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

This study has been terminated.
(The study treatment failed to demonstrate efficacy in target population in two other clinical studies (CAFQ056B2214 and CAFQ056A2212).)
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT01433354
First received: August 31, 2011
Last updated: February 24, 2016
Last verified: February 2016

August 31, 2011
February 24, 2016
November 2011
September 2014   (final data collection date for primary outcome measure)
Incidence and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Prior to first dose in extension study, Baseline (start of study treatment in extension study) to End of trial ] [ Designated as safety issue: Yes ]

Adverse events were summarized for the open-label treatment period, where the open-label treatment period is defined based on how AEs were collected and reported according to the manner in which participants entered the current study and which treatment (AFQ056 or placebo) they were receiving in the previous study.

AEs which were continuing from the core study or that started after the end of core study but prior to first dose of open-label study medication in the extension study for Category 1 participants are shown under 'Prior to Ext. first dose'.

AEs which started during the open-label treatment period are presented based on the last AFQ056 dose taken on or before the onset date of the AE (25 mg bid; 50 mg bid; 75 mg bid; or 100 mg bid). No efficacy data presented as study was terminated.

  • 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.
Complete list of historical versions of study NCT01433354 on ClinicalTrials.gov Archive Site
Not Provided
  • 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.
Not Provided
Not Provided
 
Long-term, Safety and Tolerability Study of AFQ056 in Adolescent Patients With Fragile X Syndrome (Open-label)
An Open-label Study to Evaluate the Long-term Safety and Tolerability of AFQ056 in Adolescent Patients With Fragile X Syndrome
The purpose of this study is to generate long-term safety, tolerability and efficacy data for AFQ056 in eligible adolescent patients with FXS who have participated in the CAFQ056B2214 study, the PK study CAFQ056B2131, or another study of AFQ056 which included FXS patients below 18 years of age provided the patient is at least 12 years of age at the time of entry into the current study.
Not Provided
Interventional
Phase 2
Phase 3
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Fragile X Syndrome
Drug: AFQ056
The investigational drug, AFQ056, will be provided as hard gelatin capsules. Two different oral dosage strengths,25mg and 100 mg, identical in appearance, will be used.
Experimental: AFQ056 Treatment
All patients will initiate treatment with AFQ056 at a starting dose of 25 mg b.i.d. The dose will be titrated from 25 mg b.i.d to 50 mg b.i.d., 75 mg b.i.d. and 100 mg b.i.d. 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, not to exceed 100 mg b.i.d.
Intervention: Drug: AFQ056
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Terminated
119
September 2014
September 2014   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Group 1 patients:
  • Must have completed study CAFQ056B2214 or another study of AFQ056 which included FXS patients below 18 years of age within one week of enrollment into the open-label study.
  • Has a caregiver or caregivers who spend, 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 or another study of AFQ056 which included FXS patients below 18 years of age but enrollment into the current study was delayed for more than a week.
  • Discontinued prematurely from Study CAFQ056B2214 or another study of AFQ056 which included FXS patients below 18 years of age due to intolerability of the dosage in the patient's assigned treatment group.
  • Has a caregiver or caregivers who spend, 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 Study CAFQ056B2214 or CAFQ056B2131 or another study of AFQ056 which included FXS patients below 18 years of age 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 baseline) concomitant medications that are potent inhibitors or inducers of CYP3A4
  • Using glutamatergic agents (riluzole, memantine, etc.) or lithium within 6 weeks of baseline

Other protocol-defined inclusion/exclusion criteria may apply.

Both
12 Years to 18 Years   (Child, Adult)
No
Contact information is only displayed when the study is recruiting subjects
United States,   Australia,   Belgium,   Denmark,   France,   Germany,   Israel,   Italy,   Netherlands,   Spain,   Sweden,   Switzerland,   United Kingdom
Brazil,   Canada,   Turkey
 
NCT01433354
CAFQ056B2278, 2011-002379-40
Yes
Not Provided
Not Provided
Novartis Pharmaceuticals
Novartis Pharmaceuticals
Not Provided
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
Novartis
February 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP