Fragile X Syndrome
Conditions
Keywords
Fragile X Syndrome, Martin-Bell Syndrome, Genetic Diseases, X-Linked, Escalante's syndrome
Brief summary
The purpose of this study is to generate long-term safety, tolerability and efficacy data for AFQ056 in eligible adult patients with FXS who have participated in the CAFQ056A2212 (NCT01253629).study and patients who have participated in the previous proof-of-concept study CAFQ056A2204 (NCT00718341).
Detailed description
A 148 patients were enrolled into this treatment extension trial conducted for at least 3 years. This extension trial was terminated after the decision to terminate the AFQ056 development program. The decision was based on the results of two randomized, double blind, placebo controlled phase IIb trials in adult and adolescent FXS patients (CAFQ056A2212 and CAFQ056B2214respectivly), both of which failed to demonstrate efficacy in the FXS population. As this extension trial was terminated, only the primary objective and safety are represented.
Interventions
DRUGAFQ056
The investigational drug, AFQ056, will be provided as hard gelatin capsules. Two different oral dosage strengths, identical in appearance, will be used.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Group 1 patients * Had to have completed the CAFQ056A2212 study or another study of AFQ056 which included adult FXS patients within one week of enrollment into the open-label study. * Females of child-bearing potential had to follow protocol requirements with respect to contraception. * Have a caregiver or caregivers who spent, on average, at least six hours per day with the patient, who were willing and capable of supervising treatment, providing input into efficacy and safety assessments, and accompanying the patient to study visits. Group 2: * Had to have: * Completed Study CAFQ056A2204. * Completed Study CAFQ056A2212 or another study of AFQ056 which included adult patients with FXS but enrollment into the current study was delayed for more than a week. * Discontinued prematurely from Study CAFQ056A2212 or another study of AFQ056 which included adult patients with FXS due to intolerability of the dosage in the patient's assigned treatment group. * Females of child-bearing potential had to follow protocol requirements with respect to contraception. * Have a caregiver or caregivers who spent, on average, at least six hours per day with the patient, who were willing and capable of supervising treatment, providing input into efficacy and safety assessments, and accompanying the patient to study visits
Exclusion criteria
Any advanced, severe or unstable disease * 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.) * 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, digoxin, or warfarin within 6 weeks of baseline Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs). | Prior to first dose in extension study, Baseline (start of study treatment in extension study) to End of trial | 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 patients 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 patients 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 |
Countries
Australia, Canada, Denmark, France, Germany, Italy, Spain, Switzerland, United Kingdom, United States
Participant flow
Recruitment details
The study was conducted at 28 centers in 10 countries
Pre-assignment details
A total of 148 patients were enrolled and treated, including 1 patient who discontinued and was later re-enrolled under a new patient number. Category 1 patients received AFQ056 in the core study and enrolled in the extension within 7 days of completing the core study; Category 2 included all other patients enrolled into the extension study
Participants by arm
| Arm | Count |
|---|---|
| AFQ056 Participants from a previous AFQ056 study who entered the open-label extension study were administered AFQ056 capsules at a starting dose of 25 milligram (mg) twice daily (bid) and then titrated to 50 mg bid, 75 mg bid and 100 mg bid at weekly intervals | 148 |
| Total | 148 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Administrative problems | 79 |
| Overall Study | Adverse Event | 25 |
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | protocol deviation | 1 |
| Overall Study | Subject withdrew consent | 7 |
| Overall Study | Unsatisfactory therapeutic effect | 35 |
Baseline characteristics
| Characteristic | AFQ056 |
|---|---|
| Age, Continuous | 26.6 Years STANDARD_DEVIATION 6.85 |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 138 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 40 | 26 / 147 | 28 / 148 | 36 / 141 | 88 / 135 | 117 / 148 |
| serious Total, serious adverse events | 0 / 40 | 1 / 147 | 0 / 148 | 1 / 141 | 6 / 135 | 7 / 148 |
Outcome results
Primary
Incidence and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs).
