| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Conduct Disorder (DSM-IV-TR; 312.8x; American Psychiatric Association) |
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| E.1.1.1 | Medical condition in easily understood language |
| Persistent aggressive and antisocial behaviour. |
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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 is to test the hypothesis that risperidone - given orally in a dose of 0.25-3.0mg/day depending on body weight (i.e. approximately equivalent to 0.01-0.04mg/kg/day) for 12 weeks - is superior to placebo in reducing the disruptive behavioural symptoms of DSM-IV-TR defined conduct disorder in children and adolescents (in- and out-patients) aged 5.0-17.9 years who have no developmental delay or mental retardation. This will be measured according to the last-observation-carried-forward mean change from baseline to endpoint for the pivotal scale The Nisonger Child Behaviour Rating Form-Typical IQ Version ODD/CD disruptive behaviour 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 are:-
1. to test the hypothesis that risperidone is superior to placebo in reducing the disruptive behaviours associated with conduct disorder over 12 weeks of treatment
2. to test the hypothesis that risperidone is superior to placebo in improving functional outcomes over 12 weeks of double-blind treatment
3. to test the effect of rsiperidone compared to placebo on various other behavioural domains over 12 weeks of treatment
4. to assess the effect of risperidone compared to placebo on comorbid attention-deficit hyperactivity disorder (ADHD) symptoms over 12 weeks of double-bind treatment
5. to assess the effect of risperidone compared to placebo on (impairment of) cognition/cognitive functioning (e.g. due to possible sedative effects)
6. to compare the safety and tolerability results for risperidone and placebo in children and adolescents with conduct disorder over 12 weeks of double-blind treatment. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| 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-TR conduct disorder treated with Risperidone: a randomised, double-blind, placebo-controlled discontinuation study.
Date: 01-04-13
The primary objective is to test the hypothesis that after at least 16 weeks of daily administration, risperidone - given orally at a dose of 0.25-3.0mg/day depending on body weight (approximately equivalent to 0.01-0.04mg/kg/day) - is superior to placebo in preventing a relapse of conduct disorder symptoms, as assessed through a 12 week, double-blind discontinuation trial of children and adolescents with conduct disorder and no develpmental delay or mental retardation. This will be measured using the mean change from the double-blind baseline to endpoint on the Nisonger Child Behaviour Rating Form-Typical IQ Version ODD/CD (Aman et al., 2008), using investigator ratings based on all vailable information. |
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| E.3 | Principal inclusion criteria |
Patient will only be eligible for inclusion in the acute CONCA study if they fulfil all of the following inclusion criteria:-
1. male or female aged 5.0-17.9 years at Visit 1
2. intelligence quotient of >85 (based on 4 subtests of the Weschler intelligence scales- vocabulary, matrix reasoning, block design, and similarities; compare with Crawford et al., 2010)
3. a DSM-IV-TR diagnosis of conduct disorder, as confirmed by the Kiddies-SADS Conduct Disorder Module: 312.8x (Kaufman et al., 1996), at Visit 2 and Visit 3
4. a minimum score of 27 on the Nisonger CBRF ODD/CD disruptive Behaviour Composite (D-Total) at either Visit 2 or Visit 3
5. a minimum score of 4 ("moderately ill"; or >5 "markedly ill") on the Clinical Global Impression- Severity scale at Visit 2 and Visit 3
6. in female patients of child-bearing potential, the serum pregnancy test at the time of enrollment must be negative; and these patients must agree to use a reliable method of contraception (i.e. oral contraceptives; intrauterine devices; double-barrier methods - diaphragm or condom with spermicide; Norplant or depot Provera)
7. a body weight of at least 20kg at study entry
8. patients must be able to swallow the study tablets
9. patients must have sufficient venous access to allow blood sampling and be compliant with blood sampling as stated in the protocol
10. the subject's parents/legal guardians must provide written informed consent; patients must provide informed consent and sign the consent/assent documents if capable, in accordance with the legal requirements of the respective country
11. a reliable person (primary caregiver, parent) must be available throughout the course of the study to ensure compliance with the study procedures
12. patients meeting the criteria for comorbid ADHD (according to the clinical judgement of the investigator) will not be excluded from study participation. |
|
| E.4 | Principal exclusion criteria |
A patient will be excluded from the study if he/she meets any of the following exclusion criteria:-
1. is a member of the immediate family of any investigator site personnel directly affiliated with the study. Immediate family is defined as spouse, parent, child, or sibling, whether biological or adopted
2. has been treated within the 14 day period prior to Visit 1 with a drug that has not received regulatory approval for any indication at the time of study entry
3. has participated in any investigational drug trial within the six month period prior to baseline (Visit 3)
4. has previously completed or withdrawn from this study, or has previously been identified as a non-responder to or intolerant of risperidone
5. has a current (i.e. within 6 months of the start of the study) or lifetime DSM-IV-TR diagnosis of a schizophrenia-related disorder; schizophrenia; bipolar disorder; major depression; current substance dependence disorder (given the nature of the study population, substance missue or -abuse is not exclusionary); or pervasive developmental disorder (autistic disorder or Asperger disorder)
6. in the clinical judgement of the investigator, the patient meets the criteria for a primary psychiatric disorder, e.g. an anxiety disorder, depressive disorder, Tic disorder, or Tourette Syndrome (comorbid ADHD is permitted, see inclusion criteria)
7. the patient starts any psychotropic medication during the course of the study, including health-food supplements, that may, in the opinion of the investigator, affect central nervous system activity, or is taking any other excluded medication at or beyond Visit 2 (specified in Section 5.7 of the study protocol). A long-term medication - e.g. to treat a comorbid disorder such as ADHD - is permitted as long as the compound and the dose remain unchanged throughout the course of the study
8. has any acute or unstable medical condition, physiological condition, clinically significant laboratory or ECG results that - in the opinion of the investigator - would compromise study participation
9. has a known or suspected seizure disorder
10. has a history of neuroleptic malignant syndrome or tardive dyskinesia
11. has a history of hypersensitivity to neuroleptics
12. is pregnant or nursing.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy variable will be the change from baseline to endpoint in the ODD/CD Total Composite Score of the Nisonger CBRF TIQ (Aman et al., 2008).
The primary analysis of the primary endpoint will be based on an ITT/LOCF analysis (see study protocol, section 8.2.1). The seconday analysis of the primary endpoint will rely on a marginal model for repeated measurement. A rating of 1 or 2 on the CGI-S and a 25% reduction from the baseline score on the Nisonger CBRF TIQ D-Total score (according to a peronal communication with the author M. Aman from 2010). This definition corresponds to those used in risperidone trials in children and adolescents with conduct disorder and below-average intelligence. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Within 4 years of the start of the inclusion of the first patient. |
|
| E.5.2 | Secondary end point(s) |
| Response to treatment is defined in section 2.2 of the study protocol. Time to response will be analysed using the Kaplan-Meier survival techniques, and the log-rank test will be used for group comparisons. In addition, a proportional hazards regression analysis of time-to-response will be performed to adjust the test of treatment for the stratification variables "country" and "age-group" (children, adolescents). Time-to-response is defined as the difference between the date of randomisation and the date of the visit at which score-based criteria were first met, given that the response definition of section 2.2. is achieved. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Within 4 years of the start of the inclusion of the first patient. |
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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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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