2) Quality of life will be assessed via the SF-36 v2. Plans to promote participant retention and complete follow-up {18b} All consenting and enrolled participants will receive comprehensive information regarding the potential risks and benefits of the study. Investigators will stress the importance of follow-up with each enrolled participant. To simplify this process and facilitate data collection, follow-up assessments can be conducted via telephone if desired. Participants have the right to withdraw from the study at any time. Additionally, investigators may decide to withdraw participants for reasons related to safety, behavior, or non-compliance. If a participant withdraws their participation or consent, no further assessments will be conducted and no additional data will be collected. Data management {19} The electronic Research Electronic Data Capture system ‘REDCap’ [39] will be used in this trial. Study data will be collected and managed using REDCap electronic data capture tools hosted at the University of Alberta. REDCap is a secure, web-based software platform designed to support data capture for research studies, providing 1) an intuitive interface for validated data capture; 2) audit trails for tracking data manipulation and export procedures; 3) automated export procedures for seamless data downloads to common statistical packages; and 4) procedures for data integration and interoperability with external sources [39]. Independent case report forms (CRFs) will be completed for each eligible and consented participant. Data will be entered and maintained by a study coordinator. Any changes made to CRFs will not obscure the original entry. All changes will be dated, initialled, and explained as necessary. Confidentiality {27} Each patient will be assigned a unique sequential identification number upon registration. This identification number will be crucial for tracking each patient throughout the study and will be included on all CRFs used in the trial. To ensure the confidentiality of personal information, no other identifiable data regarding the patient will be included on these CRFs. To further safeguard sensitive information, the patient's health care number, which will be linked to their identification number, will be maintained in a secure, password-protected master file. Access to this file will be restricted solely to authorized members of the study team, ensuring that patient privacy is upheld throughout the duration of the trial. This structured approach is designed to prioritize both the integrity of the trial and the confidentiality of patient information. Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33} Not applicable. This trial does not intend to collect, assess, or store biological specimens for the purpose of genetic or molecular analysis. Statistical methods Statistical methods for primary and secondary outcomes {20a} General approach All analyses will follow the intention-to-treat principle. For binary outcomes, a Chi-square or Fisher’s exact test will be used, as appropriate. If covariate imbalance is observed between the two groups (i.e., standardized mean difference > 0.1), multivariable regression models adjusting for those covariates will be applied. For outcomes measured at multiple time points, longitudinal mixed-effects models will be used. Analysis of the primary efficacy endpoint(s) The primary outcome - satisfactory pain control at 2 years - is binary. A Chi-square or Fisher’s exact test will be applied, as appropriate. If covariates are unbalanced between the two groups, a multivariable logistic regression model will be used to adjust for these factors. In the case of substantial loss to follow-up at 2 years that could compromise the intention-to-treat principle, an additional longitudinal logistic mixed-effects model incorporating all time points will be employed. Analysis of the secondary endpoint(s) For binary and categorical secondary outcomes (endpoints III, and IV), a Chi-square or Fisher’s exact test will be used. Longitudinal mixed-effects models will be used for outcomes measured at multiple time points (endpoint I, II, VIII, IX, X, XI). Proportions with 95% confidence intervals will be reported among the intervention group for secondary endpoints V, VI, and VII. Interim analyses {21b} An interim analysis is not planned nor required per institutional policy, as the study is considered low risk. Methods for additional analyses (e.g. subgroup analyses) {20b} If there is an imbalance between the two groups regarding the distribution of characteristics associated with the outcomes of interest, multivariable models will be employed to adjust for potential confounding. Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c} Appropriate efforts will be employed to minimize the lost to follow-up rate, especially the measurement of the primary efficacy outcome, i.e., satisfactory pain control at 2 years (BNI I-IIIa). All study participants including lost to follow-up individuals will be included analyses to maintain the intention-to-treat principle. When the lost to follow-up rate is substantial, longitudinal data models, generalized estimating equations (GEE), or a mixed-effect model will also be employed. Plans to give access to the full protocol, participant level-data and statistical code {31c} The primary investigator grant access to full protocol upon reasonable request. Oversight and monitoring Composition of the coordinating centre and trial steering committee {5d} Since the trial has been classified as low risk according to the University of Alberta’s Health Research Ethics Board requirements, it is not subject to regulation and does not require a steering committee. Composition of the data monitoring committee, its role and reporting structure {21a} Since this is a low-risk trial, a Data and Safety Monitoring Board (DSMB) is not required. A study coordinator will maintain comprehensive and accurate source records that serve as the basis of CRFs. These records will include all relevant data and documentation related to the study. A study coordinator will provide direct access to all pertinent documents, enabling thorough oversight and verification of the study's progress and compliance with regulatory requirements. Adverse event reporting and harms {22} Adverse events (AEs) and serious adverse events (SAEs) will be evaluated and monitored by the Principal Investigator until the patient is considered stable based on the resolution of these events. AEs and SAEs that occur following the initiation of the intervention will be reported using the International Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 [29], and recorded in the relevant REDCap database. In the case of SAEs, the principal investigator will be informed within 24 hours, and the incidents will be reported to the appropriate regulatory bodies and research ethics boards. Frequency and plans for auditing trial conduct {23} Since the trial has been classified as low risk according to the University of Alberta’s Health Research Ethics Board requirements, it is not subject to regulation and does not require auditing procedures. Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25} A member of the study team will submit reports, updates, and other information to the research ethics board, such as expedited safety reports, amendments, and administrative letters, in accordance with regulatory requirements and institutional procedures. Dissemination plans {31a} The results of the trial will be documented in a manuscript to be submitted to a peer reviewed scientific journal in the field of chronic pain, headache neurology, or neurosurgery for publication. The authorship of the resulting manuscript will include the Principal Investigator as senior author, along with all co-investigators as co-authors. Additional individuals may be added to the co-author list depending on their contributions (e.g., individuals providing additional assistance with data analysis). Discussion If GK-SRS, implemented as a first-line treatment for TN, proves safe and effective, then this trial may initiate a paradigm shift in TN management, wherein early surgical treatment with GK-SRS is accepted as a viable alternative to medical therapy. Clinically, these findings will translate to less ambiguity in optimal time to surgical referral and an increased willingness to refer participants for earlier surgery. As a result, TN treatment guidelines may adopt firmer recommendations for earlier surgical treatment, enabling both clinicians and participants with more informed decision-making potential. Importantly, generating evidence in favour of GK-SRS as a viable first-line treatment option may mitigate potentially detrimental repercussions of prolonged disease duration on pain chronification and overall detriment to quality of life with prolonged, inadequate medical management. Limitations The proposed study has important limitations. First, due to the necessity of cranial immobilization in GK-SRS, blinding the investigators and participants to treatment allocation is not feasible, which may introduce bias and compromise the validity of our results. However, carrying out a sham surgery could expose patients to unnecessary risk. Second, our study is limited to clinical diagnoses of classical and idiopathic TN, which may affect generalizability to those with secondary TN. Trial status Protocol Version Number: SRS-0301 Recruitment Start Date: August 15, 2025 Estimated Recruitment End Date: May 1, 2029 Abbreviations AAN American Academy of Neurology AEs Adverse events BNI Barrow Neurological Institute Pain Intensity Score BPI-Facial Brief Pain Inventory-Facial CBZ Carbamazepine CTCAE Common Terminology Criteria for Adverse Events CNV Cranial nerve five CRFs Case Report Form DSMB Data and Safety Monitoring Board EFNS European Federation of Neurological Societies FFP Freedom from pain GK-SRS Gamma Knife stereotactic radiosurgery GEE Generalized estimating equations HADS Hospital Anxiety and Depression Scale ICF Informed Consent Form ICHD International Classification of Headache Disorders MQS III Medication Quantification Scale version III MS Multiple sclerosis MVD Microvascular decompression NIH National Institute of Health NNH Number needed to harm OXC Oxcarbazepine PCS Pain Catastrophizing Scale PR Percutaneous rhizotomy REDCap Research Electronic Data Capture REB Research Ethics Board SAEs Serious adverse events SF-36 v2 Short Form Health Survey TTPR Time to pain relief TN Trigeminal neuralgia VAS Visual Analogue Scale Declarations Acknowledgements Not applicable. Authors’ contributions {31b} TS is the principal investigator; he conceived the study and contributed to the development of the study protocol and manuscript. AL contributed to the development of the study protocol, and wrote the first draft of the manuscript. SP, WH, MW, and GB contributed to the methodology, review, and editing of the study protocol and manuscript. NKV provided statistical and data analysis input, and reviewed the manuscript draft. All authors read and approved the final study protocol and manuscript. All authors will contribute to study execution. Funding {4} At this time, this research has not received any specific grant funding from agencies in the public, commercial, or not-for-profit sectors. Availability of data and materials {29} The final dataset will be accessible only to the research team members listed on the title page of the current protocol, Research Ethics Board (REB) officials, and University of Alberta auditors upon request. If third parties request access to the collected data, informed consent must first be obtained from all participants. Only de-identified data will be provided to third parties. Data will be stored for a minimum of 15 years after the study is completed. After 15 years, all paper documents will be securely destroyed in accordance with the University of Alberta's guidelines. Ethics approval and consent to participate {24} This study has been approved by the University of Alberta’s Health Research Ethics Board – Biomedical Panel (IRB00000927, FWA00000077). Written, informed consent to participate will be obtained from all participants. Consent for publication {32} Not applicable. Competing interests {28} All authors declare that they have no competing interests. References Olesen J, Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition, Asbtracts. CEPHALALGIA. 