Long-term, Safety and Tolerability Study of AFQ056 in Adolescent Patients With Fragile X Syndrome (Open-label)

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by Novartis
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT01433354
First received: August 31, 2011
Last updated: May 21, 2014
Last verified: May 2014
  Purpose

The purpose of this study is to generate long-term safety and tolerability data for AFQ056 in eligible adolescent patients with FXS who have participated in the CAFQ056B2214 core study and patients who have participated in the CAFQ056B2131 study.


Condition Intervention Phase
Fragile X Syndrome
Drug: AFQ056
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: An Open-label Study to Evaluate the Long-term Safety and Tolerability of AFQ056 in Adolescent Patients With Fragile X Syndrome

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Change in number of patients having any adverse events (AE) by primary system organ class and preferred term during the 24 months of the study [ Time Frame: Baseline, week 1, 2, 3, 4, 6, 8, 12, 26, 39, 52, 65, 78, 91, 104, every 13 weeks thereafter and/or upon completion/early discontinuation. AEs will be assessed 1 week after study completion or early discontinuation. ] [ Designated as safety issue: Yes ]
    Adverse events will be summarized by presenting the number of patients having any AE by primary system organ class and/or preferred term.

  • Changes in vital signs [ Time Frame: Screening for group 2 (up to -4 weeks), baseline, week 2, 4, 8, 12, 26, 39, 52, 65, 78, 91, 104, every 13 weeks thereafter and/or upon completion/early discontinuation. Vital signs will be assessed 1 week after study completion or early discontinuation. ] [ Designated as safety issue: Yes ]
    Pulse and Blood pressure will be taken sitting after five minutes. Temperature will also be taken.

  • Changes in weight [ Time Frame: Screening for group 2 (up to -4 weeks), baseline, week 2, 4, 8, 12, 26, 39, 52, 65, 78, 91, 104, every 13 weeks thereafter and/or upon completion/early discontinuation. Weight will be assessed 1 week after study completion or early discontinuation. ] [ Designated as safety issue: Yes ]
    Body weight (to the nearest 0.1 kilogram in indoor clothing, but without shoes) will be measured.

  • Changes in height [ Time Frame: Screening for group 2 (up to -4 weeks), baseline for group 1, week 26, 52, 78, 104, every 26 weeks thereafter and/or upon completion/early discontinuation. ] [ Designated as safety issue: Yes ]
    Height in centimeters (cm) will be measured.

  • Changes in standard laboratory assessments: change in standard hematology [ Time Frame: Screening (for group 2 only - up to -4 weeks), week 4, 12, 52, 104 and upon completion/early discontinuation. ] [ Designated as safety issue: Yes ]
    Standard hematology with differential (red blood cell count, white blood cell count, platelet count, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin concentration, red blood cell morphology, and white blood cell differential) will be measured.

  • Changes in standard laboratory assessments: change in standard chemistry [ Time Frame: Screening (for group 2 only - up to -4 weeks), week 4, 12, 52, 104 and upon completion/early discontinuation. ] [ Designated as safety issue: Yes ]
    Standard chemistry with albumin, alkaline phosphatase, amylase, total bilirubin, calcium, cholesterol, creatine, creatine kinase, gammaglutamyltransferase, glucose, lipase, lactate dehydrogenase, inorganic phosphorus, magnesium, potassium, total protein, aspartate aminotransferase, alanine aminotransferase, sodium, triglycerides, urea and uric acid will be measured.

  • Changes in standard laboratory assessments: change in standard urinalysis [ Time Frame: Screening (for group 2 only - up to -4 weeks), week 4, 12, 52, 104 and upon completion/early discontinuation. ] [ Designated as safety issue: Yes ]
    Specific gravity, bilirubin, blood, glucose, ketones, pH, protein and urobilinogen will be measured.

  • Changes in hormonal parameter concentrations to evaluate hypothalamic-pituitary-adrenal (HPA) axis. [ Time Frame: Screening (for group 2 only - up to -4 weeks), week 4, 12, 52, 104 and upon completion/early discontinuation. ] [ Designated as safety issue: Yes ]
    Follicle-stimulating Hormone (FSH), Luteinizing Hormone (LH), Oxytocin, Prolactin, Thyroxine-binding Globulin (TBG), Thyroid-stimulating Hormone (TSH) and Thyroxine (T4) concentrations will be measured by a specialized central laboratory.

  • Changes in ECGs [ Time Frame: Baseline, Weeks 4, 12, 52, 78, 104, every 26 weeks thereafter and/or upon completion/early discontinuation. ] [ Designated as safety issue: Yes ]
    Standard 12 lead ECGs will be performed. A central facility will be used for the interpretation and analysis of the ECGs. ECG abnormalities will be assessed and QTc intervals will be reported using summary statistics for change from baseline values by visit.

  • Change in Tanner staging score [ Time Frame: Baseline, week 26, 52, 78, 104 and upon completion/early discontinuation ] [ Designated as safety issue: Yes ]
    Tanner staging is a well-established scale of physical development that quantifies primary and secondary sex characteristics such as the size of the breasts, genitalia, and development of pubic hair (from Tanner stage I to Tanner stage V depending on the physical development). It is assessed by the clinician during physical examination. Tanner staging scores will be summarized.


Secondary Outcome Measures:
  • Change in the Aberrant Behavior Checklist-Community edition (ABC-C) [ Time Frame: Baseline, week 4, 12, 26, 39, 52, 65, 78, 91, 104, every 13 weeks thereafter and upon completion/early discontinuation. ] [ Designated as safety issue: No ]
    The ABC-C is a symptom checklist for assessing problem behaviors of children and adults with intellectual disability. The ABC-C is comprised of 5 sub-scales (irritability, lethargy/social withdrawal, stereotypic behavior, hyperactivity and inappropriate speech) plus total score. The questionnaire is completed by the caregiver by attributing a score from 0 ("not a problem") to 3 ("problem is severe in degree") to each item of the questionnaire; the total score ranks from 0 to 174. Summary and change from baseline in the ABC-C total and subscale scores will be reported.

  • Change in the Clinical Global Impression Score - Severity/Improvement (CGI-S/I) scale. [ Time Frame: Baseline, week 4, 12, 26, 39, 52, 65, 78, 91, 104, every 13 weeks thereafter and upon completion/early discontinuation. ] [ Designated as safety issue: No ]
    The CGI-I is used to assess treatment response in psychiatric patients. The scale is divided into two parts, one assessing the severity of illness (CGI-S) and one assessing the improvement (CGI-I). It is a clinician-rated scale. The CGI-I reports the global changes of the symptoms rated on a seven-point scale (from "very much improved" to "very much worse"). CGI-I will be summarized by visit. CGI-I will be evaluated using the extension study baseline visit as the reference visit.

  • Change in the Repetitive Behavior Scale - Revised (RBS-R) [ Time Frame: Baseline, week 4, 39, 52, 78, 104, and upon completion/early discontinuation ] [ Designated as safety issue: No ]
    The RBS-R is a rating tool that captures the breadth of repetitive behavior: ritualistic behavior, sameness behavior, stereotypic behavior, self-injurious behavior, compulsive behavior, and restricted interests. Every behavior falling into one of the above categories is rated from 0 (behavior does not occur) to 3(behavior occurs and it is a severe problem). The total score ranks from 0 to 129. It is a questionnaire filled by the caregivers.

  • Change in the Social Responsiveness Scale (SRS) total score [ Time Frame: Baseline, weeks 4, 39, 52, 78, 104, and upon completion/early discontinuation) ] [ Designated as safety issue: No ]
    The SRS distinguishes autism spectrum conditions from other psychiatric conditions by identifying the presence and extent of autistic social impairment and by assessing social awareness, social information processing, capacity of reciprocal social communication, social anxiety/avoidance, and autistic preoccupations and traits. Every behavior is rated from 0 (not true) to 3 (almost always true) by the caregiver. The total score ranks from 0 to 195.

  • Assessment of pharmacokinetic (PK) parameters: Plasma concentration levels of AFQ056 [ Time Frame: Week 4, 12, 52, and 104. ] [ Designated as safety issue: No ]
    Analytes: parent drug AFQ056 concentrations in plasma will be determined by a validated LC-MS-MS method. The data collected in the study will not allow the calculation of conventional PK parameters by non compartmental analysis. The data will be summarized and descriptive statistics of timed plasma concentrations levels will be provided. The pharmacokinetic data of this study may be combined with data from other studies to perform a population PK analysis which will follow the broad principles outlines in the FDA Guidance for Industry: Population Pharmacokinetic.


Estimated Enrollment: 170
Study Start Date: November 2011
Estimated Study Completion Date: August 2014
Estimated Primary Completion Date: August 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: AFQ056 Treatment
All patients will initiate treatment with AFQ056 at a starting dose and then be titrated at weekly intervals. Dose adjustments (up- and down-titrations) will be permitted as needed to manage any tolerability issues and to ensure that patients reach their highest tolerated dose.
Drug: AFQ056
The investigational drug, AFQ056, will be provided as hard gelatin capsules. Two different oral dosage strengths, identical in appearance, will be used.

  Eligibility

Ages Eligible for Study:   12 Years to 18 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Group 1 patients:
  • Must have completed the CAFQ056B2214 core study within one week of enrollment into the open-label study
  • Has a caregiver who spends, on average, at least 6 hours per day with the patient , who is willing to and capable of supervising treatment, providing input into efficacy and safety assessments, and accompanying the patient to study visits.
  • Group 2 patients:
  • Must meet one of the following conditions:
  • Completed Study CAFQ056B2131
  • Completed Study CAFQ056B2214 but enrollment into the current study was delayed for more than a week
  • Discontinued prematurely from Study CAFQ056B2214 due to intolerability of the dosage in the patient's assigned treatment group.
  • Has a caregiver who spends, on average, at least 6 hours per day with the patient , who is willing to and capable of supervising treatment, providing input into efficacy and safety assessments, and accompanying the patient to study visits.

Exclusion Criteria:

  • Discontinuation from CAFQ056B2214 or CAFQ056B2131 studies due to safety reasons
  • Female patients who are sexually active at any time during the study
  • Any advanced, severe or unstable disease
  • History and/or presence of schizophrenia, bipolar disease, psychosis, confusional states and/or repeated hallucinations as per DSM-IV criteria
  • History of suicidal behavior or considered a high suicidal risk
  • History of severe self-injurious behavior
  • History of uncontrolled seizure disorder or resistant to therapy within the past 2 years (Patients who are clinically stable under anti-convulsant therapy for the past 2 years are not excluded)
  • History of clinically significant allergies requiring hospitalization or non-inhaled corticosteroid therapy (asthma, anaphylaxis, etc.)
  • History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether or not there is evidence of local recurrence or metastases
  • Patients who are using (or used within 6 weeks before baseline) digoxin or warfarin
  • Using (or used within 6 weeks before randomization) concomitant medications that are potent inhibitors or inducers of CYP3A4
  • Using glutamatergic agents (riluzole, memantine, etc.) or lithium within 6 weeks of baseline
  • Patients who weigh less than 32 kg (= 10th percentile of body weight for a 12-year old child)

Other protocol-defined inclusion/exclusion criteria may apply.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01433354

Contacts
Contact: Novartis Pharmaceuticals 1-888-669-6682
Contact: Novartis Pharmaceuticals

  Show 39 Study Locations
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

No publications provided

Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT01433354     History of Changes
Other Study ID Numbers: CAFQ056B2278, 2011-002379-40
Study First Received: August 31, 2011
Last Updated: May 21, 2014
Health Authority: United States: Food and Drug Administration
Denmark: Danish Medicines Agency
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Germany: BfArM
Italy: Ethics Committee
United Kingdom: Medicines and Healthcare Products Regulatory Agency
Australia: National Health and Medical Research Council
Switzerland: Swissmedic
Sweden: Medical Products Agency
Canada: Health Canada
Israel: Ministry of Health
Netherlands: Medicines Evaluation Board (MEB)
Spain: Agencia Española de Medicamentos y Productos Sanitarios
Turkey: Ministry of Health

Keywords provided by Novartis:
Fragile X Syndrome
Martin-Bell Syndrome
Genetic Diseases
X-Linked
Escalante's syndrome

Additional relevant MeSH terms:
Fragile X Syndrome
Mental Retardation, X-Linked
Genetic Diseases, X-Linked
Mental Retardation
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases
Sex Chromosome Disorders
Chromosome Disorders
Congenital Abnormalities
Genetic Diseases, Inborn
Heredodegenerative Disorders, Nervous System

ClinicalTrials.gov processed this record on July 20, 2014