| 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 2000. |
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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] - Behavioral Disciplines and Activities [F04] |
| 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, 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 at a dose of 0.25-3.0 mg/day depending on body weight (equivalent to approximately 0.01-0.04 mg/kg/day is superior to placebo in preventing relapse of the symptoms of conduct disorder as assessed through a 12 week double-blind discontinuation trial (Study Period 2) of children and adolescents with conduct disorder and no developmental delay/mental retardation. This will be measured by comparing the mean change from the double-blind baseline to endpoint in the Nisonger Child Behaviour Rating Form Typical IQ version-ODD/CD disruptive behaviour composite total score (Aman et al., 2008) using all investigator ratings, based on all available information. |
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| E.2.2 | Secondary objectives of the trial |
1) to establish the long-term efficacy of treatment with risperidone measuring mean change from the double-blind baseline to endpoint on the pivotal Nisonger scale between risperidone and placebo
2) to test the effect of risperidone compared to placebo on various behavioural domains following seven months of daily administration of risperidone assessed in a 12-week, double-blind discontinuation trial
3) to compare changes (impairment) in neurocognitive function following risperidone, assessed in both the 16-week open label and the 12 week, double blind discontinuation trial
4) to assess the effect of risperidone compared to placebo on comorbid ADHD symptoms following seven months of daily administration assessed in a 12 week, double blind discontinuation trial
5) to compare safety and tolerability results for risperdione 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 |
A randomised double-blind placebo controlled study of risperidone in the treatment of DSM-IV-TR conduct disorder in children and adolescents.
Date:01.01.2013
The primary objective of this study is to test the hypothesis that risperidone given orally at a dose of 0.25-3.0mg/day depending on body weight (equivalent to approximately 0.01-0.04 mg/kg/day) for 12 weeks is superior to placebo in reducing the disruptive behavioural symptoms of conduct disorder in the treatment of in- and out-patient children and adolescents (5.0 to 17.9 years) with no developmental delay/mental retardation. This will be measured using the last-observation-carried-forward mean change from baseline to endpoint on 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.3 | Principal inclusion criteria |
Patients are only eligible for inclusion in the Dis-CONCA study if they meet all of the following inclusion criteria:
1. male or female aged 5.0 years to 17.5 years at Visit 1
2. a DSM-IV-TR diagnosis of conduct disorder, as confirmed by Kiddie-SADS, Conduct Disorder Module (Kaufman et al., 1996)
3. an IQ of at least 85, measured using 4 subtests (2 verbal, 2 performance) from the Weschler scales, assessed within 2 years of study entry using age and country-specific adaptations (cf Crawford et al., 2010)
4. a minimum score of 27 on the Nisonger Chid Behaviour Rating Form Typical IQ ODD/CD Disruptive Behaviour Composite (D-Total) at baseline (Visit 1 or 2)
5. a minimum score of 4 ("moderately ill" or "markedly ill") on the Clinical Global Impressions-Severity scale at both baseline visits (1 and 2)
6. a body mass index that lies between the 5th and 95th percentiles of the WHO age and sex specific charts
7. must be able to swallow the study drug
8. must have sufficient venous access to allow blood sampling and be compliant with the blood-draws stated in the protocol
9. for female patients of child-bearing potential, the urine pregnancy test at the time of enrollment must be neagtive, and she must agree to use a reliable form of contraception. Adequate contraception includes oral contraceptives, intrauterine devices, double barrier methods (diaphragm or condom plus spermicide), and Norpant or depot Provera
10. laboratory results, including serum chemistry, haematology, and urinalysis, must show no significant abnormalites (significant would include deviations requiring acute medical intervention or further medical evaluation) and there is no clinical information that would, in the opinion of the investigator, preclude participation
11. all patients must have an ECG at Visit 1 or 2. Results must be available before the drug is dispensed at visit 3. If an ECG shows any severe abnormality, the patient must be excluded from the study. Patients with other abnormalities may be included at the discretion of the investigator
12. educational level and degree of understanding of the patient and the parents (or legal gaurdians) must be adequate to allow appropraite communication with the investigator and study coordinator
13. subject's parents/legal guardians must provide written informed consent; patients must provide informed consent and sign the assent forms is capable, in accordance with local legal requirements.
14. a reliable person (primary caregiver, parent) must be available to ensure compliance with study procedures throughout the course of the study
15. patients meeting the criteria for comorbid ADHD (according to the clinical judgement of the investigator) will not be excluded from participation.
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| E.4 | Principal exclusion criteria |
A patient will be excluded from the study if any of the following criteria are met:
1. an immediate family member of the patient is professionally affiliated to the investigator site. Immediate family is defined as spouse, parent, child, or sibling, whether biological or adopted
2. has previously participated in or withdrawn from this study or has been identified as a non-responder to- or intolerant of risperidone
3. has been treated within 14 days of visit 1 with a drug that has not received regulatory approval for any indication at the time of study entry, or has participated in any investigational drug trial in the six months prior to baseline
4. has a current (within 6 months of the start of the study) or a lifetime DSM-IV-TR diagnosis of schizophrenia-related disorder, schizophrenia, bipolar disorder, major depressive disorder, or a current subtance dependence disorder( given the nature of the study population, substance missue or abuse is not exclusionary), pervasive developmental disorder (autism, Asperger's)
5. currently meets (in the opinion of the investigator) the criteria for a primary psychiatric diagnosis, e.g. an anxiety disorder, depression, Tic disorder, Tourette's syndrome
6. starts any psychotropic medication, including health food supplements, that the investigator feels could have central nervous system effects (e.g. St John's Wort, melatonin) during the course of the study, or is taking any other excluded concomitant medication (specified in section 5.7 of the study protocol). An ongoing long-term medication is permitted as long as the compound and the dose remain unchanged throughout the study, e.g. medication for comorbid ADHD
7. has a history of hypersensitivity to neuroleptics, or a history of tardive dyskinesia or malignant neuroleptic syndrome
8. has a known or suspected seizure disorder
9. female patients who are pregnant or nursing
10. patients with a history of severe allergy to more than one class of medications or multiple adverse drug reactions. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Clinical response is defined as a >25% reduction from baseline score on the Nisonger CBRF-TIQ D-Total subscale at endpoint (based on personal communication with the author Dr Michael Aman, June 2010), and a sore of 1 or 2 ("much" or "very much" improved) on the Clinical Global Impressions- Improvement scale.
The primary efficacy measure will be comparison between the number of days from randomisation to relapse for each treatment group using the Kaplan-Meier product limit estimator. Relapse is defined as a deterioration of >2 points on the CGI-Severity scale and a 25% increase in the Nisonger CBRF TIQ D-Total comapred to the start of Study Period 2 (average of visits 7 and 8) for at least two consecutive visits, 6-8 days apart (Reyes et al., 2006).
The CGI-severity scale is a single item rating by the clinician of the severity of symptoms in relation to their total experience with conduct disorder patients (Guy et al., 1976). Severity is rated on a seven-point scale (1= normal, not at all ill; 7= among the most extremely ill subjects). |
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| 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) |
The secondary outcome measures focus on assessment of changes with active treatment vs. placebo.
1. CGI-S and CGI-I (guy et al., 1976; NIMH, 1985)
2. C-GAS (kaufman et al., 1996)
3. ADHD-DSM-IV RS (Dupaul et al., 1998)
4. MOAS (Kay et al., 1998)
5. CHIP-CE (Riley et al., 2004)
6. Child Behaviour Checklist, parent reported (Archenbach et al., 1991a)
7. PAERS (march et al., 2007)
8. ANT (de Sonneville et al., 1999)
9. C-SSRS (Posner et al., 2007b) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Within 4 years of the start of inclusion of the first patient. |
|
| 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 | 7 |
| E.8.9.1 | In the Member State concerned days | 7 |
| 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 | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 7 |
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