E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10017324 |
E.1.2 | Term | Fragile X syndrome |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
- To assess the efficacy of multiple oral doses of AFQ056 in reducing the global score of the Aberrant Behavior Checklist – Community Edition (ABC-C) in FXS patients. - To assess the safety and tolerability of multiple titrated oral doses of AFQ056 in FXS patients.
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E.2.2 | Secondary objectives of the trial |
- To assess the efficacy of multiple oral doses of AFQ056 in reducing social withdrawal in Fragile X patients by using the Repetitive Behavior Scale (RBS), the Vineland Adaptive Behavior Scale (VABS) and the Social Responsiveness Scale (SRS). - To assess the efficacy of multiple oral doses of AFQ056 on the global improvement of symptoms in Fragile X patients by using the Clinical Global Impression Scale (CGI) and the Visual Analogue Scale (VAS), which rates the changes in one target behavior chosen by the caregiver. - To assess the efficacy of multiple doses on AFQ056 in reducing cognitive deficits in Fragile X patients by using the KITAP test battery (attentional performance) and the Peabody vocabulary Test Revised (PVTR) (receptive language). |
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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 |
- To identify the baseline conditions in FXS patients and untreated age-matched healthy subjects (used as control group) with regard to the levels of anxiety and social withdrawal by using a physiological sensorimotor social paradigm. - To identify the baseline conditions in FXS patients and untreated age-matched healthy subjects (used as a control group) with regard to the sensorimotor gating and inhibitory control by the Pre-Pulse Inhibition startle response (PPI). - To explore potential changes in the levels of anxiety and social withdrawal in FXS patients treated with AFQ056 versus placebo by using longitudinal assessments in a physiological sensorimotor social paradigm. - To explore potential changes in the sensorimotor gating and inhibitory control in FXS patients treated with AFQ056 versus placebo by using longitudinal assessments in the PPI paradigm. - To identify potential biomarkers of the Fragile X pathology (gene expression in blood) by comparing the baseline conditions in FXS patients versus untreated age-matched healthy subjects used as control group. - To identify potential biomarkers of AFQ056 activity (gene expression in blood) by performing longitudinal biomarkers assessments in FXS patients treated with AFQ056 and with placebo. The results from the exploratory objectives will be presented in the clinical study report if available on time or in a supplemental report as required.
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E.3 | Principal inclusion criteria |
- Male, non-smoking patients between 18 and 35 years of age (both inclusive).
- Patients with confirmed diagnosis of FXS based upon genetic testing results (full mutation > 200 CGG repeats), a Clinical Global Impression Severity Score (CGI-S) of > 4 (moderately ill), a score of >20 in the ABC-C scale (performed at screening) and a mental age of 48 months as measured by the Standford-Binet test.
- Patients treated with psychotropic treatment and/or anticonvulsant therapy are allowed to enter the study provided that they are on a stable regimen for at least 4 weeks prior to randomization.
- Patients must be using a double-barrier local contraception for the entire duration of the study (from screening up to the study completion visit), and refrain from fathering a child in the 3 months following last study drug administration.
- Patients whose legal guardian has signed an Informed Consent (for the exploratory sub-study, an additional separate Informed Consent has to be signed).
- See healthy subjects inclusion criteria in the protocol amendment 1 (clear version)page 43. |
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E.4 | Principal exclusion criteria |
Patients with DSM-IV diagnosis of schizophrenia.
Patients with a history and/or presence of psychosis, confusional states and/or repeated hallucinations.
Patients with a history of seizures in the past 5 years without any therapeutic treatment controlling the disorders.
Patients under stable anti-convulsant therapies that experienced seizures in the 2 years prior to randomization.
Donation or loss of 400 ml or more of blood within 8 weeks prior to first dosing, or longer if required by local regulation.
Significant illness within two weeks prior to dosing.
A past medical history of clinically significant ECG abnormalities or a family history (grandparents, parents and siblings) of a prolonged QT-interval syndrome.
History of autonomic dysfunction (e.g. history of fainting, orthostatic hypotension, sinus arrhythmia).
History of acute or chronic bronchospastic disease (including asthma and chronic obstructive pulmonary disease, treated or not treated)
History of clinically significant drug allergy or history of atopic allergy (asthma, urticaria, eczematous dermatitis).
Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism or excretion of drugs or which may jeopardize the patient in case of participation in the study. The investigator should be guided by evidence of any of the following: • history of ulcers, gastrointestinal or rectal bleeding; • history of major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, or bowel resection; • history or clinical evidence of pancreatic injury or pancreatitis; • clinical evidence of liver disease or liver injury as indicated by clinically relevant abnormal liver function tests such as SGOT, SGPT, GGT, alkaline phosphatase, or serum bilirubin. If the total bilirubin concentration is increased above 1.5 times the upper normal limit total bilirubin should be differentiated into the direct and indirect reacting bilirubin and the Investigator will make his judgment on the clinical relevance of these data. • history or presence of impaired renal function as indicated by clinically significantly abnormal creatinine or BUN values or abnormal urinary constituents (e.g., albuminuria); • evidence of urinary obstruction or difficulty in voiding at screening;
Patients using (or have used within four weeks before randomization) concomitant medications that are potent inhibitors of CYP3A4 (e.g., ketoconazole, ritonavir, etc).
Participation in any clinical investigation within 4 weeks prior to dosing or longer if required by local regulation.
Patients who in the opinion of the investigator, are unsuitable in any other way to participate in this study including being unable to comply with the requirements of the study or displaying abnormalities in safety assessments at baseline.
- See healthy subjects exclusion criteria in the protocol amendment 1 (clear version) pages 45/46.
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E.5 End points |
E.5.1 | Primary end point(s) |
To assess the efficacy of multiple oral doses of AFQ056 in reducing the global score of the Aberrant Behavior Checklist – Community Edition (ABC-C) in FXS patients. To assess the safety and tolerability of multiple titrated oral doses of AFQ056 in FXS patients. The caregiver-rated ABC-C is the Gold Clinical Standard test for Pervasive Developmental Disorders (PPD) and used for registration purposes in the PDD indication (such as autism and FXS). The ABC-C is a symptom checklist for assessing problem behaviors of children and adults with developmental disabilities at home or in residential facilities. The ABC-C is a 58-item informant-based scale including five subscales (irritability, lethargy/social withdrawal, stereotypic behavior, hyperactivity and inappropriate speech). The assessment is done by attributing to each item of the questionnaire a score from 0 (“not at all a problem”) to 3 (“problem is severe in degree”) and the total score ranks from 0 to 174. It is completed by interviewing the caregiver and it takes about 30 min. |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Biomarkers in saliva (cortisol) |
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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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | No |
E.8.1.6 | Cross over | Yes |
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.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 2 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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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 | |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |