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

Sponsor
Millennium Pharmaceuticals, Inc. (Industry)
Overall Status
Completed
CT.gov ID
NCT03990649
Collaborator
(none)
24
Enrollment
3
Locations
3
Arms
15.2
Actual Duration (Months)
8
Patients Per Site
0.5
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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).

Condition or DiseaseIntervention/TreatmentPhase
Phase 2

Detailed Description

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.

Study Design

Study Type:
Interventional
Actual Enrollment :
24 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
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
Actual Study Start Date :
Jul 23, 2019
Actual Primary Completion Date :
Jun 29, 2020
Actual Study Completion Date :
Oct 28, 2020

Arms and Interventions

ArmIntervention/Treatment
Placebo Comparator: Double-Blind Treatment Period - Part A: Placebo

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
Soticlestat matching placebo tablets

Experimental: Double-Blind Treatment Period - Part A: Soticlestat

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
Soticlestat tablets
Other Names:
  • TAK-935
  • Experimental: Open-Label Extension Period - Part B: Soticlestat

    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
    Soticlestat tablets
    Other Names:
  • TAK-935
  • Outcome Measures

    Primary Outcome Measures

    1. Change From Baseline in Mean 24-Hour Pain Intensity as Assessed by NPS Score to the End of Part A [Baseline and Week 15]

      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.

    Secondary Outcome Measures

    1. Percent Change From Baseline in Mean 24-Hour Pain Intensity as Assessed by NPS Score to the End of Part A [Baseline and Week 15]

      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.

    2. Percentage of Participants Considered Responders at the End of Part A [Week 15]

      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.

    3. Change From Baseline in Domain Score of PROMIS-29 Version 2.1 at the End of Part A [Baseline and Week 15]

      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.

    4. Percent Change From Baseline in Domain Score of PROMIS-29 Version 2.1 at the End of Part A [Baseline and Week 15]

      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.

    5. Percentage of Participants in Each Category of the Patient Global Impression of Change (PGIC) Scale at the End of Part A [Week 15]

      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.

    6. Change From Baseline in Complex Regional Pain Syndrome (CSS) at the End of Part A [Baseline and Week 15]

      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.

    7. Percent Change From Baseline in CSS at the End of Part A [Baseline and Week 15]

      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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 75 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    1. 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.

    2. 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.

    3. 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.

    4. 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:
    1. 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.

    2. Participant is receiving chronic opioid treatment at a dose that has not been stable 28 days prior to screening.

    3. Participant is receiving chronic opioid treatment >160 mg of morphine equivalent per day.

    4. Participant has a positive drug screen for phencyclidine, amphetamine/ methamphetamine, or cocaine at screening. Cannabis is allowed..

    5. 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 -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).

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1St Pancras Clinical ResearchLondonEnglandUnited KingdomWC1X 8QD
    2Lancashire Teaching Hospitals NHS Foundation TrustPrestonEnglandUnited KingdomPR2 9HT
    3University Hospital Southampton NHS Foundation TrustSouthamptonEnglandUnited KingdomSO16 6YD

    Sponsors and Collaborators

    • Millennium Pharmaceuticals, Inc.

    Investigators

    • Study Director: Study Director, Takeda

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Millennium Pharmaceuticals, Inc.
    ClinicalTrials.gov Identifier:
    NCT03990649
    Other Study ID Numbers:
    • TAK-935-2008
    First Posted:
    Jun 19, 2019
    Last Update Posted:
    Jul 15, 2021
    Last Verified:
    Jun 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Millennium Pharmaceuticals, Inc.
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment DetailsParticipants took part in the study at three investigative sites in United Kingdom (UK) from 23 July 2019 to 28 October 2020.
    Pre-assignment DetailParticipants with a diagnosis of chronic complex regional pain syndrome (CRPS) were enrolled to receive soticlestat or placebo in Part A (Double-blind [DB] Treatment Period) and soticlestat in Part B (Open-label [OL] Treatment Period). Following completion of the Part A, participants had an option to continue into Part B.
    Arm/Group TitleDouble-Blind Treatment Period - Part A: PlaceboDouble-Blind Treatment Period - Part A: SoticlestatOpen-Label Extension Period - Part B: Soticlestat
    Arm/Group DescriptionSoticlestat 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.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.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.
    Period Title: Part A: DB Treatment Period (15 Weeks)
    STARTED9150
    COMPLETED6120
    NOT COMPLETED330
    Period Title: Part A: DB Treatment Period (15 Weeks)
    STARTED0018
    COMPLETED0014
    NOT COMPLETED004

    Baseline Characteristics

    Arm/Group TitleDouble-Blind Treatment Period - Part A: PlaceboDouble-Blind Treatment Period - Part A: SoticlestatTotal
    Arm/Group DescriptionSoticlestat 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.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.Total of all reporting groups
    Overall Participants91524
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    39.0
    (13.51)
    42.1
    (10.27)
    41.0
    (11.40)
    Sex: Female, Male (Count of Participants)
    Female
    6
    66.7%
    11
    73.3%
    17
    70.8%
    Male
    3
    33.3%
    4
    26.7%
    7
    29.2%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    0
    0%
    0
    0%
    0
    0%
    Not Hispanic or Latino
    7
    77.8%
    14
    93.3%
    21
    87.5%
    Unknown or Not Reported
    2
    22.2%
    1
    6.7%
    3
    12.5%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    Asian
    0
    0%
    0
    0%
    0
    0%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    0
    0%
    0
    0%
    0
    0%
    White
    9
    100%
    15
    100%
    24
    100%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    Region of Enrollment (Count of Participants)
    United Kingdom
    9
    100%
    15
    100%
    24
    100%
    Numeric Pain Scale (NPS) Score (scores on a scale) [Mean (Full Range) ]
    Mean (Full Range) [scores on a scale]
    6.33
    6.33
    6.33
    Patient-Reported Outcomes Measurement Information System (PROMIS-29) Version 2.1 Domain Score (t-score) [Mean (Standard Deviation) ]
    Physical Function
    35.83
    (5.607)
    34.65
    (4.743)
    35.09
    (4.998)
    Anxiety
    46.30
    (11.906)
    51.94
    (8.873)
    49.83
    (10.248)
    Depression
    47.31
    (12.523)
    47.27
    (8.868)
    47.28
    (10.120)
    Fatigue
    57.17
    (8.427)
    60.55
    (8.280)
    59.28
    (8.321)
    Sleep Disturbance
    54.63
    (3.854)
    54.99
    (2.390)
    54.86
    (2.945)
    Ability to Participate in Social Roles and Activities
    40.03
    (6.205)
    39.11
    (4.723)
    39.45
    (5.213)
    Pain Interference
    66.37
    (6.710)
    64.22
    (8.039)
    65.03
    (7.492)
    CRPS Severity Score (CSS) Total Score (scores on a scale) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [scores on a scale]
    12.7
    (1.73)
    12.9
    (1.87)
    12.8
    (1.79)

    Outcome Measures

    1. Primary Outcome
    TitleChange From Baseline in Mean 24-Hour Pain Intensity as Assessed by NPS Score to the End of Part A
    DescriptionThe 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.
    Time FrameBaseline and Week 15

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set for included all participants who were randomized, received at least 1 dose of study drug, and had at least one valid post-baseline value for the assessment of average 24-hour pain score. The data is reported for Part A in this outcome measure. Overall number of participants analyzed are the number of participants with data available for analyses.
    Arm/Group TitleDouble-Blind Treatment Period - Part A: PlaceboDouble-Blind Treatment Period - Part A: Soticlestat
    Arm/Group DescriptionSoticlestat 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.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.
    Measure Participants712
    Mean (Standard Deviation) [scores on scale]
    -0.74
    (1.614)
    -1.05
    (1.310)
    2. Secondary Outcome
    TitlePercent Change From Baseline in Mean 24-Hour Pain Intensity as Assessed by NPS Score to the End of Part A
    DescriptionThe 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.
    Time FrameBaseline and Week 15

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set for included all participants who were randomized, received at least 1 dose of study drug, and had at least one valid post-baseline value for the assessment of average 24-hour pain score. The data is reported for Part A in this outcome measure. Overall number of participants analyzed are the number of participants with data available for analyses.
    Arm/Group TitleDouble-Blind Treatment Period - Part A: PlaceboDouble-Blind Treatment Period - Part A: Soticlestat
    Arm/Group DescriptionSoticlestat 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.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.
    Measure Participants712
    Mean (Standard Deviation) [percent change]
    -12.20
    (29.108)
    -18.35
    (23.699)
    3. Secondary Outcome
    TitlePercentage of Participants Considered Responders at the End of Part A
    DescriptionResponse 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.
    Time FrameWeek 15

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set for included all participants who were randomized, received at least 1 dose of study drug, and had at least one valid post-baseline value for the assessment of average 24-hour pain score. The data is reported for Part A in this outcome measure.
    Arm/Group TitleDouble-Blind Treatment Period - Part A: PlaceboDouble-Blind Treatment Period - Part A: Soticlestat
    Arm/Group DescriptionSoticlestat 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.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.
    Measure Participants915
    Number [percentage of participants]
    22.2
    246.7%
    26.7
    178%
    4. Secondary Outcome
    TitleChange From Baseline in Domain Score of PROMIS-29 Version 2.1 at the End of Part A
    DescriptionPROMIS-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.
    Time FrameBaseline and Week 15

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set for included all participants who were randomized, received at least 1 dose of study drug, and had at least one valid post-baseline value for the assessment of average 24-hour pain score. The data is reported for Part A in this outcome measure. Number analyzed are the number of participants with data available for analyses in the given category (domain).
    Arm/Group TitleDouble-Blind Treatment Period - Part A: PlaceboDouble-Blind Treatment Period - Part A: Soticlestat
    Arm/Group DescriptionSoticlestat 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.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.
    Measure Participants915
    Physical Function
    1.53
    (2.207)
    2.39
    (4.042)
    Anxiety
    3.29
    (10.348)
    -1.99
    (9.567)
    Depression
    1.15
    (10.011)
    -0.78
    (6.902)
    Fatigue
    0.45
    (12.126)
    -3.66
    (10.456)
    Sleep Disturbance
    2.13
    (5.110)
    2.55
    (1.927)
    Ability to Participate in Social Roles
    1.66
    (6.051)
    2.74
    (5.147)
    Pain Interference
    -1.53
    (6.257)
    -0.38
    (7.597)
    5. Secondary Outcome
    TitlePercent Change From Baseline in Domain Score of PROMIS-29 Version 2.1 at the End of Part A
    DescriptionPROMIS-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.
    Time FrameBaseline and Week 15

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set for included all participants who were randomized, received at least 1 dose of study drug, and had at least one valid post-baseline value for the assessment of average 24-hour pain score. The data is reported for Part A in this outcome measure. Number analyzed are the number of participants with data available for analyses in the given category (domain).
    Arm/Group TitleDouble-Blind Treatment Period - Part A: PlaceboDouble-Blind Treatment Period - Part A: Soticlestat
    Arm/Group DescriptionSoticlestat 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.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.
    Measure Participants915
    Physical Function
    4.27
    (6.197)
    8.00
    (14.106)
    Anxiety
    9.35
    (24.153)
    -2.43
    (16.584)
    Depression
    4.51
    (21.864)
    0.04
    (13.494)
    Fatigue
    2.42
    (22.902)
    -4.62
    (16.045)
    Sleep Disturbance
    4.46
    (9.611)
    4.75
    (3.600)
    Ability to Participate in Social Roles
    4.39
    (15.195)
    7.42
    (13.796)
    Pain Interference
    -1.88
    (9.149)
    0.82
    (15.571)
    6. Secondary Outcome
    TitlePercentage of Participants in Each Category of the Patient Global Impression of Change (PGIC) Scale at the End of Part A
    DescriptionThe 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.
    Time FrameWeek 15

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set for included all participants who were randomized, received at least 1 dose of study drug, and had at least one valid post-baseline value for the assessment of average 24-hour pain score. The data is reported for Part A in this outcome measure.
    Arm/Group TitleDouble-Blind Treatment Period - Part A: PlaceboDouble-Blind Treatment Period - Part A: Soticlestat
    Arm/Group DescriptionSoticlestat 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.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.
    Measure Participants915
    Much Improved
    33.3
    370%
    33.3
    222%
    Minimally Improved
    11.1
    123.3%
    13.3
    88.7%
    No Change
    22.2
    246.7%
    33.3
    222%
    Minimally Worse
    11.1
    123.3%
    0
    0%
    Missing
    22.2
    246.7%
    20.0
    133.3%
    7. Secondary Outcome
    TitleChange From Baseline in Complex Regional Pain Syndrome (CSS) at the End of Part A
    DescriptionSigns 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.
    Time FrameBaseline and Week 15

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set for included all participants who were randomized, received at least 1 dose of study drug, and had at least one valid post-baseline value for the assessment of average 24-hour pain score. The data is reported for Part A in this outcome measure. Overall number of participants analyzed are the number of participants with data available for analyses.
    Arm/Group TitleDouble-Blind Treatment Period - Part A: PlaceboDouble-Blind Treatment Period - Part A: Soticlestat
    Arm/Group DescriptionSoticlestat 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.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.
    Measure Participants613
    Mean (Standard Deviation) [scores on scale]
    -2.2
    (2.48)
    -3.1
    (3.12)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Double-Blind Treatment Period - Part A: Placebo, Double-Blind Treatment Period - Part A: Soticlestat
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value0.540
    CommentsThe p-values were estimated using a two-sample t-test.
    Methodt-test, 2 sided
    Comments
    8. Secondary Outcome
    TitlePercent Change From Baseline in CSS at the End of Part A
    DescriptionSigns 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.
    Time FrameBaseline and Week 15

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Set for included all participants who were randomized, received at least 1 dose of study drug, and had at least one valid post-baseline value for the assessment of average 24-hour pain score. The data is reported for Part A in this outcome measure. Overall number of participants analyzed are the number of participants with data available for analyses.
    Arm/Group TitleDouble-Blind Treatment Period - Part A: PlaceboDouble-Blind Treatment Period - Part A: Soticlestat
    Arm/Group DescriptionSoticlestat 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.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.
    Measure Participants613
    Mean (Standard Deviation) [percent change]
    -16.1
    (18.89)
    -23.8
    (26.29)

