Clinical Trial Results:
A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Trial of Brexpiprazole in Treatment of Children and Adolescents With Irritability Associated With Autism Spectrum Disorder
Summary
|
|
EudraCT number |
2019-000723-40 |
Trial protocol |
Outside EU/EEA |
Global end of trial date |
09 Sep 2022
|
Results information
|
|
Results version number |
v1(current) |
This version publication date |
24 Oct 2024
|
First version publication date |
24 Oct 2024
|
Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
|
|||
Trial identification
|
|||
Sponsor protocol code |
331-201-00148
|
||
Additional study identifiers
|
|||
ISRCTN number |
- | ||
US NCT number |
NCT04174365 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
|
|||
Sponsor organisation name |
Otsuka Pharmaceutical Development & Commercialization, Inc.
|
||
Sponsor organisation address |
2440 Research Boulevard, Rockville, United States, 20850
|
||
Public contact |
Krista Martinko, Otsuka Pharmaceutical Development & Commercialization, Inc., 1 8446878522, clinicaltransparency@otsuka-us.com
|
||
Scientific contact |
Krista Martinko, Otsuka Pharmaceutical Development & Commercialization, Inc., 1 8446878522, clinicaltransparency@otsuka-us.com
|
||
Paediatric regulatory details
|
|||
Is trial part of an agreed paediatric investigation plan (PIP) |
No
|
||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
Results analysis stage
|
|||
Analysis stage |
Final
|
||
Date of interim/final analysis |
09 Sep 2022
|
||
Is this the analysis of the primary completion data? |
No
|
||
Global end of trial reached? |
Yes
|
||
Global end of trial date |
09 Sep 2022
|
||
Was the trial ended prematurely? |
No
|
||
General information about the trial
|
|||
Main objective of the trial |
The purpose of this study was to find out about the potential benefits and safety of brexpiprazole in children and adolescent subjects, aged 5 to 17, with irritability associated with autism spectrum disorder.
|
||
Protection of trial subjects |
Written informed consent, assent, or both were obtained from a legally acceptable representative (eg, guardian) or from the subject.
|
||
Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
30 Oct 2019
|
||
Long term follow-up planned |
No
|
||
Independent data monitoring committee (IDMC) involvement? |
Yes
|
||
Population of trial subjects
|
|||
Number of subjects enrolled per country |
|||
Country: Number of subjects enrolled |
United States: 119
|
||
Worldwide total number of subjects |
119
|
||
EEA total number of subjects |
0
|
||
Number of subjects enrolled per age group |
|||
In utero |
0
|
||
Preterm newborn - gestational age < 37 wk |
0
|
||
Newborns (0-27 days) |
0
|
||
Infants and toddlers (28 days-23 months) |
0
|
||
Children (2-11 years) |
86
|
||
Adolescents (12-17 years) |
33
|
||
Adults (18-64 years) |
0
|
||
From 65 to 84 years |
0
|
||
85 years and over |
0
|
|
||||||||||||||||||||||||||||||||||||||||||||||
Recruitment
|
||||||||||||||||||||||||||||||||||||||||||||||
Recruitment details |
Subjects took part in the study at 40 sites in the United States from 30 October 2019 to 9 September 2022. | |||||||||||||||||||||||||||||||||||||||||||||
Pre-assignment
|
||||||||||||||||||||||||||||||||||||||||||||||
Screening details |
A total of 260 subjects were screened, of which 119 subjects were randomised to receive brexpiprazole or placebo. | |||||||||||||||||||||||||||||||||||||||||||||
Period 1
|
||||||||||||||||||||||||||||||||||||||||||||||
Period 1 title |
Overall Study (overall period)
|
|||||||||||||||||||||||||||||||||||||||||||||
Is this the baseline period? |
Yes | |||||||||||||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
|
|||||||||||||||||||||||||||||||||||||||||||||
Blinding used |
Double blind | |||||||||||||||||||||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Carer, Assessor | |||||||||||||||||||||||||||||||||||||||||||||
Arms
|
||||||||||||||||||||||||||||||||||||||||||||||
Are arms mutually exclusive |
Yes
|
|||||||||||||||||||||||||||||||||||||||||||||
Arm title
|
Brexpiprazole | |||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Subjects received flexible doses of brexpiprazole 0.25 to 3 milligram per day (mg/day), orally, once daily (QD) up to Week 8. For subjects with body weight < 50 kilograms (kg) the dose was titrated up from 0.25 mg/day on Days 1 to 3, followed by 0.5 mg on Days 4 to 7, and to 1 mg on Days 8 to 14. Based on the investigator’s judgment the dose was increased to 1.5 mg/day after Day 15. The dose was fixed after Week 6 and administration continued for another 2 weeks until Week 8. For subjects with body weight ≥ 50 kg the dose was titrated up from 0.5 mg/day on Days 1 to 3, followed by 1.5 mg on Days 4 to 7, and to 2 mg on Days 8 to 14. Based on the investigator’s judgment the dose was increased to 3 mg/day after Day 15. The dose was fixed after Week 6 and administration continued for another 2 weeks until Week 8. | |||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Brexpiprazole
|
|||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product code |
OPC-34712
|
|||||||||||||||||||||||||||||||||||||||||||||
Other name |
LuAF41156
|
|||||||||||||||||||||||||||||||||||||||||||||
Pharmaceutical forms |
Tablet
|
|||||||||||||||||||||||||||||||||||||||||||||
Routes of administration |
Oral use
|
|||||||||||||||||||||||||||||||||||||||||||||
Dosage and administration details |
Brexpiprazole tablets, flexible dosing from 0.25 to 3 mg/day administered orally up to Week 8.
|
|||||||||||||||||||||||||||||||||||||||||||||
Arm title
|
Placebo | |||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Subjects received brexpiprazole matching placebo orally, QD, in the same way as brexpiprazole up to Week 8. | |||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
|
|||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product code |
||||||||||||||||||||||||||||||||||||||||||||||
Other name |
||||||||||||||||||||||||||||||||||||||||||||||
Pharmaceutical forms |
Tablet
|
|||||||||||||||||||||||||||||||||||||||||||||
Routes of administration |
Oral use
|
|||||||||||||||||||||||||||||||||||||||||||||
Dosage and administration details |
Brexpiprazole matching placebo tablets were administered orally up to Week 8.
|
|||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Baseline characteristics reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Brexpiprazole
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Subjects received flexible doses of brexpiprazole 0.25 to 3 milligram per day (mg/day), orally, once daily (QD) up to Week 8. For subjects with body weight < 50 kilograms (kg) the dose was titrated up from 0.25 mg/day on Days 1 to 3, followed by 0.5 mg on Days 4 to 7, and to 1 mg on Days 8 to 14. Based on the investigator’s judgment the dose was increased to 1.5 mg/day after Day 15. The dose was fixed after Week 6 and administration continued for another 2 weeks until Week 8. For subjects with body weight ≥ 50 kg the dose was titrated up from 0.5 mg/day on Days 1 to 3, followed by 1.5 mg on Days 4 to 7, and to 2 mg on Days 8 to 14. Based on the investigator’s judgment the dose was increased to 3 mg/day after Day 15. The dose was fixed after Week 6 and administration continued for another 2 weeks until Week 8. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Subjects received brexpiprazole matching placebo orally, QD, in the same way as brexpiprazole up to Week 8. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||
End points reporting groups
|
|||
Reporting group title |
Brexpiprazole
|
||
Reporting group description |
Subjects received flexible doses of brexpiprazole 0.25 to 3 milligram per day (mg/day), orally, once daily (QD) up to Week 8. For subjects with body weight < 50 kilograms (kg) the dose was titrated up from 0.25 mg/day on Days 1 to 3, followed by 0.5 mg on Days 4 to 7, and to 1 mg on Days 8 to 14. Based on the investigator’s judgment the dose was increased to 1.5 mg/day after Day 15. The dose was fixed after Week 6 and administration continued for another 2 weeks until Week 8. For subjects with body weight ≥ 50 kg the dose was titrated up from 0.5 mg/day on Days 1 to 3, followed by 1.5 mg on Days 4 to 7, and to 2 mg on Days 8 to 14. Based on the investigator’s judgment the dose was increased to 3 mg/day after Day 15. The dose was fixed after Week 6 and administration continued for another 2 weeks until Week 8. | ||
Reporting group title |
Placebo
|
||
Reporting group description |
Subjects received brexpiprazole matching placebo orally, QD, in the same way as brexpiprazole up to Week 8. |
|
|||||||||||||
End point title |
Mean Change From Baseline to Week 8 in Aberrant Behavior Checklist - Irritability (ABC-I) Subscale Score | ||||||||||||
End point description |
ABC, a parent-reported scale evaluates treatment effects on problem behavior in subjects with intellectual disabilities. ABC scale has 58 items, divided in 5 subscales Irritability, Agitation; Lethargy, Social Withdrawal; Stereotypic Behavior; Hyperactivity, Noncompliance; & Inappropriate Speech. Each of 58 ABC items is rated on 4-point scale from 0=not at all a problem to 3=problem is severe in degree. ABC-I measures emotional & behavioral symptoms of ASD. ABC-I total score is sum of ratings over 15 ABC items. Individual scores were summed, thus ABC-I total score ranges from 0 to 45. Higher scores=worst condition.Negative change from baseline indicates improvement. Efficacy sample:all randomised subjects who took at least 1 dose of brexpiprazole or placebo & had baseline & at least 1 post-baseline assessment of primary efficacy variable ABC-I subscale score during double-blind treatment phase. Number of subjects analysed indicates number of subjects with data available for analysis.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
Baseline to Week 8
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Brexpiprazole, Placebo | ||||||||||||
Comparison groups |
Brexpiprazole v Placebo
|
||||||||||||
Number of subjects included in analysis |
94
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.4597 [1] | ||||||||||||
Method |
Mixed model repeated measures (MMRM) | ||||||||||||
Parameter type |
Least squares (LS) mean Difference | ||||||||||||
Point estimate |
-1.22
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-4.49 | ||||||||||||
upper limit |
2.05 | ||||||||||||
Notes [1] - MMRM method with model terms: treatment, trial site, baseline body weight stratum, visit, treatment-by-visit and baseline-by-visit interaction. |
|
|||||||||||||
End point title |
Mean Change From Baseline to Week 8 in Clinical Global Impression - Severity (CGI-S) Score | ||||||||||||
End point description |
The CGI-S is a 7-point clinician rated scale to assess severity of subject's current illness state with a focus on symptoms of irritability. The investigator (or rater) answered the following question: "Considering your total clinical experience with this particular population, how ill was the subject at this time with regard to symptoms of irritability? Response choices were from 1 (normal - not ill at all) to 7 (among the most extremely ill patients). Higher score = more severe illness. A negative change from baseline indicates improvement. Efficacy sample included all randomised subjects who took at least 1 dose of brexpiprazole or placebo and had baseline and at least 1 post-baseline assessment of the primary efficacy variable ABC-I subscale score during the double-blind treatment phase. Number of subjects analysed indicates the number of subjects with data available for analysis of this endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline to Week 8
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Brexpiprazole, Placebo | ||||||||||||
Comparison groups |
Brexpiprazole v Placebo
|
||||||||||||
Number of subjects included in analysis |
96
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.7315 [2] | ||||||||||||
Method |
MMRM | ||||||||||||
Parameter type |
LS mean difference | ||||||||||||
Point estimate |
-0.07
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.46 | ||||||||||||
upper limit |
0.32 | ||||||||||||
Notes [2] - MMRM method with model terms: treatment, trial site, baseline body weight stratum, visit, treatment-by-visit and baseline-by-visit interaction. |
|
|||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
From first dose through 21 (±2) days after last dose of study drug (up to approximately Week 11)
|
||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
Safety sample included all enrolled subjects who received at least 1 dose of brexpiprazole or placebo.
