ABILIFY (Page 19 of 24)

Pediatric Patients

The efficacy of ABILIFY (aripiprazole) in the treatment of schizophrenia in pediatric patients (13 to 17 years of age) was evaluated in one 6-week, placebo-controlled trial of outpatients who met DSM-IV criteria for schizophrenia and had a PANSS score ≥70 at baseline. In this trial (n=302) comparing two fixed doses of ABILIFY (10 or 30 mg/day) to placebo, ABILIFY was titrated starting from 2 mg/day to the target dose in 5 days in the 10 mg/day treatment arm and in 11 days in the 30 mg/day treatment arm. Both doses of ABILIFY were superior to placebo in the PANSS total score (Study 6 in Table 26), the primary outcome measure of the study. The 30 mg/day dosage was not shown to be more efficacious than the 10 mg/day dose. Although maintenance efficacy in pediatric patients has not been systematically evaluated, maintenance efficacy can be extrapolated from adult data along with comparisons of aripiprazole pharmacokinetic parameters in adult and pediatric patients.

Table 26: Schizophrenia Studies

Study Number

Treatment Group

Primary Efficacy Measure: PANSS

Mean Baseline Score (SD)

LS Mean Change from Baseline (SE)

Placebo-subtracted Differencea (95% CI)

Study 1

ABILIFY (15 mg/day)*

98.5 (17.2)

-15.5 (2.40)

-12.6 (-18.9, -6.2)

ABILIFY (30 mg/day)*

99.0 (19.2)

-11.4 (2.39)

-8.5 (-14.8, -2.1)

Placebo

100.2 (16.5)

-2.9 (2.36)

Study 2

ABILIFY (20 mg/day)*

92.6 (19.5)

-14.5 (2.23)

-9.6 (-15.4, -3.8)

ABILIFY (30 mg/day)*

94.2 (18.5)

-13.9 (2.24)

-9.0 (-14.8, -3.1)

Placebo

94.3 (18.5)

-5.0 (2.17)

Study 3

ABILIFY (10 mg/day)*

92.7 (19.5)

-15.0 (2.38)

-12.7 (-19.00, -6.41)

ABILIFY (15 mg/day)*

93.2 (21.6)

-11.7 (2.38)

-9.4 (-15.71, -3.08)

ABILIFY (20 mg/day)*

92.5 (20.9)

-14.4 (2.45)

-12.1 (-18.53, -5.68)

Placebo

92.3 (21.8)

-2.3 (2.35)

Study 4

ABILIFY (2 mg/day)

90.7 (14.5)

-8.2 (1.90)

-2.9 (-8.29, 2.47)

ABILIFY (5 mg/day)

92.0 (12.6)

-10.6 (1.93)

-5.2 (-10.7, 0.19)

ABILIFY (10 mg/day)*

90.0 (11.9)

-11.3 (1.88)

-5.9 (-11.3, -0.58)

Placebo

90.8 (13.3)

-5.3 (1.97)

Study 6 (Pediatric, 13-17 years)

ABILIFY (10 mg/day)*

93.6 (15.7)

-26.7 (1.91)

-5.5 (-10.7, -0.21)

ABILIFY (30 mg/day)*

94.0 (16.1)

-28.6 (1.92)

-7.4 (-12.7, -2.13)

Placebo

94.6 (15.6)

-21.2 (1.93)

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.

Figure 6: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Relapse (Schizophrenia Study 5)

Figure 6
(click image for full-size original)

14.2 Bipolar Disorder

Acute Treatment of Manic and Mixed Episodes

Adults

Monotherapy

The efficacy of ABILIFY as monotherapy in the acute treatment of manic episodes was established in four 3-week, placebo-controlled trials in hospitalized patients who met the DSM-IV criteria for bipolar I disorder with manic or mixed episodes. These studies included patients with or without psychotic features and two of the studies also included patients with or without a rapid-cycling course.

The primary instrument used for assessing manic symptoms was the Young Mania Rating Scale (Y-MRS), an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology in a range from 0 (no manic features) to 60 (maximum score). A key secondary instrument included the Clinical Global Impression-Bipolar (CGI-BP) Scale.

