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Clinical Trial Results:
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

Summary
EudraCT number	2018-004750-21
Trial protocol	GB
Global end of trial date	28 Oct 2020

Results information
Results version number	v1(current)
This version publication date	04 Nov 2021
First version publication date	04 Nov 2021
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

TAK-935-2008

ISRCTN number

US NCT number

NCT03990649

WHO universal trial number (UTN)

Sponsor organisation name

Takeda

Sponsor organisation address

95 Hayden Avenue, Lexington, MA, United States, 02421

Public contact

Study Director, Takeda, TrialDisclosures@takeda.com

Scientific contact

Study Director, Takeda, TrialDisclosures@takeda.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

28 Oct 2020

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

28 Oct 2020

Was the trial ended prematurely?

Main objective of the trial

The main objective this study is to investigate the effect of soticlestat (TAK-935) on calculated 24-hour average pain intensity by the numeric pain scale (NPS).

Protection of trial subjects

All the participants were required to read and sign the informed consent form (ICF).

Background therapy

Evidence for comparator

Actual start date of recruitment

23 Jul 2019

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 24

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Participants took part in the study at three investigative sites in United Kingdom (UK) from 23 July 2019 to 28 October 2020.

Screening details

Participants 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.

Period 1 title

Part A: DB Treatment Period (15 weeks)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer

Are arms mutually exclusive

Yes

Double-Blind Treatment Period - Part A: Placebo

Arm description

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.

Arm type

Placebo

Investigational medicinal product name

Matching-placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Soticlestat matching placebo tablets

Double-Blind Treatment Period - Part A: Soticlestat

Arm description

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.

Arm type

Experimental

Investigational medicinal product name

Soticlestat

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Soticlestat tablets

Number of subjects in period 1	Double-Blind Treatment Period - Part A: Placebo	Double-Blind Treatment Period - Part A: Soticlestat
Started	9	15
Completed	6	12
Not completed	3	3
Adverse event, non-fatal	-	1
Withdrawal by Subject	2	-
Lost to follow-up	-	1
Reason not Specified	1	1

Period 2 title

Part B: OL Extension Period (14 weeks)

Is this the baseline period?

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Open-Label Extension Period - Part B: Soticlestat

Arm description

Soticlestat, 2x100 mg tablets, orally, BID for Week 1, followed by 3x100 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): 3x100 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.

Arm type

Experimental

Investigational medicinal product name

Soticlestat

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Soticlestat tablets

Number of subjects in period 2	Open-Label Extension Period - Part B: Soticlestat
Started	18
Completed	14
Not completed	4
Adverse event, non-fatal	1
Withdrawal by Subject	2
Reason not Specified	1

Baseline characteristics

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Reporting group title

Double-Blind Treatment Period - Part A: Placebo

Reporting group description

Reporting group title

Double-Blind Treatment Period - Part A: Soticlestat

Reporting group description

Reporting group values	Double-Blind Treatment Period - Part A: Placebo	Double-Blind Treatment Period - Part A: Soticlestat	Total
Number of subjects	9	15	24
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	39.0 ( 13.51 )	42.1 ( 10.27 )	-
Gender categorical
Units: Subjects
Female	6	11	17
Male	3	4	7
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	0	1	1
Not Hispanic or Latino	7	13	20
Unknown or Not Reported	2	1	3
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	0
Asian	0	0	0
Native Hawaiian or Other Pacific Islander	0	0	0
Black or African American	0	0	0
White	9	15	24
More than one race	0	0	0
Unknown or Not Reported	0	0	0
Region of Enrollment
Units: Subjects
United Kingdom	9	15	24
Numeric Pain Scale (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. NPS is an 11-point scale, where scores range from 0-10, 0= no pain to 10 = most pain imaginable.
Units: scores on a scale
arithmetic mean (full range (min-max))	6.33 (4.9 to 7.8)	6.33 (4.5 to 7.6)	-
CRPS Severity Score (CSS) Total Score
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.
Units: scores on a scale
arithmetic mean (standard deviation)	12.7 ( 1.73 )	12.9 ( 1.87 )	-
Patient-Reported Outcomes Measurement Information System v2.1 Domain (Physical Function) Score
Patient-Reported Outcomes Measurement Information System (PROMIS-29) v2.1 assess health-related quality of life for 7 domains with T-scores of reference population: Physical function:1=unable to do-5=without any difficulty;T-scores:22.5-57.03. Higher scores=more of domain being measured.
Units: score on a scale
arithmetic mean (standard deviation)	35.83 ( 5.607 )	34.65 ( 4.743 )	-
PROMIS-29 v2.1 Domain (Anxiety) Score
PROMIS-29 (v2.1) assess health-related quality of life for 7 domains with T-scores of reference population: Anxiety:1=never-5=always;T-scores:40.3-81.6. Higher scores=more of domain being measured.
Units: score on a scale
arithmetic mean (standard deviation)	46.30 ( 11.906 )	51.94 ( 8.873 )	-
PROMIS-29 v2.1 Domain (Depression) Score
Measure Description: PROMIS-29 (v2.1) assess health-related quality of life for 7 domains with T-scores of reference population: Depression:1=never-5=always;T-scores:41.0-79.4. Higher scores=more of domain being measured.
Units: score on a scale
arithmetic mean (standard deviation)	47.31 ( 12.523 )	47.27 ( 8.868 )	-
PROMIS-29 v2.1 Domain (Fatigue) Score
PROMIS-29 (v2.1) assess health-related quality of life for 7 domains with T-scores of reference population: Fatigue:1=not at all-5=very much;T-scores:33.7-75.8. Higher scores=more of domain being measured.
Units: score on a scale
arithmetic mean (standard deviation)	57.17 ( 8.427 )	60.55 ( 8.280 )	-
PROMIS-29 v2.1 Domain (Sleep Disturbance) Score
PROMIS-29 (v2.1) assess health-related quality of life for 7 domains with T-scores of reference population: Sleep disturbance:1=very much-5=not at all;T-scores:32.0-73.3. Higher scores=more of domain being measured.
Units: score on a scale
arithmetic mean (standard deviation)	54.63 ( 3.854 )	54.99 ( 2.390 )	-
PROMIS-29 v2.1 Domain (Ability to Participate in Social Roles and Activities) Score
PROMIS-29 (v2.1) assess health-related quality of life for 7 domains with T-scores of reference population: Ability to participate in social roles and activities:1=always-5=never;T-scores:27.5-64.2 Higher scores=more of domain being measured.
Units: score on a scale
arithmetic mean (standard deviation)	40.03 ( 6.205 )	39.11 ( 4.723 )	-
PROMIS-29 v2.1 Domain (Pain Interference) Score
PROMIS-29 (v2.1) assess health-related quality of life for 7 domains with T-scores of reference population: Pain interference: 1=not at all-5=very much;T-scores:41.6-75.6. Higher scores=more of domain being measured.
Units: score on a scale
arithmetic mean (standard deviation)	66.37 ( 6.710 )	64.22 ( 8.039 )	-

End points

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Reporting group title

Double-Blind Treatment Period - Part A: Placebo

Reporting group description

Reporting group title

Double-Blind Treatment Period - Part A: Soticlestat

Reporting group description

Reporting group title

Open-Label Extension Period - Part B: Soticlestat

Reporting group description

Primary: Change From Baseline in Mean 24-Hour Pain Intensity as Assessed by NPS Score to the End of Part A

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End point title

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

End point description

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. Full Analysis Set (FAS) included all participants who were randomised, 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 analysed are the number of participants with data available for analyses.

End point type

Primary

End point timeframe

Baseline and Week 15

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive analysis are reported for this endpoint.

End point values	Double-Blind Treatment Period - Part A: Placebo	Double-Blind Treatment Period - Part A: Soticlestat
Number of subjects analysed	7	12
Units: scores on scale
arithmetic mean (standard deviation)	-0.74 ( 1.614 )	-1.05 ( 1.310 )

No statistical analyses for this end point

Secondary: Percent Change From Baseline in Mean 24-Hour Pain Intensity as Assessed by NPS Score to the End of Part A

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End point title

Percent Change From Baseline in Mean 24-Hour Pain Intensity as Assessed by NPS Score to the End of Part A

End point description

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. FAS included all participants who were randomised, 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 analysed are the number of participants with data available for analyses.

End point type

Secondary

End point timeframe

Baseline and Week 15

End point values	Double-Blind Treatment Period - Part A: Placebo	Double-Blind Treatment Period - Part A: Soticlestat
Number of subjects analysed	7	12
Units: percent change
arithmetic mean (standard deviation)	-12.20 ( 29.108 )	-18.35 ( 23.699 )

No statistical analyses for this end point

Secondary: Percentage of Participants Considered Responders at the End of Part A

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End point title

Percentage of Participants Considered Responders at the End of Part A

End point description

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. FAS included all participants who were randomised, 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.

End point type

Secondary

End point timeframe

Week 15

End point values	Double-Blind Treatment Period - Part A: Placebo	Double-Blind Treatment Period - Part A: Soticlestat
Number of subjects analysed	9	15
Units: percentage of participants
number (not applicable)	22.2	26.7

No statistical analyses for this end point

Secondary: Change From Baseline (CFB) in Domain Score of PROMIS-29 Version 2.1 at the End of Part A

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End point title

Change From Baseline (CFB) in Domain Score of PROMIS-29 Version 2.1 at the End of Part A

End point description

PROMIS-29(v2.1 ): assessed 7 domains with 4 questions on 5-point Likert scale.Total raw domain scores are converted into Tscores(TS):Depression and Anxiety:1 =never to S=always,TS:41.0-79.4 and 40.3-81.6; Physical function:1 =unable to do to S=without any difficulty,TS:22.5-57.0; Pain interference and Fatigue:1 =not at all to S=very much,TS:41.6-75.6 and 33.7-75.B; Sleep disturbance:1 =very much to 5=not at all,TS:32.0-73.3; Ability to participate in social activities:1 =always to S=never,TS:27.5-64.2. High scores(HS):more of domain being measured. On symptom-oriented domains,HS=worse symptomatology and negative CFB indicates improvement.On function oriented domains, HS=better functioning and positive CFB indicates improvement. FAS:all randomised, received at least 1 dose of study drug, and had at least one valid post-baseline value for assessment of average 24-hour pain score. Data is reported for part A. Here 'n' is number analysed are participants with data available for analyses.

End point type

Secondary

End point timeframe

Baseline and Week 15

End point values	Double-Blind Treatment Period - Part A: Placebo	Double-Blind Treatment Period - Part A: Soticlestat
Number of subjects analysed	9	15
Units: t-score
arithmetic mean (standard deviation)
Physical Function (n =8, 12)	1.53 ( 2.207 )	2.39 ( 4.042 )
Anxiety (n=8, 13)	3.29 ( 10.348 )	-1.99 ( 9.567 )
Depression (n=8, 13)	1.15 ( 10.011 )	-0.78 ( 6.902 )
Fatigue (n=8, 13)	0.45 ( 12.126 )	-3.66 ( 10.456 )
Sleep Disturbance (n=8, 13)	2.13 ( 5.110 )	2.55 ( 1.927 )
Ability to Participate in Social Roles (n=7, 13)	1.66 ( 6.051 )	2.74 ( 5.147 )
Pain Interference (n=7, 13)	-1.53 ( 6.257 )	-0.38 ( 7.597 )

No statistical analyses for this end point

Secondary: Percent Change From Baseline in Domain Score of PROMIS-29 Version 2.1 at the End of Part A

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End point title

Percent Change From Baseline in Domain Score of PROMIS-29 Version 2.1 at the End of Part A

End point description

PROMIS-29(v2.1 ):assessed 7 domains with 4 questions on 5-point Likert scale. Total raw domain scores are converted into T-scores(TS): Depression and Anxiety:1=never to 5=always,TS:41.0-79.4 and 40.3- 81.6; Physical function:1 =unable to do to 5=without any difficulty,TS:22.5-57.0; Pain interference and Fatigue:1=not at all to 5=very much,TS:41.6-75.6 and 33.7-75.8;Sleep disturbance:1=very much to 5=not at all,TS: 32.0-73.3;Ability to participate in social activities:1=always to 5=never,TS:27.5-64.2. High scores(HS):more of domain being measured. On symptom-oriented domains, HS=worse symptomatology and negative CFB indicates improvement. On function-oriented domains, HS=better functioning and positive CFB indicates improvement. FAS:all randomised, received at least 1 dose of study drug, and had at least one valid post-baseline value for assessment of average 24-hour pain score. Data is reported for part A. 'n' indicates number analysed are participants with data available for analyse.

End point type

Secondary

End point timeframe

Baseline and Week 15

End point values	Double-Blind Treatment Period - Part A: Placebo	Double-Blind Treatment Period - Part A: Soticlestat
Number of subjects analysed	9	15
Units: percent change
arithmetic mean (standard deviation)
Physical Function (n =8, 12)	4.27 ( 6.197 )	8.00 ( 14.106 )
Anxiety (n=8, 13)	9.35 ( 24.153 )	-2.43 ( 16.584 )
Depression (n=8, 13)	4.51 ( 21.864 )	0.04 ( 13.494 )
Fatigue (n=8, 13)	2.42 ( 22.902 )	-4.62 ( 16.045 )
Sleep Disturbance (n=8, 13)	4.46 ( 9.611 )	4.75 ( 3.600 )
Ability to Participate in Social Roles (n=7, 13)	4.39 ( 15.195 )	7.42 ( 13.796 )
Pain Interference (n=7, 13)	-1.88 ( 9.149 )	0.82 ( 15.571 )

No statistical analyses for this end point

Secondary: Percentage of Participants in Each Category of the Patient Global Impression of Change (PGIC) Scale at the End of Part A

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End point title

Percentage of Participants in Each Category of the Patient Global Impression of Change (PGIC) Scale at the End of Part A

End point description

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. FAS included all participants who were randomised, 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.

End point type

Secondary

End point timeframe

Week 15

End point values	Double-Blind Treatment Period - Part A: Placebo	Double-Blind Treatment Period - Part A: Soticlestat
Number of subjects analysed	9	15
Units: percentage of participants
number (not applicable)
Much Improved	33.33	33.33
Minimally Improved	11.1	13.3
No Change	22.2	33.3
Minimally Worse	11.1	0
Missing	22.2	20.0

No statistical analyses for this end point

Secondary: Change From Baseline in Complex Regional Pain Syndrome (CSS) at the End of Part A

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End point title

Change From Baseline in Complex Regional Pain Syndrome (CSS) at the End of Part A

End point description

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. FAS included all participants who were randomised, 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 analysed are the number of participants with data available for analyses.

End point type

Secondary

End point timeframe

Baseline and Week 15

End point values	Double-Blind Treatment Period - Part A: Placebo	Double-Blind Treatment Period - Part A: Soticlestat
Number of subjects analysed	6	13
Units: scores on scale
arithmetic mean (standard deviation)	-2.2 ( 2.48 )	-3.1 ( 3.12 )

Statistical Analysis for CSS

Comparison groups

Double-Blind Treatment Period - Part A: Placebo v Double-Blind Treatment Period - Part A: Soticlestat

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.54 ^[2]

Method

t-test, 2-sided

Confidence interval

Notes
[2] - The p-values were estimated using a two-sample t-test.

Secondary: Percent Change From Baseline in CSS at the End of Part A

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End point title

Percent Change From Baseline in CSS at the End of Part A

End point description

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. FAS included all participants who were randomised, 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 analysed are the number of participants with data available for analyses.

End point type

Secondary

End point timeframe

Baseline and Week 15

End point values	Double-Blind Treatment Period - Part A: Placebo	Double-Blind Treatment Period - Part A: Soticlestat
Number of subjects analysed	6	13
Units: percent change
arithmetic mean (standard deviation)	-16.1 ( 18.89 )	-23.8 ( 26.29 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From signing of the informed consent up to 15 days after last dose of the study drug (Up to approximately Week 32)

Adverse event reporting additional 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.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

23.0

Reporting group title

Double-Blind Treatment Period - Part A: Placebo

Reporting group description

Reporting group title

Double-Blind Treatment Period - Part A: Soticlestat

Reporting group description

Reporting group title

Open-Label Extension Period - Part B: Soticlestat

Reporting group description

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.

