ABILIFY (Page 21 of 24)

14.4 Irritability Associated with Autistic Disorder

Pediatric Patients

The efficacy of ABILIFY (aripiprazole) in the treatment of irritability associated with autistic disorder was established in two 8-week, placebo-controlled trials in pediatric patients (6 to 17 years of age) who met the DSM-IV criteria for autistic disorder and demonstrated behaviors such as tantrums, aggression, self-injurious behavior, or a combination of these problems. Over 75% of these subjects were under 13 years of age.

Efficacy was evaluated using two assessment scales: the Aberrant Behavior Checklist (ABC) and the Clinical Global Impression-Improvement (CGI-I) scale. The primary outcome measure in both trials was the change from baseline to endpoint in the Irritability subscale of the ABC (ABC-I). The ABC-I subscale measured symptoms of irritability in autistic disorder.

The results of these trials are as follows:

In one of the 8-week, placebo-controlled trials, children and adolescents with autistic disorder (n=98), aged 6 to 17 years, received daily doses of placebo or ABILIFY 2 to 15 mg/day. ABILIFY, starting at 2 mg/day with increases allowed up to 15 mg/day based on clinical response, significantly improved scores on the ABC-I subscale and on the CGI-I scale compared with placebo. The mean daily dose of ABILIFY at the end of 8-week treatment was 8.6 mg/day (Study 1 in Table 29).

In the other 8-week, placebo-controlled trial in children and adolescents with autistic disorder (n=218), aged 6 to 17 years, three fixed doses of ABILIFY (5 mg/day, 10 mg/day, or 15 mg/day) were compared to placebo. ABILIFY dosing started at 2 mg/day and was increased to 5 mg/day after one week. After a second week, it was increased to 10 mg/day for patients in the 10 and 15 mg dose arms, and after a third week, it was increased to 15 mg/day in the 15 mg/day treatment arm (Study 2 in Table 29). All three doses of ABILIFY significantly improved scores on the ABC-I subscale compared with placebo.

Table 29: Irritability Associated with Autistic Disorder Studies (Pediatric)

Study Number

Treatment Group

Primary Efficacy Measure: ABC-I

Mean Baseline Score (SD)

LS Mean Change from Baseline (SE)

Placebo-subtracted Differencea (95% CI)

Study 1

ABILIFY (2-15 mg/day)*

29.6 (6.37)

-12.9 (1.44)

-7.9 (-11.7, -4.1)

Placebo

30.2 (6.52)

-5.0 (1.43)

Study 2

ABILIFY (5 mg/day)*

28.6 (7.56)

-12.4 (1.36)

-4.0 (-7.7, -0.4)

ABILIFY (10 mg/day)*

28.2 (7.36)

-13.2 (1.25)

-4.8 (-8.4, -1.3)

ABILIFY (15 mg/day)*

28.9 (6.41)

-14.4 (1.31)

-6.0 (-9.6, -2.3)

Placebo

28.0 (6.89)

-8.4 (1.39)

SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval.

a Difference (drug minus placebo) in least-squares mean change from baseline.

* Doses statistically significantly superior to placebo.

14.5 Tourette’s Disorder

Pediatric Patients

The efficacy of ABILIFY (aripiprazole) in the treatment of Tourette’s disorder was established in one 8-week (7 to 17 years of age) and one 10-week (6 to 18 years of age), placebo-controlled trials in pediatric patients (6 to 18 years of age) who met the DSM-IV criteria for Tourette’s disorder and had a Total Tic score (TTS) ≥ 20 — 22 on the Yale Global Tic Severity Scale (YGTSS). The YGTSS is a fully validated scale designed to measure current tic severity. Efficacy was evaluated using two assessment scales: 1) the Total Tic score (TTS) of the YGTSS and 2) the Clinical Global Impressions Scale for Tourette’s Syndrome (CGI-TS), a clinician-determined summary measure that takes into account all available patient information. Over 65% of these patients were under 13 years of age.

The primary outcome measure in both trials was the change from baseline to endpoint in the TTS of the YGTSS. Ratings for the TTS are made along 5 different dimensions on a scale of 0 to 5 for motor and vocal tics each. Summation of these 10 scores provides a TTS (i.e., 0-50).

The results of these trials are as follows:

In the 8-week, placebo-controlled, fixed-dose trial, children and adolescents with Tourette’s disorder (n=133), aged 7 to 17 years, were randomized 1:1:1 to low dose ABILIFY, high dose ABILIFY, or placebo. The target doses for the low and high dose ABILIFY groups were based on weight. Patients < 50 kg in the low dose ABILIFY group started at 2 mg per day with a target dose of 5 mg per day after 2 days. Patients ≥ 50 kg in the low dose ABILIFY group, started at 2 mg per day increased to 5 mg per day after 2 days, with a subsequent increase to a target dose of 10 mg per day at day 7. Patients <50 kg in the high dose ABILIFY group started at 2 mg per day increased to 5 mg per day after 2 days, with a subsequent increase to a target dose of 10 mg per day at day 7. Patients ≥ 50 kg in the high dose ABILIFY group, started at 2 mg per day increased to 5 mg per day after 2 days, with a subsequent increase to a dose of 10 mg per day at day 7 and were allowed weekly increases of 5 mg per day up to a target dose 20 mg per day at Day 21. ABILIFY (both high and low dose groups) demonstrated statistically significantly improved scores on the YGTSS TTS (Study 1 in Table 30) and on the CGI-TS scale compared with placebo. The estimated improvements on the YGTSS TTS over the course of the study are displayed in Figure 9.

Figure 9: Least Square Means of Change from Baseline in YGTSS TTS by Week (Tourette’s Disorder Study 1)

Figure 9
(click image for full-size original)

In the 10-week, placebo-controlled, flexible-dose trial in children and adolescents with Tourette’s disorder (n=61), aged 6 to 18 years, patients received daily doses of placebo or ABILIFY, starting at 2 mg/day with increases allowed up to 20 mg/day based on clinical response. ABILIFY demonstrated statistically significantly improved scores on the YGTSS TTS scale compared with placebo (Study 2 in Table 30). The mean daily dose of ABILIFY at the end of 10-week treatment was 6.54 mg/day.

Table 30: Tourette’s Disorder Studies (Pediatric)

Study Number

Treatment Group

Primary Efficacy Measure: YGTSS TTS

Mean Baseline Score (SD)

LS Mean Change from Baseline (SE)

Placebo-subtracted Differencea (95% CI)

Study 1

ABILIFY (low dose)*

29.2 (5.63)

-13.4 (1.59)

-6.3 (-10.2, -2.3)

ABILIFY (high dose)*

31.2 (6.40)

-16.9 (1.61)

-9.9 (-13.8, -5.9)

Placebo

30.7 (5.95)

-7.1 (1.55)

Study 2

ABILIFY (2-20 mg/day)*

28.3 (5.51)

-15.0 (1.51)

-5.3 (-9.8, -0.9)

Placebo

29.5 (5.60)

-9.6 (1.64)

SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval.

a Difference (drug minus placebo) in least-squares mean change from baseline.

* Doses statistically significantly superior to placebo.

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