ABILIFY (Page 12 of 14)

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 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 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)

(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)

		Primary Efficacy Measure: YGTSS TTS
Study Number	Treatment Group	Mean Baseline Score (SD)	LS Mean Change from Baseline (SE)	Placebo-subtracted Difference * (95% CI)
SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval.
* Difference (drug minus placebo) in least-squares mean change from baseline. † Doses statistically significantly superior to placebo.
	ABILIFY (low dose)†	29.2 (5.63)	-13.4 (1.59)	-6.3 (-10.2, -2.3)
Study 1	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 to 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)	—

14.6 Agitation Associated with Schizophrenia or Bipolar Mania

The efficacy of intramuscular ABILIFY for injection for the treatment of agitation was established in three short-term (24-hour), placebo-controlled trials in agitated inpatients from two diagnostic groups: schizophrenia and bipolar I disorder (manic or mixed episodes, with or without psychotic features). Each of the trials included a single active comparator treatment arm of either haloperidol injection (schizophrenia studies) or lorazepam injection (bipolar mania study). Patients could receive up to three injections during the 24-hour treatment periods; however, patients could not receive the second injection until after the initial 2-hour period when the primary efficacy measure was assessed. Patients enrolled in the trials needed to be: (1) judged by the clinical investigators as clinically agitated and clinically appropriate candidates for treatment with intramuscular medication, and (2) exhibiting a level of agitation that met or exceeded a threshold score of ≥15 on the five items comprising the Positive and Negative Syndrome Scale (PANSS) Excited Component (i.e., poor impulse control, tension, hostility, uncooperativeness, and excitement items) with at least two individual item scores ≥4 using a 1 to 7 scoring system (1= absent, 4= moderate, 7= extreme). In the studies, the mean baseline PANSS Excited Component score was 19, with scores ranging from 15 to 34 (out of a maximum score of 35), thus suggesting predominantly moderate levels of agitation with some patients experiencing mild or severe levels of agitation. The primary efficacy measure used for assessing agitation signs and symptoms in these trials was the change from baseline in the PANSS Excited Component at 2 hours post-injection. A key secondary measure was the Clinical Global Impression of Improvement (CGI-I) Scale. The results of the trials follow:

In a placebo-controlled trial in agitated inpatients predominantly meeting DSM-IV criteria for schizophrenia (n=350), four fixed ABILIFY injection doses of 1 mg, 5.25 mg, 9.75 mg, and 15 mg were evaluated. At 2 hours post-injection, the 5.25 mg, 9.75 mg, and 15 mg doses were statistically superior to placebo in the PANSS Excited Component (Study 1 in Table 31) and on the CGI-I Scale.

In a second placebo-controlled trial in agitated inpatients predominantly meeting DSM-IV criteria for schizophrenia (n=445), one fixed ABILIFY injection dose of 9.75 mg was evaluated. At 2 hours post-injection, ABILIFY for injection was statistically superior to placebo in the PANSS Excited Component (Study 2 in Table 31) and on the CGI-I Scale.

In a placebo-controlled trial in agitated inpatients meeting DSM-IV criteria for bipolar I disorder (manic or mixed) (n=291), two fixed ABILIFY injection doses of 9.75 mg and 15 mg were evaluated. At 2 hours post-injection, both doses were statistically superior to placebo in the PANSS Excited Component (Study 3 in Table 31).

Examination of population subsets (age, race, and gender) did not reveal any differential responsiveness on the basis of these subgroupings.

Table 31: Agitation Associated with Schizophrenia or Bipolar Mania Studies

Study Number	Treatment Group	Primary Efficacy Measure: PANSS Excited Component
		Mean Baseline Score (SD)	LS Mean Change from Baseline (SE)	Placebo-subtracted Difference * (95% CI)
SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval.
* Difference (drug minus placebo) in least-squares mean change from baseline. † Doses statistically significantly superior to placebo.
Agitation Associated with Schizophrenia
Study 1	ABILIFY (1 mg)	19.16 (3.26)	-4.47 (0.72)	-1.19 (-2.96, 0.59)
	ABILIFY (5.25 mg) †	19.41 (3.31)	-5.65 (0.68)	-2.37 (-4.10, -0.63)
	ABILIFY (9.75 mg) †	19.42 (2.80)	-6.69 (0.72)	-3.40 (-5.18, -1.62)
	ABILIFY (15 mg) †	19.34 (2.38)	-5.72 (0.72)	-2.44 (-4.21, -0.68)
	Placebo	19.18 (2.95)	-3.28 (0.70)	—
Study 2	ABILIFY (9.75 mg) †	18.82 (2.67)	-7.27 (0.59)	-2.48 (-3.77, -1.19)
	Placebo	18.74 (2.71)	-4.78 (0.69)	—
Agitation Associated with Bipolar Mania
Study 3	ABILIFY (9.75 mg) †	18.77 (2.45)	-8.74 (0.57)	-2.99 (-4.53, -1.44)
	ABILIFY (15 mg) †	18.29 (2.49)	-8.67 (0.57)	-2.91 (-4.44, -1.38)
	Placebo	17.95 (2.63)	-5.76 (0.58)	—