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 patients 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 patients 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
Time frame: Prior to first dose in extension study, Baseline (start of study treatment in extension study) to End of trial
Population: The analysis was performed in the safety set (SS) population, defined as participants who received at least one dose of study medication and had at least one safety assessment occurring after first dose of extension study medication. Here, 'Number of Participants Analyzed' signifies those participants who were evaluable for this outcome measure
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Prior to Ext First Dose | Incidence and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs). | Discontinued due to non serious AE | 0 Participants |
| Prior to Ext First Dose | Incidence and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs). | Any serious or significant AE | 0 Participants |
| Prior to Ext First Dose | Incidence and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs). | Discontinued due to SAE | 0 Participants |
| Prior to Ext First Dose | Incidence and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs). | At least one AE | 9 Participants |
| Prior to Ext First Dose | Incidence and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs). | SAE | 0 Participants |
| Prior to Ext First Dose | Incidence and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs). | At least one severe AE | 1 Participants |
| AFQ056 25mg Bid | Incidence and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs). | SAE | 1 Participants |
| AFQ056 25mg Bid | Incidence and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs). | At least one severe AE | 1 Participants |
| AFQ056 25mg Bid | Incidence and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs). | Any serious or significant AE | 1 Participants |
| AFQ056 25mg Bid | Incidence and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs). | Discontinued due to non serious AE | 4 Participants |
| AFQ056 25mg Bid | Incidence and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs). | At least one AE | 49 Participants |
| AFQ056 25mg Bid | Incidence and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs). | Discontinued due to SAE | 1 Participants |
| AFQ056 50mg Bid | Incidence and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs). | Discontinued due to SAE | 0 Participants |
| AFQ056 50mg Bid | Incidence and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs). | Any serious or significant AE | 0 Participants |
| AFQ056 50mg Bid | Incidence and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs). | SAE | 0 Participants |
| AFQ056 50mg Bid | Incidence and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs). | At least one AE | 47 Participants |
| AFQ056 50mg Bid | Incidence and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs). | Discontinued due to non serious AE | 5 Participants |
| AFQ056 50mg Bid | Incidence and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs). | At least one severe AE | 2 Participants |
| AFQ056 75mg Bid | Incidence and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs). | Discontinued due to SAE | 1 Participants |
| AFQ056 75mg Bid | Incidence and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs). | SAE | 1 Participants |
| AFQ056 75mg Bid | Incidence and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs). | Discontinued due to non serious AE | 4 Participants |
| AFQ056 75mg Bid | Incidence and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs). | At least one severe AE | 5 Participants |
| AFQ056 75mg Bid | Incidence and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs). | Any serious or significant AE | 1 Participants |
| AFQ056 75mg Bid | Incidence and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs). | At least one AE | 50 Participants |
| AFQ056 100mg Bid | Incidence and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs). | At least one AE | 112 Participants |
| AFQ056 100mg Bid | Incidence and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs). | SAE | 6 Participants |
| AFQ056 100mg Bid | Incidence and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs). | Discontinued due to SAE | 1 Participants |
| AFQ056 100mg Bid | Incidence and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs). | At least one severe AE | 18 Participants |
| AFQ056 100mg Bid | Incidence and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs). | Discontinued due to non serious AE | 11 Participants |
| AFQ056 100mg Bid | Incidence and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs). | Any serious or significant AE | 6 Participants |
| AFQ056 Total | Incidence and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs). | Discontinued due to SAE | 3 Participants |
| AFQ056 Total | Incidence and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs). | Discontinued due to non serious AE | 22 Participants |
| AFQ056 Total | Incidence and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs). | SAE | 7 Participants |
| AFQ056 Total | Incidence and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs). | At least one AE | 138 Participants |
| AFQ056 Total | Incidence and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs). | Any serious or significant AE | 7 Participants |
| AFQ056 Total | Incidence and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs). | At least one severe AE | 24 Participants |