In the four positive, 3-week, placebo-controlled trials (n=268; n=248; n=480; n=485) which evaluated ABILIFY in a range of 15 mg to 30 mg, once daily (with a starting dose of 30 mg/day in two studies and 15 mg/day in two studies), ABILIFY was superior to placebo in the reduction of Y-MRS total score (Studies 1-4 in Table 27) and CGI-BP Severity of Illness score (mania). In the two studies with a starting dose of 15 mg/day, 48% and 44% of patients were on 15 mg/day at endpoint. In the two studies with a starting dose of 30 mg/day, 86% and 85% of patients were on 30 mg/day at endpoint.

Adjunctive Therapy

The efficacy of adjunctive ABILIFY with concomitant lithium or valproate in the treatment of manic or mixed episodes was established in a 6-week, placebo-controlled study (n=384) with a 2-week lead-in mood stabilizer monotherapy phase in adult patients who met DSM-IV criteria for bipolar I disorder. This study included patients with manic or mixed episodes and with or without psychotic features.

Patients were initiated on open-label lithium (0.6 to 1.0 mEq/L) or valproate (50 to 125 μg/mL) at therapeutic serum levels, and remained on stable doses for 2 weeks. At the end of 2 weeks, patients demonstrating inadequate response (Y-MRS total score ≥16 and ≤25% improvement on the Y-MRS total score) to lithium or valproate were randomized to receive either ABILIFY (15 mg/day or an increase to 30 mg/day as early as day 7) or placebo as adjunctive therapy with open-label lithium or valproate. In the 6-week, placebo-controlled phase, adjunctive ABILIFY starting at 15 mg/day with concomitant lithium or valproate (in a therapeutic range of 0.6 to 1.0 mEq/L or 50 to 125 μg/mL, respectively) was superior to lithium or valproate with adjunctive placebo in the reduction of the Y-MRS total score (Study 5 in Table 27) and CGI-BP Severity of Illness score (mania). Seventy-one percent of the patients coadministered valproate and 62% of the patients coadministered lithium were on 15 mg/day at 6-week endpoint.

Pediatric Patients

The efficacy of ABILIFY in the treatment of bipolar I disorder in pediatric patients (10 to 17 years of age) was evaluated in one 4-week, placebo-controlled trial (n=296) of outpatients who met DSM-IV criteria for bipolar I disorder manic or mixed episodes with or without psychotic features and had a Y-MRS score ≥20 at baseline. This double-blind, placebo-controlled trial compared two fixed doses of ABILIFY (10 or 30 mg/day) to placebo. The ABILIFY dose was started at 2 mg/day, which was titrated to 5 mg/day after 2 days, and to the target dose in 5 days in the 10 mg/day treatment arm, and in 13 days in the 30 mg/day treatment arm. Both doses of ABILIFY were superior to placebo in change from baseline to week 4 on the Y-MRS total score (Study 6 in Table 27).

Table 27: Bipolar Studies

Study Number

Treatment Group

Primary Efficacy Measure: Y-MRS

Mean Baseline Score (SD)

LS Mean Change from Baseline (SE)

Placebo-subtracted Differencea (95% CI)

Study 1

ABILIFY (30 / 15 mg/day)*

29.0 (5.9)

-12.52 (1.05)

-5.33 (-7.90, -2.76)

Placebo

28.5 (4.6)

-7.19 (1.07)

Study 2

ABILIFY (30 / 15 mg/day)*

27.8 (5.7)

-8.15 (1.23)

-4.80 (-7.80, -1.80)

Placebo

29.1 (6.9)

-3.35(1.22)

Study 3

ABILIFY (15 — 30 mg/day)*

28.5 (5.6)

-12.64 (0.84)

-3.63 (-5.75 , -1.51)

Placebo

28.9 (5.9)

9.01 (0.81)

Study 4

ABILIFY (15 -30 mg/day)*

28.0 (5.8)

-11.98 (0.80)

-2.28 (-4.44 , -0.11)

Placebo

28.3 (5.8)

-9.70 (0.83)

Study 5

ABILIFY (15 or 30 mg/day)* + Lithium/Valproate

23.2 (5.7)

-13.31 (0.50)

-2.62 (-4.29 , -0.95)

Placebo + Lithium/Valproate

23.0 (4.9)

-10.70 (0.69)

Study 6

(Pediatric, 10-17 years)

ABILIFY (10 mg/day)*

29.8 (6.5)

-14.2 (0.89)

-5.99 (-8.49, -3.50)

ABILIFY (30 mg/day)*

29.5 (6.3)

-16.5 (0.87)

-8.26 (-10.7, -5.77)

Placebo

30.7 (6.8)

-8.2 (0.91)

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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