Serious adverse events	Double-Blind Treatment Period - Part A: Placebo	Double-Blind Treatment Period - Part A: Soticlestat	Open-Label Extension Period - Part B: Soticlestat
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 9 (0.00%)	3 / 15 (20.00%)	0 / 18 (0.00%)
number of deaths (all causes)	0	0	0
number of deaths resulting from adverse events	0	0	0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 9 (0.00%)	2 / 15 (13.33%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	0 / 9 (0.00%)	1 / 15 (6.67%)	0 / 18 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Double-Blind Treatment Period - Part A: Placebo	Double-Blind Treatment Period - Part A: Soticlestat	Open-Label Extension Period - Part B: Soticlestat
Total subjects affected by non serious adverse events
subjects affected / exposed	9 / 9 (100.00%)	12 / 15 (80.00%)	10 / 18 (55.56%)
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	0 / 9 (0.00%)	0 / 15 (0.00%)	2 / 18 (11.11%)
occurrences all number	0	0	2
Procedural pain
subjects affected / exposed	1 / 9 (11.11%)	0 / 15 (0.00%)	1 / 18 (5.56%)
occurrences all number	1	0	1
Nervous system disorders
Dizziness
subjects affected / exposed	2 / 9 (22.22%)	4 / 15 (26.67%)	0 / 18 (0.00%)
occurrences all number	2	5	0
Headache
subjects affected / exposed	4 / 9 (44.44%)	2 / 15 (13.33%)	5 / 18 (27.78%)
occurrences all number	7	3	7
Lethargy
subjects affected / exposed	1 / 9 (11.11%)	1 / 15 (6.67%)	0 / 18 (0.00%)
occurrences all number	1	2	0
General disorders and administration site conditions
Fatigue
subjects affected / exposed	0 / 9 (0.00%)	2 / 15 (13.33%)	0 / 18 (0.00%)
occurrences all number	0	2	0
Influenza like illness
subjects affected / exposed	0 / 9 (0.00%)	2 / 15 (13.33%)	0 / 18 (0.00%)
occurrences all number	0	2	0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	1 / 9 (11.11%)	1 / 15 (6.67%)	1 / 18 (5.56%)
occurrences all number	1	1	1
Constipation
subjects affected / exposed	1 / 9 (11.11%)	2 / 15 (13.33%)	1 / 18 (5.56%)
occurrences all number	1	3	1
Dry mouth
subjects affected / exposed	0 / 9 (0.00%)	2 / 15 (13.33%)	0 / 18 (0.00%)
occurrences all number	0	2	0
Nausea
subjects affected / exposed	1 / 9 (11.11%)	3 / 15 (20.00%)	1 / 18 (5.56%)
occurrences all number	1	4	1
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	3 / 9 (33.33%)	1 / 15 (6.67%)	1 / 18 (5.56%)
occurrences all number	3	1	1
Oropharyngeal pain
subjects affected / exposed	0 / 9 (0.00%)	2 / 15 (13.33%)	0 / 18 (0.00%)
occurrences all number	0	2	0
Psychiatric disorders
Depressed mood
subjects affected / exposed	2 / 9 (22.22%)	0 / 15 (0.00%)	1 / 18 (5.56%)
occurrences all number	2	0	1
Insomnia
subjects affected / exposed	1 / 9 (11.11%)	2 / 15 (13.33%)	1 / 18 (5.56%)
occurrences all number	1	2	1
Suicidal ideation
subjects affected / exposed	0 / 9 (0.00%)	0 / 15 (0.00%)	2 / 18 (11.11%)
occurrences all number	0	0	2
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 9 (0.00%)	0 / 15 (0.00%)	2 / 18 (11.11%)
occurrences all number	0	0	2
Musculoskeletal pain
subjects affected / exposed	0 / 9 (0.00%)	2 / 15 (13.33%)	0 / 18 (0.00%)
occurrences all number	0	2	0
Neck pain
subjects affected / exposed	1 / 9 (11.11%)	1 / 15 (6.67%)	0 / 18 (0.00%)
occurrences all number	1	1	0
Infections and infestations
Conjunctivitis
subjects affected / exposed	0 / 9 (0.00%)	1 / 15 (6.67%)	2 / 18 (11.11%)
occurrences all number	0	1	2
Lower respiratory tract infection
subjects affected / exposed	1 / 9 (11.11%)	1 / 15 (6.67%)	0 / 18 (0.00%)
occurrences all number	1	1	0
Nasopharyngitis
subjects affected / exposed	2 / 9 (22.22%)	1 / 15 (6.67%)	1 / 18 (5.56%)
occurrences all number	2	1	1
Oral candidiasis
subjects affected / exposed	0 / 9 (0.00%)	1 / 15 (6.67%)	1 / 18 (5.56%)
occurrences all number	0	1	1
Oral herpes
subjects affected / exposed	1 / 9 (11.11%)	0 / 15 (0.00%)	1 / 18 (5.56%)
occurrences all number	2	0	1
Urinary tract infection
subjects affected / exposed	1 / 9 (11.11%)	1 / 15 (6.67%)	0 / 18 (0.00%)
occurrences all number	2	1	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 9 (0.00%)	2 / 15 (13.33%)	0 / 18 (0.00%)
occurrences all number	0	2	0

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Were there any global substantial amendments to the protocol? Yes

08 May 2019

Amendment 1: -Updated the language regarding unblinding procedures.

01 Jul 2019

Amendment 2: - Corrected a typographical error -Updated the language regarding contraception procedures -Updated the language regarding pharmacogenomics sample collection -Corrected the 29-item Patient-Reported Outcomes Measurement Information System (PROMIS-29) scale to version 2.1.

16 Dec 2019

Amendment 3: - Updated the dose selection rationale -Clarified the schematic of study design -Moved a secondary objective to an exploratory objective to align with endpoints -Modified Figure 4.a. -Clarified the rationale for the study -Moved the detail on pharmacogenomic analysis -Revised contraceptive requirements -Modified the detail regarding blood volumes collected during the study -Clarified the ECG procedures for specific visits -Clarified the efficacy analysis, the exploratory analysis and the interim analysis -Clarified when blood samples for plasma protein binding assessment will be collected.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results:
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

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change From Baseline in Mean 24-Hour Pain Intensity as Assessed by NPS Score to the End of Part A

Primary: Change From Baseline in Mean 24-Hour Pain Intensity as Assessed by NPS Score to the End of Part A

Secondary: Percent Change From Baseline in Mean 24-Hour Pain Intensity as Assessed by NPS Score to the End of Part A

Secondary: Percent Change From Baseline in Mean 24-Hour Pain Intensity as Assessed by NPS Score to the End of Part A

Secondary: Percentage of Participants Considered Responders at the End of Part A

Secondary: Percentage of Participants Considered Responders at the End of Part A

Secondary: Change From Baseline (CFB) in Domain Score of PROMIS-29 Version 2.1 at the End of Part A

Secondary: Change From Baseline (CFB) in Domain Score of PROMIS-29 Version 2.1 at the End of Part A

Secondary: Percent Change From Baseline in Domain Score of PROMIS-29 Version 2.1 at the End of Part A

Secondary: Percent Change From Baseline in Domain Score of PROMIS-29 Version 2.1 at the End of Part A

Secondary: Percentage of Participants in Each Category of the Patient Global Impression of Change (PGIC) Scale at the End of Part A

Secondary: Percentage of Participants in Each Category of the Patient Global Impression of Change (PGIC) Scale at the End of Part A

Secondary: Change From Baseline in Complex Regional Pain Syndrome (CSS) at the End of Part A

Secondary: Change From Baseline in Complex Regional Pain Syndrome (CSS) at the End of Part A

Secondary: Percent Change From Baseline in CSS at the End of Part A

Secondary: Percent Change From Baseline in CSS at the End of Part A

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials

Clinical Trial Results: 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

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change From Baseline in Mean 24-Hour Pain Intensity as Assessed by NPS Score to the End of Part A

Primary: Change From Baseline in Mean 24-Hour Pain Intensity as Assessed by NPS Score to the End of Part A

Secondary: Percent Change From Baseline in Mean 24-Hour Pain Intensity as Assessed by NPS Score to the End of Part A

Secondary: Percent Change From Baseline in Mean 24-Hour Pain Intensity as Assessed by NPS Score to the End of Part A

Secondary: Percentage of Participants Considered Responders at the End of Part A

Secondary: Percentage of Participants Considered Responders at the End of Part A

Secondary: Change From Baseline (CFB) in Domain Score of PROMIS-29 Version 2.1 at the End of Part A

Secondary: Change From Baseline (CFB) in Domain Score of PROMIS-29 Version 2.1 at the End of Part A

Secondary: Percent Change From Baseline in Domain Score of PROMIS-29 Version 2.1 at the End of Part A

Secondary: Percent Change From Baseline in Domain Score of PROMIS-29 Version 2.1 at the End of Part A

Secondary: Percentage of Participants in Each Category of the Patient Global Impression of Change (PGIC) Scale at the End of Part A

Secondary: Percentage of Participants in Each Category of the Patient Global Impression of Change (PGIC) Scale at the End of Part A

Secondary: Change From Baseline in Complex Regional Pain Syndrome (CSS) at the End of Part A

Secondary: Change From Baseline in Complex Regional Pain Syndrome (CSS) at the End of Part A

Secondary: Percent Change From Baseline in CSS at the End of Part A

Secondary: Percent Change From Baseline in CSS at the End of Part A

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
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