Trial Outcomes & Findings for Phase IV Long-term Maintenance Study of Aripiprazole in the Treatment of Irritability Associated With Autistic Disorder (NCT NCT01227668)

Last Updated: 2014-05-02

Results Overview

Time of relapse=date when patient meets relapse criteria. There are 4 definitions for relapse: 1. Patient meets the following criteria for 2 consecutive visits: (a) Aberrant Behavior Checklist Irritability score ≥25% than score at end of Phase 1 AND (b) Clinical Global Impression Improvement scale rating of 'Much Worse' or 'Very Much Worse' relative to rating at end of Phase 1. If relapse criteria met at 1 visit, 2nd visit should occur in about 1 week to reevaluate whether relapse criteria are still met. 2. Patient discontinues for "Lost to Follow-up" after a visit in which he or she met Definition 1 criteria (a\&b). 3. Patient begins a prohibited drug (whether a study investigator or outside source prescribed) to treat worsening symptoms of irritability of autistic disorder after a visit where patient met Definition 1 criteria (a\&b). 4. Patient discontinues due to hospitalization for worsening symptoms of irritability or due to lack of efficacy based on investigator's assessment.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

215 participants

Primary outcome timeframe

From end of Phase 1 (Date of randomization) to Week 16 of Phase 2 and end of treatment

Results posted on

2014-05-02

Participant Flow

Of 215 participants enrolled, 58 discontinued during screening and before entry into Phase 1. Of the 58 who discontinued, 1 withdrew for an adverse event, 12 withdrew consent, 8 were lost to follow-up, 36 no longer met study criteria, and 1 withdrew for other reason.

Participant milestones

Participant milestones
Measure	Aripiprazole, 2-15 mg Once Daily (Titered to Optimum Dose) Phase 1: Participants received an initial dose of aripiprazole 2 mg daily, titered up to 5, 10, or 15 mg once daily to optimize clinical benefit, for a maximum of 26 weeks. Phase 2: Aripiprazole was continued at the dose prescribed at the end of Phase 1, once daily for 16 weeks. The dose (within the range of 2-15 mg/day) could have been adjusted based on efficacy and tolerability.	Placebo Phase 2 only: Participants received placebo for 16 weeks.
Phase 1 (Stabilization Phase) STARTED	157	0
Phase 1 (Stabilization Phase) Received Treatment	155	0
Phase 1 (Stabilization Phase) COMPLETED	85	0
Phase 1 (Stabilization Phase) NOT COMPLETED	72	0
Phase 2 (Randomization Phase) STARTED	41	44
Phase 2 (Randomization Phase) Received Treatment	39	43
Phase 2 (Randomization Phase) COMPLETED	22	19
Phase 2 (Randomization Phase) NOT COMPLETED	19	25

Reasons for withdrawal

Reasons for withdrawal
Measure	Aripiprazole, 2-15 mg Once Daily (Titered to Optimum Dose) Phase 1: Participants received an initial dose of aripiprazole 2 mg daily, titered up to 5, 10, or 15 mg once daily to optimize clinical benefit, for a maximum of 26 weeks. Phase 2: Aripiprazole was continued at the dose prescribed at the end of Phase 1, once daily for 16 weeks. The dose (within the range of 2-15 mg/day) could have been adjusted based on efficacy and tolerability.	Placebo Phase 2 only: Participants received placebo for 16 weeks.
Phase 1 (Stabilization Phase) Adverse Event	12	0
Phase 1 (Stabilization Phase) Withdrawal by Subject	7	0
Phase 1 (Stabilization Phase) Lost to Follow-up	8	0
Phase 1 (Stabilization Phase) Sponsor's administrative reason	11	0
Phase 1 (Stabilization Phase) No longer meets study criteria	7	0
Phase 1 (Stabilization Phase) Lack of Efficacy	25	0
Phase 1 (Stabilization Phase) Poor compliance/noncompliance	2	0
Phase 2 (Randomization Phase) Adverse Event	0	1
Phase 2 (Randomization Phase) Withdrawal by Subject	5	0
Phase 2 (Randomization Phase) Lost to Follow-up	1	0
Phase 2 (Randomization Phase) Lack of Efficacy	13	23
Phase 2 (Randomization Phase) Poor compliance/noncompliance	0	1

