| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10017324 |
| E.1.2 | Term | Fragile X syndrome |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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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 evaluate the long-term safety and tolerability of AFQ056 in adolescent patients with FXS as assessed by:
• Incidence and severity of adverse events and serious adverse events
• Changes in vital signs, laboratory assessments, and ECGs
• Monitoring the hypothalamic-pituitary-adrenal/thyroid axis function and childhood developmental milestones |
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| E.2.2 | Secondary objectives of the trial |
To evaluate the long-term efficacy of AFQ056 treatment in both FM (Fully Methylated) and PM (Partially Methylated) patients with FXS as assessed by:
• Change from baseline in the Aberrant Behavior Checklist – Community edition (ABC-C) total score and subscale scores
• Rating of global improvement of symptoms in Fragile X patients using the Clinical Global Impression - Improvement (CGI-I) scale.
• Change from baseline in the Repetitive Behavior Scale – Revised (RBS-R) total score and subscale scores
• Change from baseline in the Social Responsiveness Scale (SRS) total score
• To collect pharmacokinetic data of AFQ056 in the target patient population |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 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.
-Male or female, between 12 and 17 years of age, inclusive, at the time of inclusion in the CAFQ056B2214 study or at least 12 years of age at the time of entry into the current study when the patient participated in another study of AFQ056 which included FXS patients below 18 years of age;
-Have a caregiver or caregivers who are willing 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:
o completed Study CAFQ056B2131
o 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
o 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 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
-The caregiver/legally acceptable representative must be able to communicate well with the investigator and must understand and support the study requirements by providing written informed consent.
Where possible the patient should also provide his or her written assent
Other protocol-defined inclusion criteria may apply
-Male or female, between 12 and 17 years of age, inclusive, at the time of inclusion in Study CAFQ056B2214, or between 12 and 18 years of age, inclusive, at the time of inclusion in Study CAFQ056B2131, or at least 12 years of age at the time of entry into the current study when the patient participated in another study of AFQ056 which included FXS patients
below 18 years of age
-Have a caregiver or caregivers who are willing and capable of supervising treatment, providing input into efficacy and safety assessments, and accompanying the patient to study visits |
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| E.4 | Principal exclusion criteria |
1) Discontinuation from study CAFQ056B2214 or CAFQ056B2131 or another study of AFQ056 which included FXS patients below 18 years of age due to safety reasons
2) Female patients who are sexually active at any time during the study
3) Any advanced, severe or unstable disease
4) past medical history of clinically significant ECG abnormalities or QTcF > 450 msec for males and > 470 msec for females during the screening period (Group 2 patients) or at the end of study visit in the previous study for Group 1 patients;
5) lab screening values that include AST, ALT, GGT, total bilirubin or creatinine ≥ 1.5 X ULN (upper limit of normal) for the central laboratory
6)history of major surgery or major medical event that requires hospitalization or major surgery within the past 6 months, unless the patient recovered fully or is considered clinically stable by the study physician
7)donated or lost more than 2.4 mL of blood per kg of body weight within (4) weeks prior to Screening (V1) or longer if required by local regulation;
8) History and/or presence of schizophrenia, bipolar disease, psychosis, confusional states and/or repeated hallucinations as per DSM-IV criteria
9) History of suicidal behavior or considered a high suicidal risk
10) History of severe self-injurious behavior
11) History of uncontrolled seizure disorder or resistant to therapy within the past 2 years (Patients who are clinically stable under anticonvulsant therapy for the past 2 years are not excluded)
12) History of clinically significant allergies requiring hospitalization or non-inhaled corticosteroid therapy (asthma, anaphylaxis, etc.)
13) 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
14)pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG serum pregnancy test;
15) Using (or used within 6 weeks before randomization) concomitant medications that are potent inhibitors or inducers of CYP3A4, In addition, patients are to avoid drinking grapefruit juice during the study
16) patients who are using (or used within 6 weeks before baseline) digoxin or warfarin
17) Using glutamatergic agents (riluzole, memantine, etc.) or lithium within 6 weeks of baseline
18)use of investigational drugs (other than AFQ056) at the time of enrollment, or within 6 weeks or 5 half-lives of baseline, whichever is longer
19)participation in any pharmacological clinical investigation (other than observational studies or those including AFQ056) within 6 weeks prior to baseline or longer if required by local regulation
20)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 bnormalities in safety assessments at baseline
21) patients who are unable to swallow study medication in a capsule formulation
Other protocol-defined exclusion criteria may apply |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1) Number of patients having any adverse events (AE) by primary system organ class and preferred term during the 24 months of the study.
Adverse events will be summarized by presenting the number of patients having any AE by primary system organ class and/or preferred term.
2) Changes in vital signs.
Pulse and Blood pressure will be taken sitting after five minutes. Temperature will also be taken.
3) Changes in weight.
Body weight (to the nearest 0.1 kilogram in indoor clothing, but without shoes) will be measured.
4) Changes in height.
Height in centimeters (cm) will be measured.
5) Changes in standard laboratory assessments: change in standard hematology.
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.
6) Changes in standard laboratory assessments: change in standard chemistry.
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.
7) Changes in standard laboratory assessments: change in standard urinalysis.
Specific gravity, bilirubin, blood, glucose, ketones, pH, protein and urobilinogen will be measured.
8) Changes in hormonal parameter concentrations to evaluate hypothalamic-pituitary-adrenal (HPA) axis.
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.
9) Changes in ECGs.
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.
10) Change in Tanner staging score.
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. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1) Baseline, week 1, 2, 3, 4, 6, 8, 12, 26, 39, 52, 65, 78, 91, 104, every 13 weeks thereafter and/or upon and 1 week after completion/early discontinuation (ED)
2),3) 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 and 1 week after completion/ED
4) 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/ED
5),6),7),8) Screening (for group 2 only - up to -4 weeks), week 4, 12, 52, 104 and upon completion/ED
9) Baseline, week 4, 12, 52, 78, 104, every 26 weeks thereafter and/or upon completion/ED
10) Baseline, week 26, 52, 78, 104 and upon completion/ED
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| E.5.2 | Secondary end point(s) |
1) Change in the Aberrant Behavior Checklist-Community edition (ABC-C)
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.
2) Change in the Clinical Global Impression Score – Severity/Improvement (CGI-S/I) scale.
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.
3) Change in the Repetitive Behavior Scale – Revised (RBS-R).
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.
4) Change in the Social Responsiveness Scale (SRS) total score.
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.
5) Assessment of pharmacokinetic (PK) parameters: Plasma concentration levels of AFQ056
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.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) Baseline, week 4, 12, 26, 39, 52, 65, 78, 91, 104, every 13 weeks thereafter and upon completion/early discontinuation.
2) Baseline, week 4, 12, 26, 39, 52, 65, 78, 91, 104, every 13 weeks thereafter and upon completion/early discontinuation.
3) Baseline, week 4, 39, 52, 78, 104, and upon completion/early discontinuation
4) Baseline, weeks 4, 39, 52, 78, 104, and upon completion/early discontinuation)
5) Week 4, 12, 52, and 104. |
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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 | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| 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 | No |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 16 |
| 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 | No |
| 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 |
| Denmark |
| France |
| Italy |
| Sweden |
| Australia |
| Germany |
| Switzerland |
| United Kingdom |
| United States |
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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 | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 26 |
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