| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Conduct Disorder DSM-IV-TR; 312.8x¸ APA, 2000 |
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| E.1.1.1 | Medical condition in easily understood language |
| aggressive antisocial behavior |
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| E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Mental Disorders [F03] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10064478 |
| E.1.2 | Term | Conduct disorder |
| E.1.2 | System Organ Class | 10037175 - Psychiatric disorders |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of this study is to test the hypothesis that risperidone given orally in a dose of 0.25 – 3.0 mg/d depending on body weight (eq. to approximately 0.01 – 0.04 mg/kg/d) for 12 weeks is superior to placebo in reducing disruptive behavioural symptoms associated with DSM-IV-TR defined Conduct Disorder (CD) in the treatment of in- and outpatient children and adolescents (6.0 - < 17.0 y.) not developmentally delayed/mentally retarded, as measured by last-observation-carried-forward (LOCF) mean change from baseline to endpoint on the pivotal scale, the Nisonger Child Behavior Rating Form (CBRF) - Typical IQ Version-ODD/CD disruptive behavior (DBD) Composite Total score (Aman et al., 2008) using investigator-ratings based on all available information. |
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are as follows:
To test the hypothesis that risperidone is superior to placebo in reducing disruptive behaviours associated with CD over 12 weeks of double-blind treatment.
To test the hypothesis that risperidone is superior to placebo in improving functional outcomes over 12 weeks of double-blind treatment.
To test the effect of risperidone compared to placebo on various other behavioural domains over 12 weeks of double-blind treatment.
To assess the effect of risperidone compared to placebo on comorbid ADHD symptoms over 12 weeks of double-blind treatment.
To assess the effect of risperidone compared to placebo on (impairment of) cognition/cognitive functioning (e.g. due to possible sedative effects) over 12 weeks of double-blind treatment.
To compare safety and tolerability results for risperidone and placebo in children and adolescents with CD over 12 weeks of double-blind treatment
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| E.2.3 | Trial contains a sub-study | No |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Relapse prevention in children and adolescents with DSM-IV Conduct Disorder treated with Risperidone:
a Randomized Double blind, Placebo-Controlled, Discontinuation Study.
Date: 01-06-2012
The primary objective is to test the hypothesis that, after at least 16 weeks of daily administration (4 for titration, 12 of relatively stable dose, 4 of which at fixed doses, (Study Period 1), risperidone given orally in a dose of 0.25 – 3.0 mg/d depending on body weight (eq. to approximately 0.01 – 0.04 mg/kg/d) is superior to placebo in preventing relapse of symptoms of CD, as assessed through a 12 week, double-blind discontinuation trial (Study Period 2) of children and adolescents not developmentally delayed/mentally retarded, and measured by comparison with mean change from the double-blind baseline to endpoint on the Nisonger Child Behavior Rating Form (CBRF) - Typical IQ Version-ODD/CD disruptive behavior (DBD) Composite Total score (Aman et al., 2008) using investigator-ratings based on all available information.
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| E.3 | Principal inclusion criteria |
Patients are eligible to be included in the study only if they meet all of the inclusion criteria below.
- Male or female patients aged 6.0 - <18.0 years at Visit 1.
-Patients must have an IQ of > 85
-Patients must meet DSM-IV-TR diagnostic criteria for DSM-IV-TR Conduct Disorder(s) as confirmed by the Kiddie-SADS, Conduct Disorder Moduleat Visit 2 or Visit 3.
-Patients must score ≥ 27 on the Nisonger CBR Form, ODD/CD Disruptive Behavior Composite (D-Total) at Visit 2 or Visit 3.
-Patients must score ≥4 (“moderately ill”) on the CGI-S rating scale at Visits 2 and 3.
-If a female of child-bearing potential, patients must test negative for pregnancy at the time of enrollment based on a serum pregnancy test and agree to use a reliable method of birth control. (Adequate contraception includes: oral contraceptives, intrauterine devices; double barrier method (diaphragm or condom plus spermicide), Norplant™ or Depot Provera™)).