2018;38(1):1-211. Koopman JS, Dieleman JP, Huygen FJ, de Mos M, Martin CG, Sturkenboom MC. Incidence of facial pain in the general population. Pain. 2009;147(1–3):122–7. Tuleasca C, Regis J, Sahgal A, De Salles A, Hayashi M, Ma L, et al. Stereotactic radiosurgery for trigeminal neuralgia: a systematic review. J Neurosurg. 2019;130(3):733–57. Jannetta PJ. Trigeminal Neuralgia. Oxford University Press; 2011. Maarbjerg S, Di Stefano G, Bendtsen L, Cruccu G. Trigeminal neuralgia - diagnosis and treatment. Cephalalgia. 2017;37(7):648–57. Simpson D, McArthur J, Dworkin R. Neuropathic pain: mechanisms, diagnosis and treatment. Oxford University Press; 2012. Cruccu G, Finnerup NB, Jensen TS, Scholz J, Sindou M, Svensson P, et al. Trigeminal neuralgia: New classification and diagnostic grading for practice and research. Neurology. 2016;87(2):220–8. Wiffen PJ, Derry S, Moore RA, McQuay HJ. Carbamazepine for acute and chronic pain in adults. Cochrane Database Syst Rev. 2011(1):Cd005451. Benoliel R, Zini A, Khan J, Almoznino G, Sharav Y, Haviv Y. Trigeminal neuralgia (part II): Factors affecting early pharmacotherapeutic outcome. Cephalalgia. 2016;36(8):747–59. Di Stefano G, La Cesa S, Truini A, Cruccu G. Natural history and outcome of 200 outpatients with classical trigeminal neuralgia treated with carbamazepine or oxcarbazepine in a tertiary centre for neuropathic pain. J Headache Pain. 2014;15(1):34. Besi E, Boniface DR, Cregg R, Zakrzewska JM. Comparison of tolerability and adverse symptoms in oxcarbazepine and carbamazepine in the treatment of trigeminal neuralgia and neuralgiform headaches using the Liverpool Adverse Events Profile (AEP). J Headache Pain. 2015;16:563. Di Stefano G, De Stefano G, Leone C, Di Lionardo A, Di Pietro G, Sgro E, et al. Real-world effectiveness and tolerability of carbamazepine and oxcarbazepine in 354 patients with trigeminal neuralgia. Eur J Pain. 2021;25(5):1064–71. Tangamornsuksan W, Chaiyakunapruk N, Somkrua R, Lohitnavy M, Tassaneeyakul W. Relationship between the HLA-B*1502 allele and carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis: a systematic review and meta-analysis. JAMA Dermatol. 2013;149(9):1025–32. Gomez-Arguelles JM, Dorado R, Sepulveda JM, Herrera A, Arrojo FG, Aragón E, et al. Oxcarbazepine monotherapy in carbamazepine-unresponsive trigeminal neuralgia. J Clin Neurosci. 2008;15(5):516–9. Zakrzewska JM, Patsalos PN. Long-term cohort study comparing medical (oxcarbazepine) and surgical management of intractable trigeminal neuralgia. Pain. 2002;95(3):259–66. Taylor JC, Brauer S, Espir ML. Long-term treatment of trigeminal neuralgia with carbamazepine. Postgrad Med J. 1981;57(663):16–8. Gronseth G, Cruccu G, Alksne J, Argoff C, Brainin M, Burchiel K, et al. Practice parameter: the diagnostic evaluation and treatment of trigeminal neuralgia (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the European Federation of Neurological Societies. Neurology. 2008;71(15):1183–90. Lambru G, Zakrzewska J, Matharu M. Trigeminal neuralgia: A practical guide. Pract Neurol. 2021;21(5):392–402. Bendtsen L, Maarbjerg S, Leal PRL, May A, Nurmikko T, Obermann M, et al. European Academy of Neurology guideline on trigeminal neuralgia. Eur J Neurol. 2019;26(6):831–49. Chong MS, Bahra A, Zakrzewska JM. Guidelines for the management of trigeminal neuralgia. Cleve Clin J Med. 2023;90(6):355–62. Leksell L. Sterotaxic radiosurgery in trigeminal neuralgia. Acta Chir Scand. 1971;137(4):311–4. Chen JC, Girvigian MR. Stereotactic radiosurgery: instrumentation and theoretical aspects-part 1. Perm J. 2005;9(4):23–6. Petit JH, Herman JM, Nagda S, DiBiase SJ, Chin LS. Radiosurgical treatment of trigeminal neuralgia: evaluating quality of life and treatment outcomes. Int J Radiat Oncol Biol Phys. 2003;56(4):1147–53. Wolf A, Naylor K, Tam M, Habibi A, Novotny J, Liščák R, et al. Risk of radiation-associated intracranial malignancy after stereotactic radiosurgery: a retrospective, multicentre, cohort study. Lancet Oncol. 2019;20(1):159–64. Régis J, Tuleasca C, Resseguier N, Carron R, Donnet A, Gaudart J, et al. Long-term safety and efficacy of Gamma Knife surgery in classical trigeminal neuralgia: a 497-patient historical cohort study. J Neurosurg. 2016;124(4):1079–87. Mousavi SH, Niranjan A, Huang MJ, Laghari FJ, Shin SS, Mindlin JL, et al. Early radiosurgery provides superior pain relief for trigeminal neuralgia patients. Neurology. 2015;85(24):2159–65. Mureb M, Golub D, Benjamin C, Gurewitz J, Strickland BA, Zada G, et al. Earlier radiosurgery leads to better pain relief and less medication usage for trigeminal neuralgia patients: an international multicenter study. J Neurosurg. 2021;135(1):237–44. Rogers CL, Shetter AG, Fiedler JA, Smith KA, Han PP, Speiser BL. Gamma knife radiosurgery for trigeminal neuralgia: the initial experience of The Barrow Neurological Institute. Int J Radiat Oncol Biol Phys. 2000;47(4):1013–9. National Institutes of Health NCI. Common Terminology Criteria for Adverse Events (CTCAE) v 5.0. 2017. Harden RN, Weinland SR, Remble TA, Houle TT, Colio S, Steedman S, et al. Medication Quantification Scale Version III: update in medication classes and revised detriment weights by survey of American Pain Society Physicians. J Pain. 2005;6(6):364–71. Hawker GA, Mian S, Kendzerska T, French M. Measures of adult pain: Visual Analog Scale for Pain (VAS Pain), Numeric Rating Scale for Pain (NRS Pain), McGill Pain Questionnaire (MPQ), Short-Form McGill Pain Questionnaire (SF-MPQ), Chronic Pain Grade Scale (CPGS), Short Form-36 Bodily Pain Scale (SF-36 BPS), and Measure of Intermittent and Constant Osteoarthritis Pain (ICOAP). Arthritis Care Res (Hoboken). 2011;63(Suppl 11):S240–52. Keller S, Bann CM, Dodd SL, Schein J, Mendoza TR, Cleeland CS. Validity of the brief pain inventory for use in documenting the outcomes of patients with noncancer pain. Clin J Pain. 2004;20(5):309–18. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 1983;67(6):361–70. Sullivan MJL, Bishop SR, Pivik J. The Pain Catastrophizing Scale: Development and validation. Psychol Assess. 1995;7(4):524–32. Ware JE, Kosinski M, Bjorner JB, Turner-Bowker D, Gandek B, Maruish ME. SF-36v2 Health Survey: Administration Guide for Clinical Trial Investigators. QualityMetric, Incorporated; 2008. Chan A-W, Boutron I, Hopewell S, Moher D, Schulz K. SPIRIT 2025 statement: updated guideline for protocols of randomised trials. BMJ. 2025;389:e081477. Heinskou T, Maarbjerg S, Rochat P, Wolfram F, Jensen RH, Bendtsen L. Trigeminal neuralgia–a coherent cross-specialty management program. J Headache Pain. 2015;16:66. Tool CTR. The National Cancer Institue’s Divison of Cancer Prevention. Accessed 19 Jun. 2025. Harris P, Taylor R, Payne J, Gonzalez J, Conde. Research electronic data capture (REDCap) - A metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inf. 2009;42:377–81. Cite Share Download PDF Status: Published Journal Publication published 04 Dec, 2025 Read the published version in Trials → Version 1 posted Editorial decision: Minor revision 08 Oct, 2025 Reviewers agreed at journal 07 Sep, 2025 Reviewers invited by journal 05 Sep, 2025 Editor assigned by journal 22 Aug, 2025 First submitted to journal 20 Aug, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7341323","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":510840372,"identity":"4fc7b9d2-ef16-4bb1-b56a-6f289a696882","order_by":0,"name":"Amanda Lussoso","email":"","orcid":"","institution":"University of Alberta","correspondingAuthor":false,"prefix":"","firstName":"Amanda","middleName":"","lastName":"Lussoso","suffix":""},{"id":510840373,"identity":"62000806-e900-4d78-8472-97855bc0fcad","order_by":1,"name":"Samir Patel","email":"","orcid":"","institution":"University of Alberta","correspondingAuthor":false,"prefix":"","firstName":"Samir","middleName":"","lastName":"Patel","suffix":""},{"id":510840374,"identity":"f2a3d40c-192e-4173-9187-d4ae5c2869f6","order_by":2,"name":"Wasif Hussain","email":"","orcid":"","institution":"University of Alberta","correspondingAuthor":false,"prefix":"","firstName":"Wasif","middleName":"","lastName":"Hussain","suffix":""},{"id":510840375,"identity":"ffd6786c-c1ad-4ca1-9e06-940a8c4d64a0","order_by":3,"name":"Michael Knash","email":"","orcid":"","institution":"University of Alberta","correspondingAuthor":false,"prefix":"","firstName":"Michael","middleName":"","lastName":"Knash","suffix":""},{"id":510840376,"identity":"4bdff386-86af-4046-98f5-f8f84274e7e8","order_by":4,"name":"Gregory Bowden","email":"","orcid":"","institution":"University of Alberta","correspondingAuthor":false,"prefix":"","firstName":"Gregory","middleName":"","lastName":"Bowden","suffix":""},{"id":510840377,"identity":"c4837113-4c26-448a-9ae9-cc8838a118d1","order_by":5,"name":"Matt Wheatley","email":"","orcid":"","institution":"University of Alberta","correspondingAuthor":false,"prefix":"","firstName":"Matt","middleName":"","lastName":"Wheatley","suffix":""},{"id":510840378,"identity":"762a8d70-4e2d-4941-89dd-0f51b2f293f6","order_by":6,"name":"Ngoc Khanh Vu","email":"","orcid":"","institution":"University of Alberta","correspondingAuthor":false,"prefix":"","firstName":"Ngoc","middleName":"Khanh","lastName":"Vu","suffix":""},{"id":510840379,"identity":"ac3f38a0-167f-406a-80ae-331c86ebd5c4","order_by":7,"name":"Tejas Sankar","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA4klEQVRIiWNgGAWjYJACxgYGBjkGBuY24pTzQLUYAymQFgPitSQ2EK3Fnv/ws4czau6lbzh+sO3Bxz1/5BnYDz/Ab4tEmrnhhmPFuRvOJLYbznhmYNjAk4bfKh4JBjPJB2wJuRsOJLZJ8xwwYGyQIOA6Hv7j3yQf/EtINzj/sE36zwED+wYJ9g/4tTDkmElubEtIMLgBtIXhgEFigwQPAVtu5JRJzuxLMJx542G7Yc8B4+Q2npwCvFrY+49vk+z5liDPdz752IMfB+Rs+9mPb8CrBROwkah+FIyCUTAKRgEWAAB8DEgpR4Hm/gAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-8821-7049","institution":"University of Alberta","correspondingAuthor":true,"prefix":"","firstName":"Tejas","middleName":"","lastName":"Sankar","suffix":""}],"badges":[],"createdAt":"2025-08-11 01:13:50","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7341323/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7341323/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13063-025-09321-8","type":"published","date":"2025-12-04T15:57:40+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":91108742,"identity":"5edf0c14-5ff2-460a-8a5e-c737dba6aa41","added_by":"auto","created_at":"2025-09-11 15:58:47","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":39701,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSPIRIT Figure \u003c/strong\u003e[36].