Baseline Characteristics

Phase IV Long-term Maintenance Study of Aripiprazole in the Treatment of Irritability Associated With Autistic Disorder

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Aripiprazole, 2-15 mg Once Daily (Titered to Optimum Dose) n=41 Participants Phase 2: Aripiprazole was continued at the dose prescribed at the end of Phase 1, once daily for 16 weeks. The dose (within the range of 2-15 mg/day) could have been adjusted based on efficacy and tolerability.	Placebo n=44 Participants Phase 2: Participants received placebo for 16 weeks.	Total n=85 Participants Total of all reporting groups
Age, Customized	10.0 Years n=5 Participants	11.0 Years n=7 Participants	10.0 Years n=5 Participants
Sex: Female, Male Female	11 Participants n=5 Participants	6 Participants n=7 Participants	17 Participants n=5 Participants
Sex: Female, Male Male	30 Participants n=5 Participants	38 Participants n=7 Participants	68 Participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Asian	0 Participants n=5 Participants	3 Participants n=7 Participants	3 Participants n=5 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized Black or African American	8 Participants n=5 Participants	11 Participants n=7 Participants	19 Participants n=5 Participants
Race/Ethnicity, Customized White	31 Participants n=5 Participants	28 Participants n=7 Participants	59 Participants n=5 Participants
Race/Ethnicity, Customized Other	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants

PRIMARY outcome

Timeframe: From end of Phase 1 (Date of randomization) to Week 16 of Phase 2 and end of treatment

Population: All participants who were randomized in Phase 2

Outcome measures

Outcome measures
Measure	Aripiprazole, 2-15 mg Once Daily (Titered to Optimum Dose) n=41 Participants Phase 2: Participants continued aripiprazole at the dose prescribed at the end of Phase 1, once daily for 16 weeks. The dose (within the range of 2-15 mg/day) could have been adjusted based on efficacy and tolerability.	Placebo n=44 Participants Phase 2 only: Participants received placebo for 16 weeks.
Percentage of Patients Relapsing by Week 16	32 Percentage of participants NA	50 Percentage of participants Interval 42.0 to

SECONDARY outcome

Timeframe: From Baseline (end of Phase 1) to Week 16 of Phase 2

Population: All participants who were randomized and took at least 1 dose of double-blind medication in Phase 2 and who had at least 1 efficacy evaluation after the start of Phase 2 study drug.

ABC is an informant-based checklist used to assess and classify problem behaviors of children and adolescents with mental retardation. The 58 items are rated on a 4-point scale (0=not at all a problem to 3=the problem is severe in degree), and resolve into 5 subscales: 1) irritability, agitation; 2) lethargy, social withdrawal; 3) stereotypic behavior; 4) hyperactivity, noncompliance; and 5) inappropriate speech. The ABC can be completed by parents, special educators, psychologists, direct caregivers, nurses, and others knowing the participant. Psychometric assessment of the ABC indicates that its subscales have high internal consistency, adequate reliability, and established validity. The ABC-I Subscale Score ranges from 0 to 45, with a negative change in score signifying improvement. LOCF data set includes data recorded at a given visit or, if no observation was recorded at that visit, data carried forward from the prior visit. chg=change; BL=baseline; APR=aripiprazole; vs=versus.

Outcome measures

Outcome measures
Measure	Aripiprazole, 2-15 mg Once Daily (Titered to Optimum Dose) n=39 Participants Phase 2: Participants continued aripiprazole at the dose prescribed at the end of Phase 1, once daily for 16 weeks. The dose (within the range of 2-15 mg/day) could have been adjusted based on efficacy and tolerability.	Placebo n=43 Participants Phase 2 only: Participants received placebo for 16 weeks.
Adjusted Mean Change From Baseline to Week 16 on the Aberrant Behavior Checklist Irritability (ABC-I) Subscale Score (Last Observation Carried Forward [LOCF])	5.2 Units on a scale Standard Error 1.61 • Interval 0.0 to 10.0	9.6 Units on a scale Standard Error 1.56 • Interval 1.0 to 19.0

SECONDARY outcome

Timeframe: From Baseline (end of Phase 1) to Week 16 of Phase 2

Population: All participants who were randomized and took at least 1 dose of double-blind medication in Phase 2 and who had at least 1 efficacy evaluation after the start of Phase 2 study drug.

CG-I rating scale permits global evaluation of patient's improvement over time. At baseline (BL), CGI Severity of Illness assessment is performed, in which the clinician rates severity of patient's condition on a 7-point scale ranging from 1=no symptoms to 7=very severe symptoms. Higher total score=worse symptoms. At subsequent visits, clinician assesses patient's improvement relative to symptoms at baseline on CGI-I 7-point scale ranging from 1=very much improved to 7=very much worse. Since the drug targets irritability symptoms, the CGI focuses on severity of irritability secondary to autistic disorder. Lower score=more improved symptoms. LOCF data set includes data recorded at a given visit or, if nothing recorded, data areccarried forward from the prior visit. For secondary endpoints (endpt), hierarchical testing was used to keep overall experiment-wise type I error rate to \<=0.05. diff=difference; IS=irritability scale; PA=primary analysis; signif=significance/significantly.

Outcome measures

Outcome measures
Measure	Aripiprazole, 2-15 mg Once Daily (Titered to Optimum Dose) n=39 Participants Phase 2: Participants continued aripiprazole at the dose prescribed at the end of Phase 1, once daily for 16 weeks. The dose (within the range of 2-15 mg/day) could have been adjusted based on efficacy and tolerability.	Placebo n=43 Participants Phase 2 only: Participants received placebo for 16 weeks.
Change From Baseline in Mean Clinical Global Impression Improvement (CGI-I) Scale Score at Week 16 (Last Observation Carried Forward [LOCF])	4.2 Units on a scale Standard Error 0.26	4.8 Units on a scale Standard Error 0.26

SECONDARY outcome

Timeframe: Weekly from Week 1 to Week 26 and continuously to end of treatment

Population: All participants who took at least 1 dose of single-blind aripiprazole in Phase 1

AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization.

Outcome measures

Outcome measures
Measure	Aripiprazole, 2-15 mg Once Daily (Titered to Optimum Dose) n=155 Participants Phase 2: Participants continued aripiprazole at the dose prescribed at the end of Phase 1, once daily for 16 weeks. The dose (within the range of 2-15 mg/day) could have been adjusted based on efficacy and tolerability.	Placebo Phase 2 only: Participants received placebo for 16 weeks.
Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), and Adverse Events (AEs) Leading to Discontinuation During Phase 1 Death	0 Participants	—
Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), and Adverse Events (AEs) Leading to Discontinuation During Phase 1 SAEs	1 Participants	—
Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), and Adverse Events (AEs) Leading to Discontinuation During Phase 1 AEs leading to discontinuation	13 Participants	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Weekly from Weeks 1 through 16 (end of treatment) of Phase 2

Population: All participants who were randomized and took at least 1 dose of double-blind medication in Phase 2

Outcome measures

Outcome measures
Measure	Aripiprazole, 2-15 mg Once Daily (Titered to Optimum Dose) n=39 Participants Phase 2: Participants continued aripiprazole at the dose prescribed at the end of Phase 1, once daily for 16 weeks. The dose (within the range of 2-15 mg/day) could have been adjusted based on efficacy and tolerability.	Placebo n=43 Participants Phase 2 only: Participants received placebo for 16 weeks.
Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Treatment-related AEs During Phase 2 Death	0 Participants	0 Participants
Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Treatment-related AEs During Phase 2 SAEs	0 Participants	0 Participants
Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Treatment-related AEs During Phase 2 AEs leading to discontinuation	0 Participants	0 Participants
Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Treatment-related AEs During Phase 2 Treatment-related AEs	9 Participants	6 Participants

Adverse Events

Aripiprazole, 2-15 mg (Phase 1)

Serious events: 1 serious events

Other events: 112 other events

Deaths: 0 deaths

Aripiprazole, 2-15 mg (Phase 2)

Serious events: 0 serious events

Other events: 11 other events

Deaths: 0 deaths

Placebo (Phase 2 Only)

Serious events: 0 serious events

Other events: 5 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Aripiprazole, 2-15 mg (Phase 1) n=155 participants at risk Phase 1: Participants received an initial dose of aripiprazole 2 mg daily, titered up to 5, 10, or 15 mg once daily to optimize clinical benefit, for a maximum of 26 weeks.	Aripiprazole, 2-15 mg (Phase 2) n=39 participants at risk Phase 2: Participants continued aripiprazole at the dose prescribed at the end of Phase 1, once daily for 16 weeks. The dose (within the range of 2-15 mg/day) could have been adjusted based on efficacy and tolerability.	Placebo (Phase 2 Only) n=43 participants at risk Phase 2 only: Participants received placebo for 16 weeks.
Psychiatric disorders Aggression	0.65% 1/155	0.00% 0/39	0.00% 0/43

Other adverse events

Other adverse events
Measure	Aripiprazole, 2-15 mg (Phase 1) n=155 participants at risk Phase 1: Participants received an initial dose of aripiprazole 2 mg daily, titered up to 5, 10, or 15 mg once daily to optimize clinical benefit, for a maximum of 26 weeks.	Aripiprazole, 2-15 mg (Phase 2) n=39 participants at risk Phase 2: Participants continued aripiprazole at the dose prescribed at the end of Phase 1, once daily for 16 weeks. The dose (within the range of 2-15 mg/day) could have been adjusted based on efficacy and tolerability.	Placebo (Phase 2 Only) n=43 participants at risk Phase 2 only: Participants received placebo for 16 weeks.
General disorders Fatigue	8.4% 13/155	2.6% 1/39	0.00% 0/43
Nervous system disorders Tremor	6.5% 10/155	2.6% 1/39	2.3% 1/43
Gastrointestinal disorders Constipation	2.6% 4/155	5.1% 2/39	0.00% 0/43
Nervous system disorders Movement disorder	1.9% 3/155	5.1% 2/39	0.00% 0/43
Gastrointestinal disorders Vomiting	14.2% 22/155	5.1% 2/39	4.7% 2/43
Psychiatric disorders Insomnia	8.4% 13/155	2.6% 1/39	2.3% 1/43
General disorders Pyrexia	5.2% 8/155	2.6% 1/39	0.00% 0/43
Nervous system disorders Somnolence	14.8% 23/155	0.00% 0/39	0.00% 0/43
Infections and infestations Nasopharyngitis	5.8% 9/155	2.6% 1/39	2.3% 1/43
Metabolism and nutrition disorders Increased appetite	12.9% 20/155	2.6% 1/39	4.7% 2/43
Nervous system disorders Lethargy	5.2% 8/155	0.00% 0/39	0.00% 0/43
Psychiatric disorders Aggression	5.2% 8/155	0.00% 0/39	2.3% 1/43
Gastrointestinal disorders Diarrhoea	7.1% 11/155	2.6% 1/39	0.00% 0/43
Nervous system disorders Headache	5.2% 8/155	0.00% 0/39	0.00% 0/43
Infections and infestations Upper respiratory tract infection	10.3% 16/155	10.3% 4/39	2.3% 1/43
Investigations Weight increased	25.2% 39/155	0.00% 0/39	0.00% 0/43

Additional Information

Bristol-Myers Squibb Study Director

Bristol-Myers Squibb

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.
Publication restrictions are in place

Restriction type: OTHER