-Patients must have a body weight of at least 20 kg at study entry.
-Patients must be able to swallow study drug.
-Patients must have venous access sufficient to allow blood sampling and are compliant with blood draws as per protocol.
-Subjects’ parents/legal guardians must provide and sign informed consent documents; patients must provide and sign consent (if > or = 16 years) or assent documents
-A reliable person (primary caregiver, parent) must be available to ensure compliance with study procedures throughout the course of the study.
-Patients meeting criteria for comorbid ADHD (as to the clinical judgment of the investigator) will not be excluded from study participation.
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| E.4 | Principal exclusion criteria |
A patient will be excluded from the study if he or she meets any exclusion criteria described below, according to the assessment of the investigator.
-Is immediate family of investigator site personnel directly affiliated with this study. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.
-Has been treated with a drug within 14 days before Visit 1 that has not received regulatory approval for any indication at the time of study entry.
-Has participated in any investigational drug trial within six months prior to baseline (visit 3).
-Has previously completed or withdrawn from this study or any other study investigating risperidone or has previously been identified as being a nonresponder or intolerant of risperidone.
-Has a current (within 6 months of the start of the study) or lifetime DSM-IV-TR diagnosis of schizophrenia-related disorders, schizophrenia, bipolar disorder, major depressive disorder, or current substance dependence disorder (given the nature of the study population substance misuse or abuse is not exlusionary), pervasive developmental disorder (autistic disorder or Asperger disorder).
-In the clinical judgment of the investigator, currently meets criteria for a primary psychiatric disorder, e.g., Anxiety Disorder, Depressive Disorder, Tic Disorder or Tourette’s Syndrome (comorbid ADHD is permitted, cf. Incl. criteria section)
-Starts any psychotropic medication, including health-food supplements that the investigator feels could have central nervous system activity (for example, St. John’s Wort, melatonin), during the course of the study, or is taking any other excluded concomitant medication(s) at/beyond Visit 2 (An ongoing long-term medication, e.g., to treat a comorbid disorder such as ADHD, is permitted as long as compound and dose are not changed throughout the course of the study.)
-Has any acute or unstable medical condition, physiological condition, clinically significant laboratory, or ECG results that, in the opinion of the investigator, would compromise participation in the study.
-Has a known or suspected seizure disorder.
-Has a history of neuroleptic malignant syndrome (NMS) or of tardive dyskinesia.
-Has a history of hypersensitivity to neuroleptics,.
-Is pregnant or nursing.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy measurement for the study is the LOCF mean change from baseline to endpoint of the double-blind phase on the Nisonger Child Behavior Rating Form for Typical IQ children-ODD/CD disruptive behavior (DBD) Total Composite score (Lecavalier at al., 2004, Aman et al., 2008) using investigator-ratings based on all available information.
The Nisonger Child Behavior Rating Form Typical IQ version (NCBRF-TIQ) is a 64-item standardized measure used to assess child and adolescent behaviour in children with (Aman et al., 2008, http://psych.med.osu.edu)). There are six Problem Behavior subscales (54 items): Conduct Problems, Oppositional, Hyperactive Inattentive, Withdrawn/Dysphoric, and Overly Sensitive. In addition there is a Disruptive Total composite (D-Total) score. Also, a Positive Social subscale (10 items) has been derived. Psychometric data for the NCBRF-TIQ have been published.
An investigator-rated version will be administered. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| will be measured at washout (wk -1), baseline (wk 0) and during trial at weeks, 1,2,4,6,8,12 and 13. will also be measured if participant leaves trial early. |
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| E.5.2 | Secondary end point(s) |
There are a range of secondary measures and end points in different domains;
ODD and CD subscores
- Both ODD and CD scores from Nisonger CBRF –TIQ, separately
- Modified Overt Aggression Scale (M-OAS, Coccaro et al., 1991; Yudofsky et al., 1986) and subscores
The Modified Overt Aggression Scale (M-OAS; Coccaro et al., 1991) is a 7-item investigator-rated instrument that assesses aggression on the dimensions of(i) verbal assault, (ii) assaults against objects, (iii) against others, (iv) against self, (v) global subjective irritability, (vi) global overt irritability, and (vii) suicidal tendencies. Most of these dimensions are rated on Likert scales ranging from 0 (no events) to 5 (concrete descriptions of severe events). The M-OAS has been used in a number of descriptive and pharmacological trials.