    Adverse Events

    Time FrameFrom signing of the informed consent up to 15 days after last dose of the study drug (Up to approximately Week 32)
    Adverse Event Reporting Description At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
    Arm/Group TitleDouble-Blind Treatment Period - Part A: PlaceboDouble-Blind Treatment Period - Part A: SoticlestatOpen-Label Extension Period - Part B: Soticlestat
    Arm/Group DescriptionSoticlestat 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.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.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.
    All Cause Mortality
    Double-Blind Treatment Period - Part A: PlaceboDouble-Blind Treatment Period - Part A: SoticlestatOpen-Label Extension Period - Part B: Soticlestat
    Affected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total0/9 (0%) 0/15 (0%) 0/18 (0%)
    Serious Adverse Events
    Double-Blind Treatment Period - Part A: PlaceboDouble-Blind Treatment Period - Part A: SoticlestatOpen-Label Extension Period - Part B: Soticlestat
    Affected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total0/9 (0%) 3/15 (20%) 0/18 (0%)
    Gastrointestinal disorders
    Abdominal pain0/9 (0%) 2/15 (13.3%) 0/18 (0%)
    Hepatobiliary disorders
    Cholecystitis0/9 (0%) 1/15 (6.7%) 0/18 (0%)
    Other (Not Including Serious) Adverse Events
    Double-Blind Treatment Period - Part A: PlaceboDouble-Blind Treatment Period - Part A: SoticlestatOpen-Label Extension Period - Part B: Soticlestat
    Affected / at Risk (%)# EventsAffected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total9/9 (100%) 12/15 (80%) 10/18 (55.6%)
    Gastrointestinal disorders
    Abdominal pain1/9 (11.1%) 1/15 (6.7%) 1/18 (5.6%)
    Constipation1/9 (11.1%) 2/15 (13.3%) 1/18 (5.6%)
    Dry mouth0/9 (0%) 2/15 (13.3%) 0/18 (0%)
    Nausea1/9 (11.1%) 3/15 (20%) 1/18 (5.6%)
    General disorders
    Fatigue0/9 (0%) 2/15 (13.3%) 0/18 (0%)
    Influenza like illness0/9 (0%) 2/15 (13.3%) 0/18 (0%)
    Infections and infestations
    Conjunctivitis0/9 (0%) 1/15 (6.7%) 2/18 (11.1%)
    Lower respiratory tract infection1/9 (11.1%) 1/15 (6.7%) 0/18 (0%)
    Nasopharyngitis2/9 (22.2%) 1/15 (6.7%) 1/18 (5.6%)
    Oral candidiasis0/9 (0%) 1/15 (6.7%) 1/18 (5.6%)
    Oral herpes1/9 (11.1%) 0/15 (0%) 1/18 (5.6%)
    Urinary tract infection1/9 (11.1%) 1/15 (6.7%) 0/18 (0%)
    Injury, poisoning and procedural complications
    Fall0/9 (0%) 0/15 (0%) 2/18 (11.1%)
    Procedural pain1/9 (11.1%) 0/15 (0%) 1/18 (5.6%)
    Metabolism and nutrition disorders
    Decreased appetite0/9 (0%) 2/15 (13.3%) 0/18 (0%)
    Musculoskeletal and connective tissue disorders
    Arthralgia0/9 (0%) 0/15 (0%) 2/18 (11.1%)
    Musculoskeletal pain0/9 (0%) 2/15 (13.3%) 0/18 (0%)
    Neck pain1/9 (11.1%) 1/15 (6.7%) 0/18 (0%)
    Nervous system disorders
    Dizziness2/9 (22.2%) 4/15 (26.7%) 0/18 (0%)
    Headache4/9 (44.4%) 2/15 (13.3%) 5/18 (27.8%)
    Lethargy1/9 (11.1%) 1/15 (6.7%) 0/18 (0%)
    Psychiatric disorders
    Depressed mood2/9 (22.2%) 0/15 (0%) 1/18 (5.6%)
    Insomnia1/9 (11.1%) 2/15 (13.3%) 1/18 (5.6%)
    Suicidal ideation0/9 (0%) 0/15 (0%) 2/18 (11.1%)
    Respiratory, thoracic and mediastinal disorders
    Cough3/9 (33.3%) 1/15 (6.7%) 1/18 (5.6%)
    Oropharyngeal pain0/9 (0%) 2/15 (13.3%) 0/18 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    In general, Investigators may publish clinical data after the earlier of (i) publication by the Sponsor or (ii) 12 months following the abandonment, early termination or database lock; provided a copy of the publication provided to Sponsor at least 30 days ahead of publication, the Sponsor's confidential information is removed as may be requested by Sponsor and Investigator defers publication for up to 60 days in the event Sponsor provides notice that it intends to file a patent application.

    Results Point of Contact

    Name/TitleStudy Director
    OrganizationTakeda
    Phone+1-877-825-3327
    EmailTrialDisclosures@takeda.com
    Responsible Party:
    Millennium Pharmaceuticals, Inc.
    ClinicalTrials.gov Identifier:
    NCT03990649
    Other Study ID Numbers:
    • TAK-935-2008
    First Posted:
    Jun 19, 2019
    Last Update Posted:
    Jul 15, 2021
    Last Verified:
    Jun 1, 2021