| 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 |
| troubles des conduites DSM-IV-TR; 312.8x APA, 2000 |
|
| E.1.1.1 | Medical condition in easily understood language |
| aggressive antisocial behavior |
| Troubles du comportement |
|
| 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 |
|
| 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. |
| L’objectif principal est de tester l’hypothèse que la rispéridone per os à une dose de 0,25 à 3 mg/jour pendant 12 semaines est supérieure au placebo pour améliorer les troubles du comportements associés au TC chez des enfants et adolescents sans retard mental. Le critère d’efficacité principal est la variation moyenne entre le début et la fin de l’étude (mesurée en intention de traiter) de l’échelle Nisonger Child Behavior Rating Form (CBRF) – Version pour QI normal-D sous score composite total (Aman et al., 2008) utilisant des évaluations par l’investigateur. |
|
| 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
|
Les objectifs secondaires sont :
- tester l’efficacité de la rispéridone versus placebo sur le taux de réponse (score de 1 ou 2 à la CGI-I et une diminution de > 25 % du sous score Nisonger CBRF-TIQ D-Total ), la CGI-S et l’échelle modifiée d’aggression ouverte M-OAS
- tester l’efficacité de la rispéridone sur d’autres domaines du comportement,
- sur les symptômes de trouble deficit d’attention/hyperactivité,
- sur les variables cognitives (4 sous test de la batterie ANT)
- d’étudier la tolérance de la rispéridone versus placebo en utilisant le recueil spontané d’effets indésirables, un entretien structuré, les échelles de Barnes, Simpson-Angus, AIMS, la surveillance des signes vitaux, de l’ECG, de la température, de la taille et du poids, des paramètres biologiques, de la suicidalité
- des analyses complémentaires sur les procedures de consentement, de compliance, des médiateurs et modérateurs des effets thérapeutiques. |
|
| 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 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.
|
Etude DIS-CONCA (n°EudraCT:2010-021884-34) : Une étude d’arrêt randomisé en double aveugle controlée versus placebo de prévention de la rechute, d’efficacité et de tolérance dans le trouble des conduites DSM-IV chez l’enfant et l’adolescent de 5-17 ans 5 mois ayant auparavant répondu à un traitement en ouvert par rispéridone.
L’objectif principal est de tester l’hypothèse qu’après au moins 15 semaines de traitement en ouvert la rispéridone per os à une dose de 0,25 à 3 mg /jour est supérieure au placebo pour la prévention des rechutes des symptômes de trouble des conduites dans un étude d’arrêt randomisé double aveugle contrôlé versus placebo de 11 semaines chez des enfants et adolescents d’intelligence normale ayant un trouble des conduites répondant au critères DSM-IV. |
|
| 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 - <17.0 years at Visit 1.
- Patients must have an IQ of > 85 (based on, e.g., 4 WISC subtests): vocabulary, similarities, block design, and matrix reasoning (cf. Crawford et al., 2010. Age- and country-specific adaptations will be used.
- Patients must meet DSM-IV-TR diagnostic criteria for DSM-IV-TR Conduct Disorder(s) as confirmed by the Kiddie-SADS, Conduct Disorder Module: 312.8x. (Kaufman et al., 1996) both at Visit 2 and Visit 3.
- Patients must score = 27 on the Nisonger CBR Form, ODD/CD Disruptive Behavior Composite (D-Total) either at Visit 2 or Visit 3.
- Patients must score =4 (moderately ill (or > 5, markedly 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 contra- ception includes: oral contraceptives, intraueterine devices; double barrier method (diaphragm or condom plus spermicide), Norplant or Depot Provera)).
- Patients must have a body weight of at least 25 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 informed consent, and sign consent or assent documents if capable, according to the legal requirements in the very country.[11] 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.
|
Les patients éligibles pour cette étude devront remplir tous les critères suivants:
- Garçons ou filles entre 5;0 - <17;9 ans à V1,
- ayant un QI > 85 3) répondant aux critères de TC selon le DSM-IV-TR à V2 ou V3,
- ayant un score ≥ 27 au sous score D Nisonger CBR (D-Total) à V2 ou V3,
- ayant un score de CGI-S ≥4,
- pour les filles test de grossesse négatif et contraception efficace
- faisant plus de 20 kg,
- capables d’avaler le medicament,
- ayant un accès veineux suffisant et compliants avec le protocole de prélèvement,
- Parents et enfants /adolescents ayant signé un consentement,
- Présence d’un parent/responsible legal assurant le respect du protocole
- Les patients ayant un TDAH (jugement clinique) ne sont pas exclus de l’étude. |
|
| 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, meets criteria for a primary psychiatric disorder, e.g., Anxiety Disorder, Depressive Disorder, Tic Disorder or Tourettes 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. Johns Wort, melatonin), during the course of the study, or is taking any other excluded concomitant medication(s) at/beyond Visit 2 (specified in Section 5.7). (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, of tardive dyskinesia, or neuroleptic malignant syndrome.
- Is pregnant or nursing.
|
Un patient ne pourra pas être inclus dans l'étude si un des critères définis ci-dessous est recontré, selon le jugement de l'investigateur:
- Famille du personnel du site,
- A été traité dans les 14 jours avant la V1 par un médicament hors AMM
- A participé à un essai clinique dans les 6 mois avant la V3
- A déjà participé à cette étude ou à une autre impliquant la rispéridone ou non répondeur/intolerant à ce produit
- a un diagnostic de trouble schizophrénique, trouble bipolaire, trouble dépressif ou une dependence (le TDAH et l’abis de substance ne sont pas un critrère d’’exclusion) ou un trouble envahissant du développement.
- a un diagnostic primaire actuel de trouble anxieux, dépressif, tic chroniques ousyndrome de Gilles de la Tourette
- Commence un traitement psychoactive après V2 (les traitements des comorbidities sont permis à dose stable).
- A une pathologie somatique évolutive ou des anomalies du bilan paraclinique
- A une épilepsie
- Antécedents de syndrome malin des neuroleptiques ou de dyskinesia tardive
- Antécédents d’hypersensibilité aux neuroleptiques
- Grossesse ou allaitement. |
|
| 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 8.2.1). The secondary analysis of the primary endpoint will rely on a marginal model for repeated measurement.
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.
Improvement on C-GAS |
Le critère d’efficacité principal est la variation moyenne entre le début et la fin de l’étude (mesurée en intention de traiter) de l’échelle Nisonger Child Behavior Rating Form (CBRF) – Version pour QI normal-D sous score composite total (Aman et al., 2008) utilisant des évaluations par l’investigateur.
Une analyse secondaire du critère principal sera réalisée à l'aide d'un modèle de varaince à mesures répétées. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| within four years of start of inclusion of first patient |
| dans les quatre ans après l'inclusion du premier patient |
|
| E.5.2 | Secondary end point(s) |
| Response to treatment is defined in Section 2.2 of the protocol. Time to response will be analyzed using Kaplan-Meier survival techniques, and the log-rank test will be used for group comparison. In addition, a Proportional Hazards regression analysis of time to response will be performed to adjust the test of treatment for the stratification variables of country, age group (children, adolescents.) Time to response is defined as the difference between the date of randomization and the date of the visit at which score-based response criteria were first met given that the response definition of Section 2.2. is achieved. |
| La réponse au traitement est défini dans la section 2.2 du protocole. Le délai de réponse sera comparé entre les groupes à l'aide d'une analyse de survie selon la méthode de Kaplan-Meier et d'un test du log-rank. En complément, un modèle de Cox sera réalisé afin d'évaluer le délai de réponse après ajustement sur les variables de stratification du pays, du groupe d'âge (enfants, adolescents). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Within four years of start of inclusion of first patient |
| dans les quatre ans après l'inclusion du premier 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) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| 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 | 3 |
| 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
|
| LVLS |
| Dernière visite du dernier patient |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 14 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 14 |
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