Prescription Drug Information: Aripiprazole (Page 11 of 12)

14.3 Adjunctive Treatment of Major Depressive Disorder

Adults

The efficacy of aripiprazole in the adjunctive treatment of major depressive disorder (MDD) was demonstrated in two short-term (6-week), placebo-controlled trials of adult patients meeting DSM-IV criteria for MDD who had had an inadequate response to prior antidepressant therapy (1 to 3 courses) in the current episode and who had also demonstrated an inadequate response to 8 weeks of prospective antidepressant therapy (paroxetine controlled-release, venlafaxine extended-release, fluoxetine, escitalopram, or sertraline). Inadequate response for prospective treatment was defined as less than 50% improvement on the 17-item version of the Hamilton Depression Rating Scale (HAMD17), minimal HAMD17 score of 14, and a Clinical Global Impressions Improvement rating of no better than minimal improvement. Inadequate response to prior treatment was defined as less than 50% improvement as perceived by the patient after a minimum of 6 weeks of antidepressant therapy at or above the minimal effective dose.

The primary instrument used for assessing depressive symptoms was the Montgomery-Asberg Depression Rating Scale (MADRS), a 10-item clinician-rated scale used to assess the degree of depressive symptomatology. The key secondary instrument was the Sheehan Disability Scale (SDS), a 3-item self-rated instrument used to assess the impact of depression on three domains of functioning with each item scored from 0 (not at all) to 10 (extreme).

In the two trials (n=381, n=362), aripiprazole was superior to placebo in reducing mean MADRS total scores (Studies 1, 2 in Table 28). In one study, aripiprazole was also superior to placebo in reducing the mean SDS score.

In both trials, patients received aripiprazole adjunctive to antidepressants at a dose of 5 mg/day. Based on tolerability and efficacy, doses could be adjusted by 5 mg increments, one week apart. Allowable doses were: 2, 5, 10, 15 mg/day, and for patients who were not on potent CYP2D6 inhibitors fluoxetine and paroxetine, 20 mg/day. The mean final dose at the end point for the two trials was 10.7 and 11.4 mg/day.

An examination of population subgroups did not reveal evidence of differential response based on age, choice of prospective antidepressant, or race. With regard to gender, a smaller mean reduction on the MADRS total score was seen in males than in females.

Table 28: Adjunctive Treatment of Major Depressive Disorder Studies

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.

Study Number Treatment Group Primary Efficacy Measure: MADRS
Mean Baseline Score (SD) LS Mean Change From Baseline (SE) Placebo-subtracted difference a (95%CI)
Study 1 Aripiprazole (5 to 20 mg/day)* + Antidepressant Placebo + Antidepressant 25.2 (6.2) 27.0 (5.5) -8.49(0.66) -5.65(0.64) -2.84(-4.53, -1.15) —
Study 2 Aripiprazole (5 to 20 mg/day)* + Antidepressant Placebo + Antidepressant 26.0 (6.0) 26.0 (6.5) -8.78(0.63) -5.77(0.67) -3.01(-4.66, -1.37) —

14.4 Irritability Associated with Autistic Disorder

Pediatric Patients

The efficacy of 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 aripiprazole 2 to 15 mg/day. Aripiprazole, 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 aripiprazole 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 aripiprazole (5 mg/day, 10 mg/day, or 15 mg/day) were compared to placebo. Aripiprazole 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 aripiprazole significantly improved scores on the ABC-I subscale compared with placebo.

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

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.

Study Number Treatment Group Primary Efficacy Measure: ABC-I
Mean Baseline Score (SD) LS Mean Change From Baseline (SE) Placebo-subtracted difference a (95%CI)
Study 1 Aripiprazole (2 to 15 mg/day)* Placebo 29.6 (6.37) 30.2 (6.52) -12.9 (1.44) -5.0 (1.43) -7.9 (-11.7, -4.1) —
Study 2 Aripiprazole (5 mg/day) * Aripiprazole (10 mg/day) * Aripiprazole (15 mg/day) * Placebo 28.6 (7.56) 28.2 (7.36) 28.9 (6.41) 28.0 (6.89) -12.4 (1.36) -13.2 (1.25) -14.4 (1.31) -8.4 (1.39) -4.0 (-7.7, -0.4) -4.8 (-8.4,-1.3) -6.0 (-9.6,-2.3) —

14.5 Tourette’s Disorder

Pediatric Patients

The efficacy of 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 to 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 to 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 aripiprazole, high dose aripiprazole, or placebo. The target doses for the low and high dose aripiprazole groups were based on weight. Patients < 50 kg in the low dose aripiprazole 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 aripiprazole 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 aripiprazole 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 aripiprazole 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. Aripiprazole (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.

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 aripiprazole, starting at 2 mg/day with increases allowed up to 20 mg/day based on clinical response. Aripiprazole demonstrated statistically significantly improved scores on the YGTSS TTS scale compared with placebo (Study 2 in Table 30). The mean daily dose of aripiprazole at the end of 10-week treatment was 6.54 mg/day.

Table 30: Tourette’s Disorder Studies (Pediatric)

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.

Study Number Treatment Group Primary Efficacy Measure: YGTSS TTS
Mean Baseline Score (SD) LS Mean Change From Baseline (SE) Placebo-subtracted difference a (95%CI)
Study 1 Aripiprazole (low dose) * Aripiprazole (high dose) * Placebo 29.2 (5.63) 31.2 (6.40) 30.7 (5.95) -13.4 (1.59) -16.9 (1.61) -7.1 (1.55) -6.3 (-10.2, -2.3) -9.9 (-13.8, -5.9) —
Study 2 Aripiprazole (2 to 20 mg/day) * Placebo 28.3 (5.51) 29.5 (5.60) -15.0 (1.51) -9.6 (1.64) -5.3 (-9.8, -0.9) —

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