Open Label Trial of Aripiprazole in the Treatment of CD in Adolescents
Phase: PHASE4
Conditions: Conduct Disorder
Sponsor: University of Iowa

PROTOCOL: An Open Label Trial of Aripiprazole in the Treatment of Conduct 
Disorder in Adolescents. 
 
Rationale: 
 
The use of atypical antipsychotics in children began in 1992 with several small 
case series with clozapine.  Since that time, five other atypical agents, risperidone, 
olanzapine, quetiapine, ziprasidone and aripiprazole have been introduced into the US 
market.  The newer atypical agents are not associated with agranulocytosis that has 
limited the usefulness of clozapine.  Among the atypical antipsychotics, risperidone has 
remained the most extensively studied in children and adolescents, for a variety of 
problems, including Tourette’s disorder, conduct disorder, schizophrenia, aggression, and 
pervasive development disorder.  Risperidone has been shown to be an effective 
treatment in many of these disorders. However, weight gain, hyperprolactinemia, and 
extrapyramidal symptoms (EPS) are troublesome adverse effects more commonly 
associated with risperidone such that the drug’s utility in this aged patient population is 
limited. We expect that the utility of aripiprazole in treating the pediatric population will 
not be limited by adverse effects like the other atypical antipsychotics. 
 
Previous Work: 
 
 
Several small studies have found risperidone to be more effective than placebo in 
treating children and adolescents with either aggression or conduct disorder.  In a 10-
week, randomized, double-blind study (n=20), risperidone was superior to placebo in 
reducing most measures of the Rating of Aggression Against People and/or Property 
Scale (RAAPP), when dosed at an average of 0.028mg/kg/day [range = 0.75-1.50 
mg/day] (Findling et al 2000).  The data also suggested that treatment with risperidone 
was associated with weight gain. The predicted weight gain from a repeated measures 
analysis for the risperidone group of 4.2±0.7kg was greater than the placebo group 
(p=0.003).  There was no difference in the incidence of EPS at endpoint according the 
Simpson-Angus EPS (SAEPS) rating scale. 
 
Buitelaar et al (2001) assessed the efficacy of risperidone in the treatment of 
aggression.  Thirty-eight adolescents were randomized to either risperidone or placebo in 
a double-blind fashion.  The mean daily dose of risperidone at end of treatment (6 weeks) 
was 2.9mg [range = 1.5-4 mg].  Risperidone treatment produced improvement on the 
Clinical Global Impression-Severity (CGI-S) scale (LOCF, p<0.001) and the at-school 
Aberrant Behavior Checklist (ABC) overall and hyperactivity scales (p<0.05). In the 
risperidone group, following a 2-week washout following the 6-week trial worsening on 
all efficacy measures (CGI-S, Overt Aggression Scale-Modified (OAS-M), and the ABC. 
Weight gain was significant in the risperidone group (3.5% body weight increase, range –
1 to +6kg, p<0.05).  Transient tiredness was also noted in 58% of drug-treated subjects, 
and was also the reason for dose reduction in five of the drug-treated subjects.  
Extrapyramidal Side Effect Rating Scale (ESRS) scores increased for Parkinsonism 
(cluster II) at endpoint compared to placebo (p<0.05). 
 

 
Bellinghen et al (2001) compared risperidone (n=6) to placebo (n=7) in the 
treatment of behavioral disturbances in children and adolescents.  Thirteen patients were 
enrolled in a 4-week double-blind, placebo-controlled study.  Risperidone (mean dose = 
0.05mg/kg; mean total dose = 1.2 mg/day) was more effective than placebo in improving 
ABC cluster scores for irritation and hyperactivity, the CGI scale.  No significant 
differences in EPS symptoms or weight gain were seen between the treatment groups.  
The lack of any adverse effect differences is not surprising considering the low dose of 
risperidone and the small number of patients enrolled in the study. 
 
Methods: 
 
Dose and Schedule of Treatment: The proposed study will be a 6-week open label 
study evaluating aripiprazole in the treatment of 12 male post-pubertal adolescents (13-17 
years, Tanner Stage 4) diagnosed with conduct disorder. The initial dose depending on 
the weight of the patient will be as follows:  < 25 kg = 1 mg/d; 25-50 kg = 2 mg/d; 50-70 
kg = 5 mg/d; > 70 kg = 10 mg/d (Data on File, 2003, Bristol-Myers Squibb).  Thereafter 
the dose will be flexible based on response and tolerance. 
 
Main outcome measures: The primary outcome efficacy measures will be the Rating of 
Aggression Against People and/or Property Scale (RAAPP) (Kemph et al 1993), Overt 
Aggression Scale-Modified (OAS-M) (Kay et al 1988), and Children’s Aggression Scale-
Parent Version (CAS-P) (Halpern et al 2002) while the secondary outcome measure will 
be the CGI severity and improvement scale (NIMH, 1985a).  Safety measures for 
extrapyramidal adverse effects will include the AIMS (NIMH, 1985b) for tardive 
dyskinesia, Barnes Akathisia Scale (Barnes 1989) (BAS) and the Simpson-Angus Scale 
(SAS) (Simpson and Angus 1970).   The UKU (Lingjaerde et al 1987) will be used for 
monitoring non-motor adverse effects.  Height, weight and body mass index 
measurements as well as initial and endpoint fasting blood sugars and lipids will assess 
the effect of weight change.  Obtaining serum prolactin levels as well as screening for the 
sexual dysfunction adverse effects including galactorrhea, gynecomastia, menstrual 
irregularities and changes in libido will assess sexual dysfunction adverse effects.  An 
initial and endpoint ECG will be obtained to monitor patients for any changes in the QT-
corrected interval.  A gamma-GT will be collected to monitor liver function. 
 
Schedule of Events: 
 
Procedure 
screening 
baseline week 1 week 2 week 4 week 6 
 
(-7 to –28days) 
 
 
 
 
 
History-Demographics 
X 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
X 
ECG 
X 
 
 
 
 
X 
Vitals, Height, Weight, BMI 
X 
X 
X 
X 
X 
X 
Urine Collection 
X 
 
 
 
 
X 
Phlebotomy 
X 
 
 
 
 
X 
Dispense Study Drug 
 
X 
X 
X 
X 
X 
Determine medication compliance 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 

Laboratory Tests 
 
 
 
 
 
 
 
 
 
 
 
 
 
fasting glucose 
X 
 
 
 
 
X 
fasting lipid profile: 
 
 
 
 
 
 
total cholesterol 
X 
 
 
 
 
X 
HDL-cholesterol 
X 
 
 
 
 
X 
LDL-cholesterol 
X 
 
 
 
 
X 
Triglicerides 
X 
 
 
 
 
X 
Prolactin 
X 
 
 
 
 
X 
Gamma GT 
X 
 
 
 
 
X 
CBC 
X 
 
 
 
 
X 
Urine Drugs of Abuse Screen 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
Psychiatric Rating Scales 
 
 
 
 
 
 
 
 
 
 
 
 
 
RAAPP 
 
X 
X 
X 
X 
X 
CAS-P 
 
X 
X 
X 
X 
X 
OAS 
 
X 
X 
X 
X 
X 
CGI-S 
 
X 
X 
X 
X 
X 
CGI-I 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
Side Effect Rating Scales 
 
 
 
 
 
 
 
 
 
 
 
 
 
AIMS 
 
X 
X 
X 
X 
X 
SAS 
 
X 
X 
X 
X 
X 
UKU 
 
X 
X 
X 
X 
X 
BAS 
 
X 
X 
X 
X 
X 
 
 
 
References: 
 
Buitelaar JK, van der Gaag, R, Cohen-Kettenis P, et al (2001).  A randomized controlled 
trial of risperidone in the treatment of aggression in hospitalized adolescents with 
subaverage cognitive abilities.  J Clin Psychiatry 62:239-48. 
 
Barnes TRE (1989).  A rating scale for drug-induced akathisia.  Br j Psychiatry 154:672-
6. 
 
Data on File, 2003, Bristol-Myers Squibb Company, Princeton, NJ 08536 
 
Kemph JO DeVane CL, Levin GM, et al (1993).  Treatment of aggressive children with 
clonidine: results of an open pilot study. Am Acad Child Adolesc Psychiatry 
32:577-81. 
 

Findling RL, McNamara NK, Branicky L, et al (2000).  A double-blind pilot study of 
risperidone in the treatment of conduct disorder.  J Am Acad Child Adolesc 
Psychiatry 39:509-16. 
 
Kay SR, Wolkenfeld F, Murrill LM (1988).  Profiles of aggression among psychiatric 
patients : I. nature and prevalence.  J Nerv Ment Dis 176:539-46. 
 
Lingjaerde O, Ahlfors UG, Bech P, et al (1987).  The UKU side effect rating scale.  A 
new comprehensive rating scale for psychotropic drugs and a cross-section study 
of side effect in neuroleptic-treated patient.  Acta Psychiatr Scand Suppl 334:1-
100. 
 
National Institute of Mental Health (1985a).  CGI (Clinical Global Impression) Scale.  
Psychopharmacol Bull 21:839-43.  
 
National Institute of Mental Health (1985b).  AIMS (Abnormal Involuntary Movement 
Scale).  Psychopharmacol Bull 21:839-43.  
 
Simpson GM, Angus JWS (1970).  A rating scale for extrapyramidal side effects.  Acta 
Psychiatr Scand Suppl 212:11-9. 
 
Van Bellinghen M, DeTroch C ( 2001).  Risperidone in the treatment of behavior 
disturbances in children and adolescents with borderline intellectual functioning: 
A double-blind placebo-controlled pilot trial.  J Child Adolesc Psychopharmacol 
11:5-13. 
 

 
Budget: Open label Aripiprazole-Conduct Disorder study  
 
 
 
 
 
 
 
 
 
 
Procedure 
Screening Baseline Week 1 Week 2 Week 4 Week 6 
 
 
 
 
 
 
 
History-Demographics 
50.00  
 
 
 
 
Physical Exam 
100.00  
 
 
 
100.00 
ECG 
125.00  
 
 
 
125.00 
Vitals, Height, Weight, BMI 
10.00 
10.00 
10.00 
10.00 
10.00 
10.00 
Urine Collection 
5.00  
 
 
 
5.00 
Phlebotomy 
10.00  
 
 
 
10.00 
 
 
 
 
 
 
 
Laboratory Tests 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting glucose 
12.00  
 
 
 
12.00 
Fasting lipid profile: 
 
 
 
 
 
 
Total cholesterol 
15.00  
 
 
 
15.00 
HDL-cholesterol 
29.00  
 
 
 
29.00 
LDL-cholesterol 
0.00  
 
 
 
0.00 
Triglycerides 
19.00  
 
 
 
19.00 
Prolactin 
53.00  
 
 
 
53.00 
Gamma GT 
21.00  
 
 
 
21.00 
CBC 
27.00  
 
 
 
27.00 
Urine Drugs of Abuse Screen 
85.00  
 
 
 
85.00 
 
 
 
 
 
 
 
Psychiatric Rating Scales 
 
 
 
 
 
 
 
 
 
 
 
 
 
RAAPP 
 
25.00 
25.00 
25.00 
25.00 
25.00 
CAS-P 
 
25.00 
25.00 
25.00 
25.00 
25.00 
OAS 
 
25.00 
25.00 
25.00 
25.00 
25.00 
CGI-S 
 
25.00 
25.00 
25.00 
25.00 
25.00 
CGI-I 
 
25.00 
25.00 
25.00 
25.00 
25.00 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Side Effect Rating Scales 
 
 
 
 
 
 
 
 
 
 
 
 
 
AIMS/BAS/SAS 
 
25.00 
25.00 
25.00 
25.00 
25.00 
UKU 
 
25.00 
25.00 
25.00 
25.00 
25.00 
 
 
 
 
 
 
 
Investigator Fee 
100.00 
100.00 100.00 100.00 100.00 100.00 
Study Coordinator Fee 
50.00 
50.00 
50.00 
50.00 
50.00 
50.00 
Subject Compensation 
25.00 
25.00 
25.00 
25.00 
25.00 
25.00 
 
 
 
 
 
 
 

Total direct costs per visit 
886.00 
360.00 360.00 360.00 360.00 861.00 
Total direct costs per completed subject  
 
 
 
 
3187.00 
 
 
 
 
 
 
 
Total indirect costs per visit (25%) 
184.00 
90.00 
90.00 
90.00 
90.00 215.25 
Total indirect costs per completed 
subject 
 
 
 
 
 
759.25 
 
 
 
 
 
 
 
Total costs per completed subject 
 
 
 
 
 
3796.25