\u003c/p\u003e\n\u003cp\u003eParticipant timeline: Schedule of enrolment, intervention, and assessments.\u003c/p\u003e\n\u003cp\u003eBNI = Barrow Neurological Institute Pain Intensity Score; BNI Facial Numbness Scale = Barrow Neurological Institute Facial Numbness Scale; BPI-Facial = Brief Pain Inventory-Facial; VAS = Visual Analogue Scale; MQS-III = Medication Quantification Scale version III; HADS = Hospital Anxiety and Depression Scale; PCS = Pain Catastrophizing Scale; SF-36 v2 = Short Form Health Survey, version 2.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7341323/v1/b13d61a36e6eef413284670b.png"},{"id":91108743,"identity":"52edbe5b-781c-4c83-8ae6-14a0c389324f","added_by":"auto","created_at":"2025-09-11 15:58:47","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":78757,"visible":true,"origin":"","legend":"\u003cp\u003eSchematic flowchart representation of study design.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7341323/v1/4f0834164e58c06a0ea2c7ac.png"},{"id":97723868,"identity":"2a147c23-6e17-4091-8a0e-2842c2d29482","added_by":"auto","created_at":"2025-12-08 16:08:53","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1668175,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7341323/v1/8ea09d01-6590-498d-9d0d-36ff9598b184.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003eUltra-early Gamma Knife stereotactic radiosurgery for trigeminal neuralgia (URGEnt-TN): Feasibility and potential benefit: study protocol for a single-centre, two-arm, parallel group design, pragmatic, noninferiority, phase II, randomized controlled trial with intention-to-treat analysis for pre-refractory GK-SRS in classical or idiopathic TN\u003c/p\u003e","fulltext":[{"header":"Administrative information","content":"\u003cp\u003eNote: the numbers in curly brackets in this protocol refer to SPIRIT checklist item numbers. The order of the items has been modified to group similar items (see http://www.equator-network.org/reporting-guidelines/spirit-2013-statement-defining-standard-protocol-items-for-clinical-trials/).\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"639\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34.1158%;\"\u003e\n \u003cp\u003eTitle {1}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65.8842%;\"\u003e\n \u003cp\u003eUltra-early Gamma Knife stereotactic radiosurgery for trigeminal neuralgia: Feasibility and potential benefit\u003c/p\u003e\n \u003cp\u003eURGEnt-TN\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34.1158%;\"\u003e\n \u003cp\u003eTrial registration {2a and 2b}.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65.8842%;\"\u003e\n \u003cp\u003eTrial registry: ClinicalTrials.gov\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eClinicalTrials.gov ID: NCT06949436\u003c/p\u003e\n \u003cp\u003eTrial registration date: April 28, 2025\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34.1158%;\"\u003e\n \u003cp\u003eProtocol version {3}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65.8842%;\"\u003e\n \u003cp\u003eSRS-0301\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34.1158%;\"\u003e\n \u003cp\u003eFunding {4}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65.8842%;\"\u003e\n \u003cp\u003eThis trial is currently unfunded.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34.1158%;\"\u003e\n \u003cp\u003eAuthor details {5a}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65.8842%;\"\u003e\n \u003cp\u003eAmanda Lussoso (1), Samir Patel (2), Wasif Hussain (3), Michael Knash(3), Matt Wheatley (4), Gregory Bowden (4),\u0026nbsp;Ngoc Khanh Vu (5), Tejas Sankar (4)\u003c/p\u003e\n \u003cp\u003e1 -Neuroscience and Mental Health Institute, University of Alberta,\u0026nbsp;Edmonton,\u0026nbsp;AB,\u0026nbsp;Canada\u003c/p\u003e\n \u003cp\u003e2 -Division of Radiation Oncology, Department of Oncology, University of Alberta,\u0026nbsp;Edmonton,\u0026nbsp;AB,\u0026nbsp;Canada\u003c/p\u003e\n \u003cp\u003e3 -Division of Neurology, University of Alberta, Edmonton, AB,\u0026nbsp;Canada\u003c/p\u003e\n \u003cp\u003e4 - Division of\u0026nbsp;Neurosurgery, University of\u0026nbsp;Alberta,\u0026nbsp;Edmonton,\u0026nbsp;AB,\u0026nbsp;Canada\u003c/p\u003e\n \u003cp\u003e5- Real World Evidence Unit, Faculty of Medicine and Dentistry, University of Alberta,\u0026nbsp;Edmonton, AB, Canada\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34.1158%;\"\u003e\n \u003cp\u003eName and contact information for the trial sponsor {5b}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65.8842%;\"\u003e\n \u003cp\u003eNot applicable. This trial is unsponsored.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34.1158%;\"\u003e\n \u003cp\u003eRole of sponsor {5c}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65.8842%;\"\u003e\n \u003cp\u003eNot applicable. This trial is unsponsored.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Introduction","content":"\n\u003ch3\u003eBackground and rationale {6a}\u003c/h3\u003e\n\u003cp\u003eTrigeminal neuralgia (TN) is a chronic, often severely debilitating, neuropathic facial pain condition characterized by \u0026ldquo;recurrent unilateral brief electric shock-like pains, abrupt in onset and termination, limited to the distribution of one or more divisions of the trigeminal nerve (cranial nerve five - CNV) and triggered by innocuous stimuli\u0026rdquo; [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. TN has an approximate global incidence of 12 cases per 100,000 and a female predominance of 3:2 [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], and occurs predominantly in the sixth decade of life, peaking around 70 years [\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The severe lancinating pain of TN is triggered by common somatosensory stimuli experienced in everyday life, such as chewing, speaking, brushing teeth, temperature changes, or tactile pressure to the face; pain attacks may also occur entirely spontaneously [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eGiven the severity of TN, prompt pain management is critically important. In general, pharmaceutical therapy is the first-line treatment, with carbamazepine (CBZ) being the gold standard. However, CBZ is associated with a high incidence of adverse effects (40%-66%) [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], including somnolence, dizziness, double vision, rash, nausea, headache, vomiting, tremor, ataxia, disturbed sleep, mood changes, lack of concentration, memory loss, and hyponatremia [\u003cspan additionalcitationids=\"CR10 CR11\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. In rare circumstances, severe adverse effects can occur, including myelosuppression, hepatotoxicity, lymphadenopathy, systemic lupus erythematosus, elevated liver enzymes, hematologic dyscrasias, thrombocytopenia, aplastic anaemia [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], and dosages reaching toxic levels [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In addition, the presence of the \u003cem\u003eHLA-B*15:02\u003c/em\u003e allele found almost exclusively in Asian genealogy warrants genetic testing for participants with Asian lineage to determine their potential risk of CBZ-induced Stevens-Johnson syndrome and toxic epidermal necrolysis that may be life-threatening [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Oxcarbazepine (OXC) is an enantiomer of CBZ associated with fewer side effects, contraindications, and overall better tolerability [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]; however, similar to CBZ, it can cause sedation, dizziness, poor concentration, diplopia, nausea, headache, somnolence, ataxia, and thrombocytopenia, typically experienced to a lesser degree [\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Of note, the incidence of hyponatremia is dose-dependent and of particular concern [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], so OXC use needs to be monitored carefully to avoid electrolyte imbalance.\u003c/p\u003e\u003cp\u003eA large retrospective study examining the natural history of classical TN demonstrated robust initial responsiveness of 98% for CBZ and 94% for OXC. However, following means of 8.6 (CBZ) and 13 (OXC) months, a significant proportion of participants (27% CBZ, 18% OXC) developed intolerability and required subsequent dosage reduction to inadequate levels for appropriate pain management [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Other quantitative examinations of the frequency of adverse effects and overall tolerability of CBZ and OXC for neuralgiform pain, have found that dosage increases sufficient for pain management subsequently increase adverse cognitive effects [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. More specifically, a standard one-unit dosage increase, the dosage necessary to generate a pharmacologically significant effect, results in a 50% increase in the likelihood of worsening side effects and eventual incapacity to reach therapeutic dosage for adequate pain suppression [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Taylor et al. [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] examined CBZ treatment for classical TN over a 16-year period, and found a significant decline in efficacy by year four, with an overall 44% failure rate necessitating alternative treatment. Despite the favourable tolerability of OXC, a long-term cohort study comparing OXC and surgical management of intractable TN found that effectiveness was short-term, subsequently necessitating surgical intervention as a rescue therapy [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAccording to the American Academy of Neurology (AAN) and the European Federation of Neurological Societies (EFNS) guidelines on TN management, when medical therapy becomes ineffective due to poor pain control or intolerability, referral for surgery is the next reasonable step [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Current surgical options in TN include microvascular decompression (MVD), percutaneous rhizotomy (PR), and Gamma Knife stereotactic radiosurgery (GK-SRS), and are typically reserved for participants deemed \u003cem\u003e\u0026ldquo;\u003c/em\u003emedically refractory\u003cem\u003e\u0026rdquo;\u003c/em\u003e [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. However, there is no consensus as to the number of failed medical treatments required before surgical referral. Although some guidelines state that up to three groups of medications be trialed [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], some experts suggest that participants failing first-line medical therapy are unlikely to respond to other medications and should be referred for surgery earlier [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Furthermore, pain becomes increasingly intractable with disease duration [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], and there is evidence that participants refractory to medical therapy prefer earlier surgery [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Accordingly, there is a need for further evaluation of the potential benefits of early surgery.