Study of TAK-935 as an Adjunctive Therapy in Adult Participants With Complex Regional Pain Syndrome (CRPS)

Study Overview
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Brief Summary
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The purpose of this study is to investigate the effect of soticlestat (TAK-935) on calculated 24-hour average pain intensity by the numeric pain scale (NPS).

Detailed Description
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The drug being tested in this study is called soticlestat (TAK-935). Soticlestat is being tested to treat people with chronic complex regional pain syndrome (CRPS). This study will look at the efficacy, safety, and tolerability of soticlestat as an adjunctive therapy in participants with CRPS. The study will enroll approximately 24 patients. Participants will be randomly assigned (by chance, like flipping a coin) in 2:1 ratio to one of the two treatment groups-which will remain undisclosed to the patient and study doctor during the study (unless there is an urgent medical need): Soticlestat 100 mg tablets, 100, 200 or 300 mg twice daily (BID) Placebo (dummy inactive pill) - this is a tablet that looks like the study drug but has no active ingredient Participants will receive 100 mg soticlestat tablets or soticlestat matching placebo tablets, BID for Week 1, 2x100 mg soticlestat tablets or soticlestat matching placebo tablets, BID for Week 2 and followed by 3x100 mg soticlestat tablets or soticlestat matching placebo tablets, BID for Week 3. Dose will be uptitrated based on safety and tolerability in titration period. Participants will continue to receive the same dose in maintenance period. Dose adjustments during maintenance period may take place due to safety and tolerability. Participants will then enter Part B (optional) or taper period. In Part B all participants will receive soticlestat 2x100 mg tablets, BID for 1 Week, followed by soticlestat 3x100 mg tablets, BID for 1 Week. Dose will be uptitrated/downtitrated based on safety and tolerability in titration period (Part B), participants will continue to receive the same dose in maintenance period (Part B) and followed by a taper period. This multi-center trial will be conducted in United Kingdom. The overall time to participate in this study is approximately 36 weeks. Participants will make multiple visits to the clinic and will be contacted by telephone 15 days after last dose of study drug for a follow-up assessment.

Official Title
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A Phase 2a, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, and Tolerability of TAK-935 as an Adjunctive Therapy in Adult Subjects With Chronic Complex Regional Pain Syndrome

Conditions
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Complex Regional Pain Syndrome

Intervention / Treatment
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* Drug: Soticlestat
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant meets the Budapest clinical diagnosis of complex regional pain syndrome (CRPS) at the screening visit and is at least 6 months since onset of symptoms. Participant's pain medications and nondrug treatments must be stable (regimented per prescription) for 1 month prior to screening and remain stable throughout Part A. Participant agrees to use a single previously prescribed rescue medication within the prescribed dose during Part A of the study and to record the daily use of these medications. Participant must have an average 24-hour pain intensity score ≥4 and ≤9 on the 24-hour average pain intensity numeric pain scale (NPS) during screening/baseline. This score will be calculated by averaging the daily 24 hour pain intensity scores for the past seven days prior to randomization. The participant must have daily 24-hour pain intensity scores recorded for at least 6 of the past 7 days. Exclusion Criteria: Currently receiving intravenous (IV) or oral ketamine, history of IV or oral ketamine use within the past 6 weeks prior to screening, or planned use of IV or oral ketamine during this study. Participant is receiving chronic opioid treatment at a dose that has not been stable 28 days prior to screening. Participant is receiving chronic opioid treatment >160 mg of morphine equivalent per day. Participant has a positive drug screen for phencyclidine, amphetamine/ methamphetamine, or cocaine at screening. Cannabis is allowed.. Participant is positive for hepatitis B or hepatitis C infection at screening. (Note that participants who have been vaccinated against hepatitis B [hepatitis B surface antibody {Ab}-positive] who are negative for other markers of prior hepatitis B infection [eg, negative for hepatitis B core Ab] are eligible. Also, note that participants who are positive for hepatitis C Ab are eligible if they have a negative hepatitis C viral load by quantitative polymerase chain reaction).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Double-Blind Treatment Period - Part A: Placebo<br>Soticlestat matching placebo tablets, orally, twice daily (BID) for Weeks 1, 2 and 3 in Double blind Titration Period. Soticlestat matching placebo tablets, orally BID for 12 weeks in Double blind Maintenance Period. Taper period (if participant did not continue to Part B): Dose of soticlestat matching placebo tablets was reduced to next lower dose every 3 days (maximum 6 days) until discontinuation. | Drug: Placebo<br>* Soticlestat matching placebo tablets<br>|
| Experimental: Double-Blind Treatment Period - Part A: Soticlestat<br>Soticlestat, tablet, orally, 100 mg BID for Week 1, followed by 2×100 mg tablets, soticlestat, orally BID for Week 2, further followed by 3×100 mg tablets, soticlestat, orally BID for Week 3. Dose was uptitrated every week based on safety and tolerability. Part A (Double blind Maintenance Period): 3×100 mg tablets, soticlestat, orally BID for 12 weeks. Dose was adjusted during Maintenance Period due to safety and tolerability. Taper Period (if participant did not continue to Part B): Dose of soticlestat was reduced to next lower dose every 3 days (maximum 6 days) until soticlestat was discontinued. | Drug: Soticlestat<br>* Soticlestat tablets<br>* Other names: TAK-935;|
| Experimental: Open-Label Extension Period - Part B: Soticlestat<br>Soticlestat, 2×100 mg tablets, orally, BID for Week 1, followed by 3×100 mg tablets, soticlestat, orally, BID for Week 2. Dose was uptitrated every week based on safety and tolerability. Part B (Open label extension: Maintenance Period): 3×100 mg tablets, soticlestat, orally, BID for 12 weeks. Dose was adjusted during Maintenance Period due to safety and tolerability. Taper Period: Dose of soticlestat was reduced to next lower dose every 3 days (maximum 6 days) until soticlestat was discontinued. | Drug: Soticlestat<br>* Soticlestat tablets<br>* Other names: TAK-935;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Mean 24-Hour Pain Intensity as Assessed by NPS Score to the End of Part A | The 24-hour average pain intensity was calculated from current pain intensity scores collected three times a day as measured by the electronic pain diary daily using NPS. NPS is an 11-point scale, where scores range from 0-10, 0= no pain to 10 = most pain imaginable. Negative change from Baseline indicated improvement. | Baseline and Week 15 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Mean 24-Hour Pain Intensity as Assessed by NPS Score to the End of Part A | The 24-hour average pain intensity was calculated from current pain intensity scores collected three times a day as measured by the electronic pain diary daily using NPS. NPS is an 11-point scale, where scores range from 0-10, 0= no pain to 10 = most pain imaginable. Negative percent change from Baseline indicated improvement. | Baseline and Week 15 | 
| Percentage of Participants Considered Responders at the End of Part A | Response was defined as ≥ 30% improvement on the 24-hour pain intensity as assessed by the NPS score. The 24-hour average pain intensity was calculated from current pain intensity scores collected three times a day as measured by the electronic pain diary daily using NPS during Part A. NPS is an 11-point scale, where scores range from 0-10, 0= no pain to 10 = most pain imaginable. | Week 15 | 
| Change From Baseline in Domain Score of PROMIS-29 Version 2.1 at the End of Part A | PROMIS-29 (v2.1) is a health-related quality of life survey assessing 7 domains with 4 questions on a 5-point Likert scale. Total raw domain scores are converted into T-scores from a reference population: Depression: 1=never to 5=always, T-scores:41.0-79.4; Physical function: 1=unable to do to 5=without any difficulty, T-scores: 22.5-57.0; Anxiety: 1=never to 5=always, T-scores: 40.3-81.6; Pain interference: 1=not at all to 5=very much, T-scores: 41.6-75.6; Fatigue: 1=not at all to 5=very much, T-scores: 33.7-75.8; Sleep disturbance: 1=very much to 5=not at all, T-scores: 32.0-73.3; Ability to participate in social roles or activities: 1=always to 5=never, T-scores: 27.5-64.2. High scores signify more of domain being measured. Thus, on symptom-oriented domains, higher scores=worse symptomatology and a negative change from Baseline indicates improvement. On function-oriented domains, higher score=better functioning and a positive change from Baseline indicates improvement. | Baseline and Week 15 | 
| Percent Change From Baseline in Domain Score of PROMIS-29 Version 2.1 at the End of Part A | PROMIS-29 (v2.1) is a health-related quality of life survey assessing 7 domains with 4 questions on a 5-point Likert scale. Total raw domain scores are converted into T-scores from a reference population: Depression: 1=never to 5=always, T-scores:41.0-79.4; Physical function: 1=unable to do to 5=without any difficulty, T-scores: 22.5-57.0; Anxiety: 1=never to 5=always, T-scores: 40.3-81.6; Pain interference: 1=not at all to 5=very much, T-scores: 41.6-75.6; Fatigue: 1=not at all to 5=very much, T-scores: 33.7-75.8; Sleep disturbance: 1=very much to 5=not at all, T-scores: 32.0-73.3; Ability to participate in social roles or activities: 1=always to 5=never, T-scores: 27.5-64.2. High scores signify more of domain being measured. Thus, on symptom-oriented domains, higher scores=worse symptomatology and a negative change from Baseline indicates improvement. On function-oriented domains, higher score=better functioning and a positive change from Baseline indicates improvement. | Baseline and Week 15 | 
| Percentage of Participants in Each Category of the Patient Global Impression of Change (PGIC) Scale at the End of Part A | The PGIC is a 7-point Likert scale to address the following question: Since beginning treatment at this clinic would you describe any changes (if any) in activity, limitations, symptoms, emotions and overall quality of life related to your painful condition compared to before treatment? Participants select from scale range of 1-7: very much improved (1); much improved (2); minimally improved (3); no change (4); minimally worse (5); much worse (6); very much worse (7). Only categories with at least 1 participant were reported. | Week 15 | 
| Change From Baseline in Complex Regional Pain Syndrome (CSS) at the End of Part A | Signs and symptoms reflecting the sensory, vasomotor, sudomotor/edema, and motor/trophic disturbances of CRPS had been incorporated into a clinically feasible CSS. Total CSS is a 16-point score which was calculated by the number of yes answers to the questions on the 8 symptoms and 8 signs when all 16 questions were answered. Negative change from Baseline indicates improvement. | Baseline and Week 15 | 
| Percent Change From Baseline in CSS at the End of Part A | Signs and symptoms reflecting the sensory, vasomotor, sudomotor/edema, and motor/trophic disturbances of CRPS had been incorporated into a clinically feasible CSS. Total CSS is a 16-point score which was calculated by the number of yes answers to the questions on the 8 symptoms and 8 signs when all 16 questions were answered. Negative percent change from Baseline indicates improvement. | Baseline and Week 15 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug Therapy, Soticlestat, TAk-935