A multi-centre, randomized, double-blind, placebo-controlled, two-period, crossover proof-of-concept study in patients with Fragile X Syndrome to assess the efficacy, safety and tolerability of multiple oral doses of AFQ056

• Register: EUCTR
• Last refreshed on: 26 January 2015
• Main ID: EUCTR2007-005088-82-FR
• Date of registration: 20/11/2007
• Prospective Registration: Yes
• Primary sponsor: Novartis Pharma Services AG
• Public title: A multi-centre, randomized, double-blind, placebo-controlled, two-period, crossover proof-of-concept study in patients with Fragile X Syndrome to assess the efficacy, safety and tolerability of multiple oral doses of AFQ056
• Scientific title: A multi-centre, randomized, double-blind, placebo-controlled, two-period, crossover proof-of-concept study in patients with Fragile X Syndrome to assess the efficacy, safety and tolerability of multiple oral doses of AFQ056
• Date of first enrolment: 15/05/2008
• Target sample size: 30
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2007-005088-82
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: no Cross over: yes Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no

Countries of recruitment

France, Italy

Key inclusion & exclusion criteria

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.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

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.



Age minimum:
Age maximum:
Gender:
Female: no
Male: yes

Health Condition(s) or Problem(s) studied

Fragile X Syndrome
MedDRA version: 9.1 Level: PT Classification code 10017324 Term: Fragile X syndrome

Intervention(s)

Product Code: AFQ056
Pharmaceutical Form: Capsule, hard
Current Sponsor code: AFQ056
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 25-
Pharmaceutical form of the placebo: Capsule, hard
Route of administration of the placebo: Oral use

Product Code: AFQ056
Pharmaceutical Form: Capsule, hard
Current Sponsor code: AFQ056
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-
Pharmaceutical form of the placebo: Capsule, hard
Route of administration of the placebo: Oral use

Primary Outcome(s)

Main Objective: - 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.

Secondary Objective: - 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).

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.

Secondary ID(s)

CAFQ056A2204