\u003c/p\u003e\u003cp\u003eDeveloped in 1951, GK-SRS uses radioactive cobalt-60 isotope sources to produce converging radiation beams intersecting a target volume and was ultimately adapted for treating TN[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. The least invasive neurosurgical approach to TN, GK-SRS is entirely non-invasive other than the use of stereotactic headframe immobilization [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. In a single session, GK-SRS delivers a highly concentrated dose of ionizing radiation to a precise treatment target along the trigeminal nerve (typically the mid-cisternal segment at 70\u0026ndash;90 Gy) with minimal irradiation of surrounding normal healthy tissues beyond the treatment margins [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], and no need to stop anticoagulation in participants requiring it [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eTuleasca et al. [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] summarized evidence in support of GK-SRS across 45 studies (5687 participants), by way of a systematic review and meta-analysis reporting freedom from pain (FFP), time to pain relief (TTPR), recurrence rates, time to recurrence, and presence of hypesthesia or other complications. Mean FFP outcome with or without medication adjustment was 84.8% and mean FFP outcome without the need for medication entirely was 53.1%, with TTPR ranging from 15\u0026ndash;78 days. Mean pain recurrence rate was 24.6%, occurring between 7.5\u0026ndash;20.4 months. Additionally, the maintenance of pain relief at 7 and 10 years was noteworthy in five studies, ranging between 22% and 59.7% (7 years) and 30% and 45.3% (10 years). Incidence of facial sensory dysfunction (i.e., hypesthesia) is the most significant complication of GK-SRS (21.7%), occurring between 6 to 36 months. However, the development of bothersome or very bothersome hypesthesia occurred in only a tiny proportion of participants (0%-17.3% mean\u0026thinsp;=\u0026thinsp;3.1%). Other rare side effects included dry eye, deafferentation pain, and keratitis. In 27/45 GK-SRS studies, there were no reported side effects at all [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. In addition, post GK-SRS associated malignancies are rare, with a cumulative incidence of 0.00045% over 10 years [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. It is pertinent to consider that the number needed to harm (NNH) for the most significant complication of GK-SRS (hypesthesia) is approximately 4.7 [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], compared to approximately 2.6 for at least one adverse effect of CBZ[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThere remains a notable gap in the literature exploring very early GK-SRS. Of particular importance, of the 45 studies reviewed by Tuleasca et al. [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], only one retrospective study analyzed GK-SRS when used exclusively as the primary surgical treatment in TN [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Mousavi et al. [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] reported initial pain relief in 88% of participants, with earlier GK-SRS treatment within 3 years of pain onset resulting in earlier pain relief (median 1 week) compared to 6 weeks for participants with TN\u0026thinsp;\u0026gt;\u0026thinsp;3 years. Longer duration of adequate pain control was also seen in a larger percentage of participants whose pain history was \u0026lt;\u0026thinsp;3 years (1 year 93%, 10 years 73%) compared to participants with a longer pre-operative pain history (1 year 63%, 10 years 28%). Moreover, a longer interval of pain relief without medication (89% at 3 years) was seen in a greater proportion of participants with a history of pain\u0026thinsp;\u0026lt;\u0026thinsp;3 years compared to those with \u0026gt;\u0026thinsp;3-year history of pain (52% at 3 years). Participants with a history of pain for \u0026gt;\u0026thinsp;3 years prior to GK-SRS had an 8% likelihood of being pain-free without medication by year 5 and 0% at year 10, compared to 73% and 40%, respectively in participants with pain\u0026thinsp;\u0026lt;\u0026thinsp;3 years [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. In line with these data, a recent international multicenter study proposed consideration of earlier radiosurgery (within 4 years of diagnosis), finding a shorter interval to pain relief and significant decreases in medication utilization for participants treated within this time-frame [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Taken together, these findings point to the potential of early GK-SRS to provide faster and more durable medication-free pain relief with a very low rate of adverse side effects.\u003c/p\u003e\u003cp\u003eWhat is not known is whether ultra-early intervention with GK-SRS\u0026mdash;before the actual development of medical-refractoriness (however that is defined)\u0026mdash;may alter the natural progression of TN, avoiding the need for long term high-dose medical therapy with its associated side effects. In this study, we aim to evaluate the feasibility and potential benefit of GK-SRS as an ultra-early treatment option for TN. We hypothesize that ultra-early GK-SRS will:\u003c/p\u003e\u003cp\u003e(1) provide more durable pain relief compared to ongoing best medical management\u003c/p\u003e\u003cp\u003e(2) reduce or eliminate the need for high-dose medical therapy\u003c/p\u003e\u003cp\u003e(3) have a lower rate of adverse effects compared to best medical management\u003c/p\u003e\n\u003ch3\u003eObjectives {7}\u003c/h3\u003e\n\u003cp\u003eTo assess the efficacy of ultra-early (i.e., prior to medical-refractoriness) GK-SRS as a treatment for TN compared to standard best medical management.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eTrial design {8}\u003c/h2\u003e\u003cp\u003eThis is a single-centre, two-arm, parallel group design, pragmatic, noninferiority, phase II, randomized controlled trial of ultra-early GK-SRS for TN in participants treated prior to developing a medically-refractory state and within 2 years of diagnosed TN per study neurologist. Two parallel cohorts will be studied: 1) participants treated with GK-SRS (intervention arm/treatment group); and 2) participants treated with ongoing best medical management (non-intervention/control group). Crossover will be allowed from the non-intervention arm to the intervention arm. An intention-to-treat analysis will be carried out.\u003c/p\u003e\u003c/div\u003e"},{"header":"Methods: Participants, interventions and outcomes","content":"\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003eStudy setting {9}\u003c/h2\u003e\u003cp\u003eThe primary location of the intervention is the Brown \u0026amp; Scott Families Advanced Imaging and Gamma Knife Centre at the University of Alberta Hospital, Edmonton, Alberta, Canada.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eEligibility criteria {10}\u003c/h3\u003e\n\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003eInclusion Criteria:\u003c/h2\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eAge\u0026thinsp;\u0026ge;\u0026thinsp;18 years\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eClinical diagnosis of classical or idiopathic TN [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], based on clinical history and MRI scan\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eOnset of pain within 2 years prior to enrolment\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eNot deemed medically-refractory (defined as suboptimal pain control despite \u0026ge;\u0026thinsp;2 medication trials of adequate dose)\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eIf currently on medication, on stable dose for at least 3 months\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eExclusion Criteria:\u003c/h2\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eSecondary TN\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eBilateral TN\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eAny contraindication to GK-SRS\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eAny prior cranial radiation\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eAny prior surgical intervention for TN\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eHistory of new psychiatric diagnoses within 2 years of study participation, or uncontrolled, concurrent psychiatric illness (e.g., depression with recent suicide attempts)\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eFemales who are pregnant or breast-feeding\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eWho will take informed consent? {26a}\u003c/h3\u003e\n\u003cp\u003eInvestigators will ensure all study aspects are thoroughly discussed with potential participants, including accessing electronic health records (to assess eligibility) and all potential risks and benefits prior to enrolment. Participants will have the opportunity to ask questions at any stage of enrolment. Written informed consent for access to health care records and consent to contact will be obtained by the referring physician. Following the determination of eligibility, written consent will be obtained by a study coordinator or team physician (other than the participant's treating physician) to ensure that there is no undue pressure on potential participants to agree to the study at the time of enrolment. Participants will state their complete understanding of risks, benefits, intervention details, and ability to withdraw their consent at any time without compromising the quality of their treatment. A written informed consent form (ICF) will be obtained for each participant, signed and dated by the participant and the study team member who conducted the informed consent procedure.\u003c/p\u003e\n\u003ch3\u003eAdditional consent provisions for collection and use of participant data and biological specimens {26b}\u003c/h3\u003e\n\u003cp\u003eNot applicable. The process of collecting biological specimens will not be carried out for this research.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInterventions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExplanation for the choice of comparators {6b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe intervention group receiving GK-SRS will be compared to a non-intervention/control group treated with current standard of care medical therapy. Among these, carbamazepine and oxcarbazepine are the most commonly prescribed due to their established efficacy in managing symptoms of TN.