Clinical Global Impression-Severity (CGI-S)
The Clinical Global Impressions-Severity (CGI-S) is a single-item rating of the clinician’s assessment of the severity of symptoms in relation to the clinician’s total experience with CD patients (Guy 1976; NIMH 1985). Severity is rated on a 7-point scale (1 = normal, not at all ill; 7 = among the most extremely ill subjects).
Clinical Global Impressions-Improvement (CGI-I)
The Clinical Global Impressions-Improvement (CGI-I) is a single-item clinician rating of the total improvement (or worsening) of the patient’s symptoms since the beginning of treatment regardless of whether the improvement (or worsening) was thought to be due entirely to the drug treatment (Guy 1976; NIMH 1985). Improvement is rated on a 7-point scale (1 = very much improved; 7 = very much worsened).
Response Rate
The percentage of patients who achieve response will serve as a secondary efficacy measure. Response will be defined as follows:
a rating of 1 or 2 on the CGI-I and a 25 % reduction from the baseline score on the Nisonger CBRF TIQ D—Total score (according to a personal information by the first author, M. Aman, 2010). This definition is corresponding to those used in the risperidone trials in children and adolescents with CD and sub-average IQ (e.g., Reyes et al., 2006a).
Children’s Global Assessment (C-GAS)
The Children’s Global Assessment (C-GAS) is a global, unidimensional clinician rating of social and psychiatric functioning in children aged 4 to 16 years. Scores on the measure range from 1 (most impaired) to 100 (healthiest).
ADHD- DSM-IV Rating Scale (ADHD-RS IV)
This instrument (investigator-rated) will be used to assess (as a secondary outcome) comorbid ADHD symptomatology over the course of the study (DuPaul et al., 1998). It has been used extensively in various registration trials for the indication of ADHD.
Cognition
In order to assess potential cognitive impairment, the following parameters/instrument will be used: a cognitive battery including attentional and set-shifting tests, e.g.:
shifting attention set-visual (10-15 mins), baseline speed (4 min), tracking (2 min), pursuit (4 min),with a total time of approximately 20 - 35 min (4 subtasks of the Amsterdam Neuropsychological Tasks, ANT; de Sonneville 1999).
Additional symptom assessment
The Child Behavior Checklist (CBCL), parent-reported (Achenbach, 1991a) will be applied at baseline in order to assess general symptomatology (cf. Schedule of Events, SOE, in the annex).
It is a standard instrument that allows evaluating various behavioural domains in children and adolescents; it has been validated and is available in the very country languages involved in this study.
It may also allow for analyses on mediating factors for primary and secondary outcome parameters.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
ODD and CD subscores
- Both ODD and CD scores from Nisonger CBRF –TIQ
will be measured at washout (wk -1), baseline (wk 0) and during trial at weeks, 1,2,4,6,8,12 and 13.
- Modified Overt Aggression Scale (M-OAS)
will be measured at washout (wk -1), baseline (wk 0) and during trial at weeks, 4,8,12 and 13.
Clinical Global Impression-Severity and impairment (CGI-S & I)
will be measured at washout (wk -2 and -1), baseline (wk 0) and during trial at weeks, 1,2,4,6,8,12 and 13.
Response Rate
at last valid visit
Children’s Global Assessment (C-GAS),ADHD- DSM-IV Rating Scale (ADHD-RS IV), CHIP-CE, cognition
will be measured at washout (wk -1), baseline (wk 0) and during trial at weeks, 4,12 and 13.
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 13 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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