|
||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
22.0
|
||||||||||||||||||||||||||||||||||||||||||
Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Brexpiprazole
|
||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Subjects received flexible doses of brexpiprazole 0.25 to 3 mg/day, orally, QD up to Week 8. For subjects with body weight < 50 kg the dose was titrated up from 0.25 mg/day on Days 1 to 3, followed by 0.5 mg on Days 4 to 7, and to 1 mg on Days 8 to 14. Based on the investigator’s judgment the dose was increased to 1.5 mg/day after Day 15. The dose was fixed after Week 6 and administration continued for another 2 weeks until Week 8. For subjects with body weight ≥ 50 kg the dose was titrated up from 0.5 mg/day on Days 1 to 3, followed by 1.5 mg on Days 4 to 7, and to 2 mg on Days 8 to 14. Based on the investigator’s judgment the dose was increased to 3 mg/day after Day 15. The dose was fixed after Week 6 and administration continued for another 2 weeks until Week 8. | ||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
|
||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Subjects received brexpiprazole matching placebo orally, QD, in the same way as brexpiprazole up to Week 8. | ||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||
Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||
|
|
|||
Substantial protocol amendments (globally) |
|||
Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
14 Aug 2019 |
-Revised Week 2 visit to occur in-clinic.
-Clarified caregiver and subject interacting for virtual visit.
-Clarifications provided for details around urogenital assessment, procedures on clinical laboratory tests at screening and use of propanolol.
-Visits were adjusted for prolactin, clinical laboratory tests, electrocardiogram (ECG), extrapyramidal symptoms (EPS) scales, thyroid stimulating hormone (TSH), and coagulation assessments.
-Clarification provided that ECGs done at screening do not need to be repeated if within normal ranges.
-The pharmacogenomic and future biospecimen research (FBR) sampling should be taken with pharmacokinetic (PK) draws.
-Added additional tests under hematology assessments.
-Washout days updated for washout medications.
-Revised the appendices and corresponding protocol sections containing normal ranges for glucose levels, TSH, free thyroxine (T4), prothrombin time, activated partial thromboplastin time, and international normalized ratio. |
||
22 Nov 2019 |
- Added bicarbonate to the laboratory tests at screening, baseline, and Week 8. Parameters and criteria also added to Appendix 2. |
||
12 Feb 2020 |
- Revised lower limit of adolescent systolic blood pressure.
- Revised glycosylated hemoglobin laboratory value of potential relevance.
- Added assessments and laboratory value of potential relevance for adrenocorticotropic hormone and cortisol. |
||
06 Jul 2020 |
- A COVID-19 Addendum was introduced for any protocol specified activities that are not able to be performed or cannot be performed due to COVID-19 considerations.
- Corrected PK parameter values in the Introduction.
- Excluded the simultaneous participation of siblings or unrelated members of the same residence.
- Stated that the Kiddie-Schedule for Affective Disorders and Schizophrenia - Present and Lifetime version (K-SADS-PL) does not need to be repeated at the screening visit for subjects that are rescreened.
- Allowed for the extension of the screening period to accommodate repeating clinical laboratory tests or ECGs. |
||
07 Jul 2022 |
- Revised the treatment effect assumption from 5.5 to 6.0, resulting in a new sample size of 102 randomised subjects.
- Allowed in clinic visits in lieu of virtual visits if investigators and caregivers feel that an in person visit may be more appropriate. This change reflects feedback/requests from the trial site staff and principal investigators.
- Introduced an estimand.
- Clarified that the ± 2 day visit window is applicable to the dose titration schedule.
- Added clarifications to prohibited and permitted medications.
- Updated information based on the latest Investigator Brochure. Clarified/added abbreviations. |
||
Interruptions (globally) |
|||
Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |