# Abstract

 We evaluated the efficacy and safety of aripiprazole in the treatment of irritability in children and adolescents (6--17 years) with autism spectrum disorder (ASD) in a randomized, double-blind, placebo-controlled 8-week study in Japan. Patients received flexibly dosed aripiprazole (1--15 mg/day) or placebo. Ninety-two patients were randomized to placebo (n = 45) or aripiprazole (n = 47). Aripiprazole produced a significant improvement in the mean parent/caregiver-rated Aberrant Behavior Checklist Japanese Version irritability subscale score relative to placebo from week 3 through week 8. Administration of aripiprazole provided significantly greater improvement in the mean clinician-rated Clinical Global Impression-Improvement scores than placebo from week 2 through week 8. All patients randomized to aripiprazole completed the study, and no serious adverse events were reported. Three patients in placebo group discontinued. Aripiprazole was effective and generally safe and well-tolerated in the treatment of irritability associated with ASD in Japanese children and adolescents. # Results 

## Subject Disposition and Demographics In total, 99 patients were enrolled and 92 patients were randomly assigned to receive placebo (n = 45) or aripiprazole (n = 47). Forty-two (93.3%) patients in the placebo group and 47 (100%) patients in the aripiprazole group completed the trial; subject disposition is shown in Fig.  [1](#) . All randomized patients (n = 92) were included the efficacy and safety sample. <figure> <p><img src="" /></p> <figcaption>Subject disposition</figcaption> </figure> The demographic and clinical characteristics at baseline are shown in Table  [1](#) . The mean age of the randomized patients was 10.1 years old, and the majority of patients were males and younger than 13 years. Fifty-eight (63.0%) patients with intellectual disability were included in the trial. ::::table-wrap

::: caption
Baseline demographics and clinical characteristics
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```
                                      Placebo (n = 45)   Aripiprazole (n = 47)   Total (n = 92)
```

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Gender\
Male 36 (80.0) 39 (83.0) 75 (81.5)
Female 9 (20.0) 8 (17.0) 17 (18.5)
Age, years ^a^ 9.9 (3.1) 10.3 (3.3) 10.1 (3.2)
6--12 years 36 (80.0) 33 (70.2) 69 (75.0)
13--17 years 9 (20.0) 14 (29.8) 23 (25.0)
Height, cm ^a^ 137.6 (18.1) 140.7 (19.0) 139.2 (18.5)
Weight, kg ^a^ 36.4 (15.5) 39.1 (17.6) 37.8 (16.5)
\<40 kg 31 (68.9) 26 (55.3) 57 (62.0)
≥40 kg 14 (31.1) 21 (44.7) 35 (38.0)
Body mass index, kg/m ^2a^ 18.4 (3.8) 18.7 (4.2) 18.6 (4.0)
Intellectual disability ^b^ 29 (64.4) 29 (61.7) 58 (63.0)
Intelligence quotient (IQ) ^c^\
Mild 16 (35.6) 16 (34.0) 32 (34.8)
Moderate 7 (15.6) 7 (14.9) 14 (15.2)
Severe 6 (13.3) 6 (12.8) 12 (13.0)
ABC-J irritability subscale score ^a^ 26.8 (6.5) 27.1 (7.2) 27.0 (6.9)
CGI-S ^a^ 5.0 (0.8) 4.9 (0.7) 4.9 (0.8)

Data are expressed as number (%)

^a^Mean (standard deviation)

^b^Intellectual disability was diagnosed based on DSM-IV-TR

^c^Mild (IQ level: 50--55 to approximately 70), moderate (IQ level:
35--40 to 50--55), severe (IQ level: 20--25 to 35--40):::: 

## Study Medication The mean daily dose of aripiprazole for the whole treatment was 5.7 ± 2.7 mg (±SD). It ranged from 8.1 to 8.4 mg after day 43, at which time the dose was fixed for each patient, with a mean (±SD) daily dose of 8.2 ± 4.9 mg at endpoint. The last dose of aripiprazole (n = 47) was distributed as follows: 1 mg/day, n = 2 (4.3%); 3 mg/day, n = 13 (27.7%); 6 mg/day, n = 8 (17.0%); 9 mg/day, n = 9 (19.1%); 12 mg/day, n = 3 (6.4%); and 15 mg/day, n = 12 (25.5%) (Fig.  [2](#) ). The mean daily dose of placebo corresponding to aripiprazole was 8.1 ± 2.0 mg (±SD) during the treatment phase. The mean (± SD) daily dose of placebo at endpoint was 12.8 ± 3.6 mg and the prescription pattern of the last dose of placebo corresponding to aripiprazole (n = 45) was distributed as follows: 1 mg/day, n = 1 (2.2%); 3 mg/day, n = 1 (2.2%); 6 mg/day, n = 2 (4.4%); 9 mg/day, n = 7 (15.6%); 12 mg/day, n = 5 (11.1%); and 15 mg/day, n = 29 (64.4%) (Fig.  [2](#) ). <figure> <p><img src="" /></p> <figcaption>Patient distribution of the last doses of aripiprazole and placebo corresponding to aripiprazole</figcaption> </figure> Hypnotic/sedative/anxiolytic agents [placebo n = 0 (0%); aripiprazole n = 2 (4.3%)] were used concomitantly during the study. Antiparkinson agents were not used by any enrolled patients during the study period. 

## Efficacy Outcomes Table  [2](#) shows the results for primary and secondary endpoints. At week 8, the least square mean decrease from baseline in the parent/caregiver-rated ABC-J irritability subscale score was significantly greater for patients who received aripiprazole (Table  [2](#) ; Fig.  [3](#) ). The TD was −3.94 showing statistical significance (Table  [2](#) ). Significant TDs in favor of aripiprazole were detected from week 3 through week 8 (Fig.  [3](#) ). At week 8, aripiprazole group showed a statistically significant improvement in mean clinician-rated CGI-I scores greater than the placebo group [2.7 (0.1) vs 3.4 (0.1); TD: −0.62 (95% CI: −1.02 to − 0.22); p = 0.003]. Significant TDs in favor of aripiprazole were observed from week 2 through week 8 (Fig.  [4](#) ). Response rates were significantly greater for patients who received aripiprazole from week 3 through week 8 (Table  [2](#) ; Fig.  [5](#) ). Patients who received aripiprazole demonstrated significant improvement versus placebo on the mean ABC-J hyperactivity subscale score. Subjects treated with aripiprazole demonstrated statistically significant improvement compared to placebo in the mean CGI-S score from week 2 through week 8 and the CGAS score at weeks 4 and 8. There was no significant difference between aripiprazole group and the placebo group in the mean ABC-J stereotypy, inappropriate speech and lethargy/social withdrawal subscale scores, as well as ABC-J response rate, CY-BOCS (compulsion scale) (Table  [2](#) ). ::::table-wrap
::: caption
Result of efficacy endpoints (Week 8 LOCF, Efficacy sample)
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```
                                          Placebo (n = 45)            Aripiprazole (n = 47)   Difference or ratio (95% confidence interval) P value                   
```

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Mean baseline Mean change from baseline Mean baseline Mean change from baseline

ABC-J irritability subscale 26.1 (1.0) −7.5 (1.4) 26.9 (1.0) −11.4 (1.3) −3.94 (−7.77, −0.12) ^b^
0.044

Response rate 9 (20.0) ^a^ 19 (40.4) ^a^ 2.02 (1.02, 3.99) ^c^
0.033

ABC-J hyperactivity subscale 26.8 (1.6) −5.5 (1.5) 29.6 (1.5) −13.0 (1.4) −7.55 (−11.53, −3.57) ^b^
\<0.001

ABC-J stereotypy subscale 7.7 (1.0) −2.6 (0.6) 8.2 (1.0) −3.3 (0.6) −0.67 (−2.42, 1.08) ^b^
0.450

ABC-J inappropriate speech subscale 7.3 (0.6) −1.5 (0.4) 7.6 (0.5) −2.2 (0.4) −0.77 (−1.94, 0.41) ^b^
0.197

ABC-J lethargy/social withdrawal subscale 14.8 (1.4) −4.7 (1.1) 15.0 (1.4) −5.2 (1.0) −0.44 (−3.40, 2.51) ^b^
0.768

ABC-J response rate 12 (26.7) ^a^ 20 (42.6) ^a^ 1.60 (0.89, 2.87) ^c^
0.110

CGI-S 5.0 (0.1) −0.7 (0.2) 4.9 (0.1) −1.4 (0.1) −0.62 (−1.03, −0.21) ^b^
0.003

CY-BOCS (compulsion scale only) 5.4 (0.9) −1.3 (0.5) 6.3 (0.9) −2.0 (0.5) −0.69 (−2.03, 0.66) ^b^
0.311



## CGAS 42.3 (2.3) 4.5 (1.4) 42.9 (2.2) 9.8 (1.3) 5.25 (1.53, 8.96) ^b^ 0.006

Data are expressed as least squares mean (standard error). Response rate
is defined as ≥25% reduction from baseline in the ABC-J irritability
subscale score and a CGI-I score of 1 or 2. ABC-J response rate is
defined as ≥50% reduction from baseline in at least 2 subscales and
\<10% increase from baseline in the remaining subscales

*CY-BOCS*Children's yale-brown obsessive--compulsive scale

^a^Number of patients (%)

^b^Difference between aripiprazole and placebo

^c^Ratio between aripiprazole and placebo:::: <figure> <p><img src="" /></p> <figcaption>Mean change from baseline in ABC-J Irritability score by week (LOCF; efficacy sample). Data are expressed as least squares mean (standard error). <em>ABC-J</em> Aberrant Behavior Checklist Japanese Version, <em>LOCF</em> last observation carried forward. \*P \< 0.05; \*\*P \< 0.01 versus placebo</figcaption> </figure> <figure> <p><img src="" /></p> <figcaption>Mean CGI-I score by week (LOCF; efficacy sample). Data are expressed as least squares mean (standard error). <em>CGI-I</em> clinical global impressions-improvement score, <em>LOCF</em> last observation carried forward. \*\*P \< 0.01; \*\*\*P \< 0.001 versus placebo</figcaption> </figure> <figure> <p><img src="" /></p> <figcaption>Treatment response rate by week (LOCF; efficacy sample). The treatment response was defined as ≥25% reduction from baseline in the Aberrant Behavior Checklist Japanese Version Irritability subscale score and a Clinical Global Impressions-Improvement score of 1 or 2. <em>LOCF</em> last observation carried forward. \*P \< 0.05; \*\*P \< 0.01 versus placebo</figcaption> </figure> 

## Safety Outcomes During the study, 33 (73.3%) patients in the placebo group and 39 (83.0%) patients in the aripiprazole group experienced at least one AE. AEs that occurred at an incidence ≥5% in any treatment group are shown in Table  [3](#) . All AEs were mild to moderate in severity in both treatment groups. No deaths were reported. Discontinuation due to AEs (exacerbation of the ASD) occurred in 1 (2.2%) patient in the placebo group. A serious AE (heat disorder) occurred in 1 (2.2%) patient in the placebo group. No serious adverse events were reported in the aripiprazole group, in which all patients completed the study. ::::table-wrap
::: caption
Treatment-Emergent Adverse Events that occurred in ≥5% of patients in
any group
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```
                   Placebo (n = 45)   Aripiprazole (n = 47)
```

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Adverse event 33 (73.3) 39 (83.0)
Somnolence 4 (8.9) 24 (51.1)
Nasopharyngitis 11 (24.4) 10 (21.3)
Decreased appetite 1 (2.2) 6 (12.8)
Nausea 1 (2.2) 3 (6.4)
Vomiting 0 (0.0) 3 (6.4)
Fatigue 0 (0.0) 3 (6.4)
Gastroenteritis 4 (8.9) 1 (2.1)
Bruise 3 (6.7) 1 (2.1)

Data are expressed as number (%):::: EPS-related AEs were found in 1 (2.2%) patient in the placebo group and in 3 (6.4%) patients in the aripiprazole group. In the aripiprazole group, EPS-related AEs were observed in 2 (4.3%) patients (salivary hypersecretion) or 1 (2.1%) patient each (akathisia, gait disturbance, bradykinesia, lisp and tremor). One patient in the aripiprazole group experienced salivary hypersecretion, gait disturbance, bradykinesia, lisp and tremor. One (2.2%) patient in the placebo group experienced salivary hypersecretion as EPS. The severity of all observed EPS-related AEs were considered mild in both groups. Mean serum prolactin concentrations at baseline were 16.7 ng/mL for placebo and 14.3 ng/mL for aripiprazole. Aripiprazole was associated with a significant decrease in serum prolactin concentrations compared with placebo from baseline to week 8 (−13.8 vs −2.0 ng/mL; p \< 0.001). No patient in the aripiprazole group experienced increase in serum prolactin concentrations. Sedation was reported as an AE in 2.1% (n = 1) of the aripiprazole group and no patients in the placebo group. Increased appetite was reported as an AE in 4.3% (n = 2) of the aripiprazole group and 2.2% (n = 1) in the placebo group. Weight gain was reported as an AE in 2.2% (n = 1) of the placebo group and no patients in the aripiprazole group. An increase in body weight of ≥7% from baseline was seen in 6.7% of the placebo group and 27.7% of the aripiprazole group. However, the mean change in weight from baseline to week 8 was not significantly different between aripiprazole and placebo (1.24 vs 0.58 kg; p = 0.085). The mean change in BMI from baseline to week 8 was significantly different between aripiprazole and placebo (0.40 versus 0.03 kg/m ^2^ ; p = 0.035). After treatment, the incidence rates of total cholesterol ≥200 mg/dL were: placebo, 9.1% and aripiprazole, 17.0%. No patients experienced fasting blood glucose ≥115 mg/dL, non-fasting blood glucose ≥200 mg/dL, fasting triglyceride ≥200 mg/dL, non-fasting triglyceride ≥500 mg/dL. No marked abnormalities were observed in the other clinical laboratory tests along with vital sign assessments and the 12-lead ECG, except for the decrease in serum prolactin concentrations in the aripiprazole group as described above. There were no adverse events regarding treatment-related suicidal ideation and behavior during the treatment phase.


Extracted trial result:
Outcome: Social withdrawal (continuous)
Intervention: Aripiprazole
Comparator: Placbeo
Intervention group size: 45
Intervention mean: -4.7
Intervention standard deviation: 1.1
Comparator group size: 47
Comparator mean: -5.2
Comparator standard deviation: 1
Notes: table 2, given as mean change