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIntervention description {11a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIntervention Arm:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGK-SRS treatment will be carried out to the mid-cisternal segment of the trigeminal nerve ipsilateral to the affected side of the face. Under local anaesthesia, a Leksell stereotactic head frame will fixed to the patient\u0026rsquo;s head to allow for complete cranial immobilization during treatment. The mid-cisternal segment will be treated using a single 4 mm isocenter. A dose of 40 Gy (maximum point dose 80 Gy) will be administered to the 50% isodose line while limiting the brainstem dose to 12 Gy [3].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eNon-intervention/Control Arm:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipants allocated to the non-intervention/control arm\u0026nbsp;will continue medical management per the judgment of their treating physician (see 11b).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCriteria for discontinuing or modifying allocated interventions {11b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFor the GK-SRS intervention arm, the intervention is a single surgical procedure occurring on a single day. It is possible that the treatment may need to be halted prematurely due to patient discomfort or technical issues, though this would be a very rare event. In the event that GK-SRS treatment needs to be stopped prematurely, it will be allowed to be completed at a later date, per usual practice.\u003c/p\u003e\n\u003cp\u003eTwo neurologist members of the study team (MWH and MK) with expertise in the medical management of TN will manage medication use in all enrolled participants across both groups. Where appropriate, medication dosage will be modified as necessary, depending on whether the patient\u0026apos;s condition improves or worsens. These adjustments will be made at the discretion of the treating neurologist, who will carefully evaluate the patient\u0026apos;s response to the treatment and any request for modifications (including weaning off medications).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStrategies to improve adherence to interventions {11c}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGiven GK-SRS is a one-time intervention, \u0026ldquo;adherence to interventions\u0026rdquo; applies only to medication management, study visits, and\u0026nbsp;performance surveillance labs\u0026nbsp;in both the intervention arm and the non-intervention/control arm. To improve adherence to the intervention protocol, at each follow-up visit (6, 12, 24 months and 5 years), participants will be asked by the study team of any changes to their medication, additional surgical procedures, or non-surgical treatments for TN. A medication diary will be requested to improve adherence to medical therapy for both the intervention arm and the non-intervention/control arms.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRelevant concomitant care permitted or prohibited during the trial {11d}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipants allocated to the intervention arm will receive ongoing medical management tailored to their specific needs, as determined by the clinical judgment of the treating neurologist.\u0026nbsp;Participants may receive other medications as required.\u0026nbsp;Crossover will be permitted from the non-intervention/control arm to the\u0026nbsp;intervention\u0026nbsp;arm at any time.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cbr\u003e\u0026nbsp;Provisions for post-trial care {30}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn accordance with the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans (TCPS 2), if a participant is harmed as a result of participating in this trial, the research team and the University of Alberta will ensure access to appropriate care and support, including follow-up care where warranted. Post-trial access to care or interventions shown to be beneficial during the study may be provided where feasible and ethically appropriate.\u003c/p\u003e\n\u003cp\u003eAt the conclusion of the trial, all enrolled participants will be given the option of continuing ongoing care by the neurologist who managed their medications during the trial.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcomes {12}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary endpoint is satisfactory pain control at 2 years after GK-SRS treatment (for intervention arm) or 2 years after enrolment in the non-intervention/control arm, measured using\u0026nbsp;Barrow Neurological Institute Pain Intensity Score (BNI) (satisfactory pain control = BNI I, II, IIIa) [28].\u003c/p\u003e\n\u003cp\u003eSecondary endpoints include:\u0026nbsp;\u003c/p\u003e\n\u003col style=\"list-style-type: upper-roman;\"\u003e\n \u003cli\u003eWorst incidence of treatment-related adverse events by intervention arm. Adverse events will be determined using the International Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 [29] at 6, 12, 24 months, and 5 years after the day of GK-SRS treatment, for participants in the intervention arm and at 6, 12, 24 months, and 5 years after enrolment, for participants in the non-intervention/control arm.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003ePain medication equivalent dose measured with the Medication Quantification Scale version III\u0026nbsp;(MQS III) [30]. Intervention arm: Baseline visit; GK-SRS treatment visit; follow-up visits 6, 12, 24 months, and 5 years after day of GK-SRS treatment. Non-intervention/control arm: Baseline visit; follow-up visits 6, 12, 24 months, and 5 years after enrolment.\u003c/li\u003e\n \u003cli\u003eScore of BNI I 2 years after the day of GK-SRS treatment.\u003c/li\u003e\n \u003cli\u003eProportion of participants with satisfactory pain control at long-term: those participants classified as BNI I-IIIa 5 years after day of GK-SRS treatment, or 5 years after enrolment in the non-intervention/control arm.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003ePresence and severity of facial numbness in the intervention arm after GK-SRS treatment measured using the Barrow Neurological Institute Facial Numbness Scale [28] at 6, 12, 24 months, and 5 years after GK-SRS treatment.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eNumber of participants crossing over from non-intervention/control arm to intervention arm during follow up period at 6, 12, 24 months, and 5 years after enrolment.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eNumber of participants in GK-SRS arm referred for repeat surgery at 6, 12, 24 months, and 5 years after GK-SRS treatment.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003ePatient-rated pain severity (0-100) measured with the Visual Analogue Scale (VAS) [31]. Intervention arm: Baseline visit; GK-SRS treatment visit; follow-up visits 6, 12, 24 months, and 5 years after day of GK-SRS treatment. Non-intervention/control arm: Baseline visit; follow-up visits 6, 12, 24 months, and 5 years after enrolment.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eBrief Pain Inventory-Facial (BPI-Facial) [32] to evaluate three additional pain domains: intensity, interference in general activities, and interference in face-specific activities. Baseline visit; GK-SRS treatment visit; follow-up visits 6, 12, 24 months, and 5 years after day of GK-SRS treatment. Non-intervention/control arm: Baseline visit; follow-up visits 6, 12, 24 months, and 5 years after enrolment.\u003c/li\u003e\n \u003cli\u003ePsychological status measured using the Hospital Anxiety and Depression Scale (HADS) [33] and Pain Catastrophizing Scale (PCS) [34]. Baseline visit; GK-SRS treatment visit; follow-up visits 6, 12, 24 months, and 5 years after day of GK-SRS treatment. Non-intervention/control arm: Baseline visit; follow-up visits 6, 12, 24 months, and 5 years after enrolment.\u003c/li\u003e\n \u003cli\u003eQuality of life measured using the Short Form Health Survey (SF-36 v2) [35]. Baseline visit; follow-up visits 6, 12, 24 months, and 5 years after day of GK-SRS treatment. Non-intervention/control arm: Baseline visit; follow-up visits 6, 12, 24 months, and 5 years after enrolment.\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003e\u003cstrong\u003eParticipant timeline {13}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipant timelines are summarized in figures 1 (SPIRIT figure) and 2 (flowchart).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSample size {14}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe sample size is estimated based on the primary outcome over 2 years using a non-inferiority design for two proportions, i.e., the proportion of participants with satisfactory pain control at 2 years (BNI I-IIIa).\u0026nbsp;We aim to detect a difference of 10% satisfactory pain control between the 2 groups, i.e., over 2 years the GK-SRS group would have a proportion of satisfactory pain control not lower than the medical therapy by 10%. We aim for 80% power and a 0.05 significance level for detecting the aforementioned difference. Using a 35% failure rate for medical therapy over 2 years, a 7% failure rate for GK-SRS at 1 year, and an 11% failure rate at 3 years for GK-SRS [26,37], the required sample size ranges from 32 to 47 participants per group, with 40 being a practical recommendation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRecruitment {15}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOutreach is occurring to the local population of referring physicians. The study team includes individuals who are heavily involved in the surgical treatment and medical management of TN and are aware of other practitioners within the catchment area.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eStudy information flyers will be distributed via email (e.g., Alberta College of Family Physicians, Alberta Dental Association, Canadian Headache Society,\u0026nbsp;Trigeminal Neuralgia Association of Canada, and TN facial pain groups) to family physicians, neurologists, dentists/oral pain specialists within the catchment area. The intention of the flyers is to inform potential referring clinicians so that they can identify potentially eligible participants for further evaluation by the study team. Flyers may also be made available via email newsletters and/or social media outlets. Additionally, in-person outreach (flyer distribution) will be carried out in the Urgent Neurology Clinic at the primary institution.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAssignment of interventions: allocation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSequence generation {16a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo minimize bias, participants will be allocated by blocked randomization, on a 1:1 basis, to either the non-intervention/control or intervention arm via the National Institute of Health (NIH) Clinical Trial Randomization Tool [38].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConcealment mechanism {16b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo ensure allocation concealment, we will implement the following procedures: A study coordinator or team physician will log into the NIH Clinical Trial Randomization Tool to input participant information. The NIH Clinical Trial Randomization Tool will randomly assign participants to either group in a 1:1 ratio. After inputting all required baseline information, a unique profile for each patient will be generated. Access to these data will be restricted to an authorized third party.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImplementation {16c}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA study coordinator or team physician will enroll eligible participants. The NIH Clinical Trial Randomization Tool will randomly assign participants to either group in a 1:1 ratio. Per the NIH Clinical Trial Randomization Tool requirements, all essential researchers will not have access to the output. Access to the output sequence will be restricted to a study coordinator who will reveal each successive trial participants allocation, following consent and acceptance into the trial.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAssignment of interventions: Blinding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWho will be blinded {17a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis trial will, by definition, be non-blinded due to the nature of the head frame application in the intervention arm where participants will be treated with GK-SRS, and by administration of medication and performance surveillance labs for the non-intervention/control group. However, team members (i.e., statistician) will remain blinded to the group assignment of individual participants.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eProcedure for unblinding if needed {17b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData collection and management\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans for assessment and collection of outcomes {18a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEfficacy Assessments:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAssessment of Pain:\u0026nbsp;\u003c/em\u003eAt each time point, pain-related outcome variables will be assessed by:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e(1) pain relief status (BNI I-IIIa = response, BNI IIIb-V = non-response) using the BNI score (I - no pain, no medication; II - occasional pain, no medication required; III - some pain, adequately controlled with medication; IIIa - no pain, continued medication; IIIb - persistent pain, controlled with medication; IV - some pain, not adequately controlled with medications; V - severe pain or no pain relief).\u003c/p\u003e\n\u003cp\u003e(2) patient-rated pain severity (0-100) using the VAS.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e(3) BPI-Facial to evaluate three additional pain domains: intensity, interference in general activities, and interference in face-specific activities.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAssessment of Medication:\u003c/em\u003e At each time point, medication-related outcome variables will be quantitatively assessed for drug class, dosage, and detriment (risk) using the MQS III, which provides a single numeric value for all patient\u0026rsquo;s pain medication profiles.\u003c/p\u003e\n\u003cp\u003eSafety and Other Assessments\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAssessment of Adverse Events\u003c/em\u003e: Adverse events will be assessed, if necessary, using the CTCAE, version 5.0.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eHistory and physical examination:\u0026nbsp;\u003c/em\u003eA routine neurological examination will be performed by a neurologist on our study team at initial screening, and on an as needed basis during follow-up per standard of care in TN management.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePsychological Assessments:\u0026nbsp;\u003c/em\u003eAt each time point, we will assess psychological status using the HADS and PCS. Both measures are widely used in clinical applications, have strong psychometric properties, low patient burden, and have proven valid and reliable.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eOther Assessments:\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e(1) Bothersome facial numbness will be assessed using the\u0026nbsp;BNI facial numbness scale\u003cstrong\u003e\u0026nbsp;(\u003c/strong\u003eI= no facial numbness; II= mild facial numbness that is not bothersome; III= somewhat bothersome facial numbness; IV= very bothersome facial numbness).\u003c/p\u003e\n\u003cp\u003e(2) Quality of life will be assessed via the SF-36 v2.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans to promote participant retention and complete follow-up {18b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll consenting and enrolled participants will receive comprehensive information regarding the potential risks and benefits of the study. Investigators will stress the importance of follow-up with each enrolled participant. To simplify this process and facilitate data collection, follow-up assessments can be conducted via telephone if desired.\u003c/p\u003e\n\u003cp\u003eParticipants have the right to withdraw from the study at any time. Additionally, investigators may decide to withdraw participants for reasons related to safety, behavior, or non-compliance. If a participant withdraws their participation or consent, no further assessments will be conducted and no additional data will be collected.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData management {19}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe electronic Research Electronic Data Capture system \u0026lsquo;REDCap\u0026rsquo; [39] will be used in this trial. Study data will be collected and managed using REDCap electronic data capture tools hosted at the University of Alberta. REDCap is a secure, web-based software platform designed to support data capture for research studies, providing 1) an intuitive interface for validated data capture; 2) audit trails for tracking data manipulation and export procedures; 3) automated export procedures for seamless data downloads to common statistical packages; and 4) procedures for data integration and interoperability with external sources [39].\u003c/p\u003e\n\u003cp\u003eIndependent case report forms (CRFs) will be completed for each eligible and consented participant. Data will be entered and maintained by a study coordinator. Any changes made to CRFs will not obscure the original entry. All changes will be dated, initialled, and explained as necessary. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConfidentiality {27}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEach patient will be assigned a unique sequential identification number upon registration. This identification number will be crucial for tracking each patient throughout the study and will be included on all CRFs used in the trial. To ensure the confidentiality of personal information, no other identifiable data regarding the patient will be included on these CRFs.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTo further safeguard sensitive information, the patient\u0026apos;s health care number, which will be linked to their identification number, will be maintained in a secure, password-protected master file. Access to this file will be restricted solely to authorized members of the study team, ensuring that patient privacy is upheld throughout the duration of the trial. This structured approach is designed to prioritize both the integrity of the trial and the confidentiality of patient information.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable. This trial does not intend to collect, assess, or store biological specimens for the purpose of genetic or molecular analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical methods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical methods for primary and secondary outcomes {20a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eGeneral approach\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAll analyses will follow the intention-to-treat principle. For binary outcomes, a Chi-square or Fisher\u0026rsquo;s exact test will be used, as appropriate. If covariate imbalance is observed between the two groups (i.e., standardized mean difference \u0026gt; 0.1), multivariable regression models adjusting for those covariates will be applied. For outcomes measured at multiple time points, longitudinal mixed-effects models will be used.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAnalysis of the primary efficacy endpoint(s)\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe primary outcome - satisfactory pain control at 2 years - is binary. A Chi-square or Fisher\u0026rsquo;s exact test will be applied, as appropriate. If covariates are unbalanced between the two groups, a multivariable logistic regression model will be used to adjust for these factors. In the case of substantial loss to follow-up at 2 years that could compromise the intention-to-treat principle, an additional longitudinal logistic mixed-effects model incorporating all time points will be employed.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAnalysis of the secondary endpoint(s)\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eFor binary and categorical secondary outcomes (endpoints III, and IV), a Chi-square or Fisher\u0026rsquo;s exact test will be used. Longitudinal mixed-effects models will be used for outcomes measured at multiple time points (endpoint I, II, VIII, IX, X, XI). Proportions with 95% confidence intervals will be reported among the intervention group for secondary endpoints V, VI, and VII.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInterim analyses {21b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAn interim analysis is not planned nor required per institutional policy, as the study is considered low risk.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods for additional analyses (e.g. subgroup analyses) {20b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIf there is an imbalance between the two groups regarding the distribution of characteristics associated with the outcomes of interest, multivariable models will be employed to adjust for potential confounding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAppropriate efforts will be employed to minimize the lost to follow-up rate, especially the measurement of the primary efficacy outcome, i.e., satisfactory pain control at 2 years (BNI I-IIIa).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll study participants including lost to follow-up individuals will be included analyses to maintain the intention-to-treat principle. When the lost to follow-up rate is substantial, longitudinal data models, generalized estimating equations (GEE), or a mixed-effect model will also be employed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans to give access to the full protocol, participant level-data and statistical code {31c}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary investigator grant access to full protocol upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOversight and monitoring\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eComposition of the coordinating centre and trial steering committee {5d}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSince the trial has been classified as low risk according to the University of Alberta\u0026rsquo;s Health Research Ethics Board requirements, it is not subject to regulation and does not require a steering committee.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eComposition of the data monitoring committee, its role and reporting structure {21a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSince this is a low-risk trial, a Data and Safety Monitoring Board (DSMB) is not required.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA study coordinator will maintain comprehensive and accurate source records that serve as the basis of CRFs. These records will include all relevant data and documentation related to the study. A study coordinator will provide direct access to all pertinent documents, enabling thorough oversight and verification of the study\u0026apos;s progress and compliance with regulatory requirements.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdverse event reporting and harms {22}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAdverse events (AEs) and serious adverse events (SAEs) will be evaluated and monitored by the Principal Investigator until the patient is considered stable based on the resolution of these events. AEs and SAEs that occur following the initiation of the intervention will be reported using the International Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 [29], and recorded in the relevant REDCap database. In the case of SAEs, the principal investigator will be informed within 24 hours, and the incidents will be reported to the appropriate regulatory bodies and research ethics boards.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFrequency and plans for auditing trial conduct {23}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSince the trial has been classified as low risk according to the University of Alberta\u0026rsquo;s Health Research Ethics Board requirements, it is not subject to regulation and does not require auditing procedures.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA member of the study team will submit reports, updates, and other information to the research ethics board, such as expedited safety reports, amendments, and administrative letters, in accordance with regulatory requirements and institutional procedures.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDissemination plans {31a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe results of the trial will be documented in a manuscript to be submitted to a peer reviewed scientific journal in the field of chronic pain, headache neurology, or neurosurgery for publication. The authorship of the resulting manuscript will include the Principal Investigator as senior author, along with all co-investigators as co-authors. Additional individuals may be added to the co-author list depending on their contributions (e.g., individuals providing additional assistance with data analysis).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIf GK-SRS, implemented as a first-line treatment for TN, proves safe and effective, then this trial may initiate a paradigm shift in TN management, wherein early surgical treatment with GK-SRS is accepted as a viable alternative to medical therapy. Clinically, these findings will translate to less ambiguity in optimal time to surgical referral and an increased willingness to refer participants for earlier surgery. As a result, TN treatment guidelines may adopt firmer recommendations for earlier surgical treatment, enabling both clinicians and participants with more informed decision-making potential. Importantly, generating evidence in favour of GK-SRS as a viable first-line treatment option may mitigate potentially detrimental repercussions of prolonged disease duration on pain chronification and overall detriment to quality of life with prolonged, inadequate medical management.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLimitations\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe proposed study has important limitations. First, due to the necessity of cranial immobilization in GK-SRS, blinding the investigators and participants to treatment allocation is not feasible, which may introduce bias and compromise the validity of our results. However, carrying out a sham surgery could expose patients to unnecessary risk. Second, our study is limited to clinical diagnoses of classical and idiopathic TN, which may affect generalizability to those with secondary TN.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial status\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eProtocol Version Number: SRS-0301\u003c/p\u003e\n\u003cp\u003eRecruitment Start Date: August 15, 2025\u003c/p\u003e\n\u003cp\u003eEstimated Recruitment End Date: May 1, 2029\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAAN \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;American Academy of Neurology\u003c/p\u003e\n\u003cp\u003eAEs \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Adverse events\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBNI\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Barrow Neurological Institute Pain Intensity Score\u003c/p\u003e\n\u003cp\u003eBPI-Facial\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Brief Pain Inventory-Facial\u003c/p\u003e\n\u003cp\u003eCBZ \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Carbamazepine\u003c/p\u003e\n\u003cp\u003eCTCAE\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Common Terminology Criteria for Adverse Events\u003c/p\u003e\n\u003cp\u003eCNV \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Cranial nerve five\u003c/p\u003e\n\u003cp\u003eCRFs \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Case Report Form\u003c/p\u003e\n\u003cp\u003eDSMB \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Data and Safety Monitoring Board\u003c/p\u003e\n\u003cp\u003eEFNS\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;European Federation of Neurological Societies\u003c/p\u003e\n\u003cp\u003eFFP\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Freedom from pain\u003c/p\u003e\n\u003cp\u003eGK-SRS \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Gamma Knife stereotactic radiosurgery\u003c/p\u003e\n\u003cp\u003eGEE \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Generalized estimating equations\u003c/p\u003e\n\u003cp\u003eHADS\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Hospital Anxiety and Depression Scale\u003c/p\u003e\n\u003cp\u003eICF Informed Consent Form\u003c/p\u003e\n\u003cp\u003eICHD International Classification of Headache Disorders\u003c/p\u003e\n\u003cp\u003eMQS III\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Medication Quantification Scale version III\u003c/p\u003e\n\u003cp\u003eMS\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Multiple sclerosis\u003c/p\u003e\n\u003cp\u003eMVD \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Microvascular decompression\u003c/p\u003e\n\u003cp\u003eNIH \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; National Institute of Health\u003c/p\u003e\n\u003cp\u003eNNH\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Number needed to harm\u003c/p\u003e\n\u003cp\u003eOXC \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Oxcarbazepine\u003c/p\u003e\n\u003cp\u003ePCS\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Pain Catastrophizing Scale\u003c/p\u003e\n\u003cp\u003ePR \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Percutaneous rhizotomy\u003c/p\u003e\n\u003cp\u003eREDCap \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Research Electronic Data Capture\u003c/p\u003e\n\u003cp\u003eREB \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Research Ethics Board\u003c/p\u003e\n\u003cp\u003eSAEs \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Serious adverse events\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSF-36 v2 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Short Form Health Survey\u003c/p\u003e\n\u003cp\u003eTTPR\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Time to pain relief\u003c/p\u003e\n\u003cp\u003eTN \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Trigeminal neuralgia\u003c/p\u003e\n\u003cp\u003eVAS\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Visual Analogue Scale\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ contributions {31b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTS is the principal investigator; he conceived the study and contributed to the development of the study protocol and manuscript. AL contributed to the development of the study protocol, and wrote the first draft of the manuscript. SP, WH, MW, and GB contributed to the methodology, review, and editing of the study protocol and manuscript. NKV provided statistical and data analysis input, and reviewed the manuscript draft. All authors read and approved the final study protocol and manuscript. All authors will contribute to study execution.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding {4}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAt this time, this research has not received any specific grant funding from agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials {29}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe final dataset will be accessible only to the research team members listed on the title page of the current protocol, Research Ethics Board (REB) officials, and University of Alberta auditors upon request. If third parties request access to the collected data, informed consent must first be obtained from all participants. Only de-identified data will be provided to third parties.\u0026nbsp;Data will be stored for a minimum of 15 years after the study is completed. After 15 years, all paper documents will be securely destroyed in accordance with the University of Alberta's guidelines.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate {24}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study has been approved by the University of Alberta’s Health Research Ethics Board – Biomedical Panel (IRB00000927, FWA00000077).\u0026nbsp;\u003cem\u003eWritten, informed consent to participate will be obtained from all participants.\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication {32}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests {28}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors declare that they have no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eOlesen J, Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition, Asbtracts. 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Oxford University Press; 2012.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCruccu G, Finnerup NB, Jensen TS, Scholz J, Sindou M, Svensson P, et al. Trigeminal neuralgia: New classification and diagnostic grading for practice and research. Neurology. 2016;87(2):220\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWiffen PJ, Derry S, Moore RA, McQuay HJ. Carbamazepine for acute and chronic pain in adults. Cochrane Database Syst Rev. 2011(1):Cd005451.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBenoliel R, Zini A, Khan J, Almoznino G, Sharav Y, Haviv Y. Trigeminal neuralgia (part II): Factors affecting early pharmacotherapeutic outcome. Cephalalgia. 2016;36(8):747\u0026ndash;59.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDi Stefano G, La Cesa S, Truini A, Cruccu G. 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Relationship between the HLA-B*1502 allele and carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis: a systematic review and meta-analysis. JAMA Dermatol. 2013;149(9):1025\u0026ndash;32.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGomez-Arguelles JM, Dorado R, Sepulveda JM, Herrera A, Arrojo FG, Arag\u0026oacute;n E, et al. Oxcarbazepine monotherapy in carbamazepine-unresponsive trigeminal neuralgia. J Clin Neurosci. 2008;15(5):516\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZakrzewska JM, Patsalos PN. Long-term cohort study comparing medical (oxcarbazepine) and surgical management of intractable trigeminal neuralgia. Pain. 2002;95(3):259\u0026ndash;66.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTaylor JC, Brauer S, Espir ML. Long-term treatment of trigeminal neuralgia with carbamazepine. Postgrad Med J. 1981;57(663):16\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGronseth G, Cruccu G, Alksne J, Argoff C, Brainin M, Burchiel K, et al. Practice parameter: the diagnostic evaluation and treatment of trigeminal neuralgia (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the European Federation of Neurological Societies. Neurology. 2008;71(15):1183\u0026ndash;90.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLambru G, Zakrzewska J, Matharu M. Trigeminal neuralgia: A practical guide. Pract Neurol. 2021;21(5):392\u0026ndash;402.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBendtsen L, Maarbjerg S, Leal PRL, May A, Nurmikko T, Obermann M, et al. European Academy of Neurology guideline on trigeminal neuralgia. Eur J Neurol. 2019;26(6):831\u0026ndash;49.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChong MS, Bahra A, Zakrzewska JM. Guidelines for the management of trigeminal neuralgia. Cleve Clin J Med. 2023;90(6):355\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLeksell L. Sterotaxic radiosurgery in trigeminal neuralgia. Acta Chir Scand. 1971;137(4):311\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChen JC, Girvigian MR. Stereotactic radiosurgery: instrumentation and theoretical aspects-part 1. Perm J. 2005;9(4):23\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePetit JH, Herman JM, Nagda S, DiBiase SJ, Chin LS. Radiosurgical treatment of trigeminal neuralgia: evaluating quality of life and treatment outcomes. Int J Radiat Oncol Biol Phys. 2003;56(4):1147\u0026ndash;53.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWolf A, Naylor K, Tam M, Habibi A, Novotny J, Lišč\u0026aacute;k R, et al. Risk of radiation-associated intracranial malignancy after stereotactic radiosurgery: a retrospective, multicentre, cohort study. Lancet Oncol. 2019;20(1):159\u0026ndash;64.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eR\u0026eacute;gis J, Tuleasca C, Resseguier N, Carron R, Donnet A, Gaudart J, et al. Long-term safety and efficacy of Gamma Knife surgery in classical trigeminal neuralgia: a 497-patient historical cohort study. J Neurosurg. 2016;124(4):1079\u0026ndash;87.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMousavi SH, Niranjan A, Huang MJ, Laghari FJ, Shin SS, Mindlin JL, et al. Early radiosurgery provides superior pain relief for trigeminal neuralgia patients. Neurology. 2015;85(24):2159\u0026ndash;65.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMureb M, Golub D, Benjamin C, Gurewitz J, Strickland BA, Zada G, et al. Earlier radiosurgery leads to better pain relief and less medication usage for trigeminal neuralgia patients: an international multicenter study. J Neurosurg. 2021;135(1):237\u0026ndash;44.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRogers CL, Shetter AG, Fiedler JA, Smith KA, Han PP, Speiser BL. Gamma knife radiosurgery for trigeminal neuralgia: the initial experience of The Barrow Neurological Institute. Int J Radiat Oncol Biol Phys. 2000;47(4):1013\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNational Institutes of Health NCI. Common Terminology Criteria for Adverse Events (CTCAE) v 5.0. 2017.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHarden RN, Weinland SR, Remble TA, Houle TT, Colio S, Steedman S, et al. Medication Quantification Scale Version III: update in medication classes and revised detriment weights by survey of American Pain Society Physicians. J Pain. 2005;6(6):364\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHawker GA, Mian S, Kendzerska T, French M. Measures of adult pain: Visual Analog Scale for Pain (VAS Pain), Numeric Rating Scale for Pain (NRS Pain), McGill Pain Questionnaire (MPQ), Short-Form McGill Pain Questionnaire (SF-MPQ), Chronic Pain Grade Scale (CPGS), Short Form-36 Bodily Pain Scale (SF-36 BPS), and Measure of Intermittent and Constant Osteoarthritis Pain (ICOAP). Arthritis Care Res (Hoboken). 2011;63(Suppl 11):S240\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKeller S, Bann CM, Dodd SL, Schein J, Mendoza TR, Cleeland CS. Validity of the brief pain inventory for use in documenting the outcomes of patients with noncancer pain. Clin J Pain. 2004;20(5):309\u0026ndash;18.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 1983;67(6):361\u0026ndash;70.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSullivan MJL, Bishop SR, Pivik J. The Pain Catastrophizing Scale: Development and validation. Psychol Assess. 1995;7(4):524\u0026ndash;32.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWare JE, Kosinski M, Bjorner JB, Turner-Bowker D, Gandek B, Maruish ME. SF-36v2 Health Survey: Administration Guide for Clinical Trial Investigators. QualityMetric, Incorporated; 2008.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChan A-W, Boutron I, Hopewell S, Moher D, Schulz K. SPIRIT 2025 statement: updated guideline for protocols of randomised trials. BMJ. 2025;389:e081477.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHeinskou T, Maarbjerg S, Rochat P, Wolfram F, Jensen RH, Bendtsen L. Trigeminal neuralgia\u0026ndash;a coherent cross-specialty management program. J Headache Pain. 2015;16:66.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTool CTR. The National Cancer Institue\u0026rsquo;s Divison of Cancer Prevention. Accessed 19 Jun. 2025.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHarris P, Taylor R, Payne J, Gonzalez J, Conde. Research electronic data capture (REDCap) - A metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inf. 2009;42:377\u0026ndash;81.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Trigeminal neuralgia, Gamma Knife, stereotactic radiosurgery, surgery, ultra-early surgery","lastPublishedDoi":"10.21203/rs.3.rs-7341323/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7341323/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eTrigeminal neuralgia (TN) is a chronic, often debilitating neuropathic facial pain condition. First-line treatment is medical therapy, with carbamazepine being the gold standard. Surgery, including stereotactic radiosurgery in particular with Gamma Knife (GK-SRS), is usually considered when medical management fails, which occurs in \u0026gt; 50% of participants. While surgery can provide long-term relief, prolonged disease duration before intervention is linked to a reduced response rate. A highly precise type of radiation therapy, GK-SRS is a non-invasive management option in TN, with a low risk of serious complications and fewer bothersome side effects compared to medical therapy. Evidence supports the safety and efficacy of GK-SRS in medically-refractory TN, with published data suggesting that earlier intervention (within 3 years of pain onset) leads to improved long-term outcomes. However, the safety and efficacy of ultra-early GK-SRS—administered soon after TN diagnosis and before medical refractoriness—have not been examined. We hypothesize that ultra-early GK-SRS will yield superior long-term pain relief compared to ongoing medical management while also having a lower incidence of treatment-related adverse events.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eWe will perform a single-centre, two-arm, randomized, controlled, parallel-group design, pragmatic, noninferiority, phase II trial\u003cem\u003e \u003c/em\u003eof ultra-early GK-SRS for TN in participants who will be treated before they have developed a medically-refractory state and within 2 years of diagnosed TN per study neurologist. Eighty participants will be randomized 1:1 to either GK-SRS (intervention arm) or ongoing medical management (non-intervention/control arm). Crossover from the non-intervention/control arm to the intervention arm will be permitted. An intention-to-treat analysis will be conducted. The primary outcome will be the proportion of participants with satisfactory pain control at 2 years by the Barrow Neurological Institute Facial Pain Scale.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiscussion: \u003c/strong\u003eThis trial aims to test ultra-early GK-SRS as a first-line option in TN, based on a sound rationale for offering GK-SRS prior to failure of medical therapy. If validated, ultra-early GK-SRS will represent a paradigm shift in TN management leading to improved long-term pain control free from adverse medication-related side effects.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial Registration: \u003c/strong\u003eThis clinical trial has been registered with ClinicalTrials.gov under the identifier number NCT06949436. Registered on April 28, 2025.\u003c/p\u003e","manuscriptTitle":"Ultra-early Gamma Knife stereotactic radiosurgery for trigeminal neuralgia (URGEnt-TN): Feasibility and potential benefit: study protocol for a single-centre, two-arm, parallel group design, pragmatic, noninferiority, phase II, randomized controlled trial with intention-to-treat analysis for pre-refractory GK-SRS in classical or idiopathic TN","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-11 15:58:42","doi":"10.21203/rs.3.rs-7341323/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Minor revision","date":"2025-10-08T09:49:02+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2025-09-07T08:06:17+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-05T14:12:59+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-08-22T10:22:34+00:00","index":"","fulltext":""},{"type":"submitted","content":"Trials","date":"2025-08-20T12:41:54+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ac7a0a5d-2697-4691-9d9d-dd2e3fbaca34","owner":[],"postedDate":"September 11th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-12-08T16:01:34+00:00","versionOfRecord":{"articleIdentity":"rs-7341323","link":"https://doi.org/10.1186/s13063-025-09321-8","journal":{"identity":"trials","isVorOnly":false,"title":"Trials"},"publishedOn":"2025-12-04 15:57:40","publishedOnDateReadable":"December 4th, 2025"},"versionCreatedAt":"2025-09-11 15:58:42","video":"","vorDoi":"10.1186/s13063-025-09321-8","vorDoiUrl":"https://doi.org/10.1186/s13063-025-09321-8","workflowStages":[]},"version":"v1","identity":"rs-7341323","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7341323","identity":"rs-7341323","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}