Long-term, Safety, Tolerability and Efficacy Study of AFQ056 in Adult Patients With Fragile X Syndrome

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01348087
• Collaborator: (none)
• Enrollment: 148
• Locations: 28
• Arm: 1
• Duration (Months): 37
• Patients Per Site: 5.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Fragile X Syndrome	Drug: AFQ056	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 148 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label Study to Evaluate the Long-term Safety, Tolerability and Efficacy of AFQ056 in Adult Patients With Fragile X Syndrome
• Study Start Date: Aug 1, 2011
• Actual Primary Completion Date: Sep 1, 2014
• Actual Study Completion Date: Sep 1, 2014

Arms and Interventions

Arm

Intervention/Treatment

Experimental: AFQ056 100 mg (Bid) All patients initiated treatment with AFQ056 at a starting dose of 25 milligram (mg) twice daily. The dose was titrated from 25mg bid to 50mg bid, 75mg bid and 100mg bid at weekly intervals. Dose adjustments (up- and down titrations) were permitted as needed to manage any tolerability issues and to ensure that patients reach their highest tolerated dose not to exceed 100mg bid.

Drug: AFQ056; The investigational drug, AFQ056, will be provided as hard gelatin capsules. Two different oral dosage strengths, identical in appearance, will be used.

Outcome Measures

Primary Outcome Measures

1. 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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/exclusion criteria may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Phoenix	Arizona	United States	85006
2	Novartis Investigative Site	Sacramento	California	United States	95817
3	Novartis Investigative Site	Decatur	Georgia	United States	30033
4	Novartis Investigative Site	Chicago	Illinois	United States	60612
5	Novartis Investigative Site	Indianapolis	Indiana	United States	46202
6	Novartis Investigative Site	Boston	Massachusetts	United States	02115
7	Novartis Investigative Site	Omaha	Nebraska	United States	68198-5575
8	Novartis Investigative Site	Staten Island	New York	United States	10314
9	Novartis Investigative Site	Media	Pennsylvania	United States	19063
10	Novartis Investigative Site	Nashville	Tennessee	United States	37212
11	Novartis Investigative Site	Ryde	New South Wales	Australia	2112
12	Novartis Investigative Site	Waratah	New South Wales	Australia	2298
13	Novartis Investigative Site	Caulfield	Victoria	Australia	3161
14	Novartis Investigative Site	Brampton	Ontario	Canada	L6Y 1M5
15	Novartis Investigative Site	Sherbrooke	Quebec	Canada	J1H 5N4
16	Novartis Investigative Site	Glostrup		Denmark	2600
17	Novartis Investigative Site	Bron Cedex		France	69677
18	Novartis Investigative Site	Paris		France	75013
19	Novartis Investigative Site	Berlin		Germany	12203
20	Novartis Investigative Site	Mainz		Germany	55131
21	Novartis Investigative Site	Tübingen		Germany	72076
22	Novartis Investigative Site	Würzburg		Germany	97070
23	Novartis Investigative Site	Genova	GE	Italy	16147
24	Novartis Investigative Site	Malaga	Andalucia	Spain	29010
25	Novartis Investigative Site	Sant Cugat	Catalunya	Spain	08190
26	Novartis Investigative Site	Lausanne		Switzerland	1011
27	Novartis Investigative Site	Zurich		Switzerland	8091
28	Novartis Investigative Site	Edinburgh		United Kingdom	EH10 5HF

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01348087
• Other Study ID Numbers: CAFQ056B2279; 2011-001952-12
• First Posted: May 5, 2011
• Last Update Posted: May 25, 2016
• Last Verified: Apr 1, 2016

• Keywords provided by Novartis Pharmaceuticals: Fragile X Syndrome; Martin-Bell Syndrome; Genetic Diseases; X-Linked; Escalante's syndrome
• Additional relevant MeSH terms: Fragile X Syndrome; Syndrome

Study Results

Participant Flow

Recruitment Details	The study was conducted at 28 centers in 10 countries
Pre-assignment Detail	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

Arm/Group Title	AFQ056 Total
Arm/Group Description	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
Period Title: Overall Study
STARTED	148
COMPLETED	0
NOT COMPLETED	148

Baseline Characteristics

Arm/Group Title	AFQ056
Arm/Group Description	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
Overall Participants	148
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	26.6 (6.85)
Sex: Female, Male (Count of Participants)
Female	10 6.8%
Male	138 93.2%

Outcome Measures

1. Primary Outcome

Title	Incidence and Severity of Adverse Events (AEs) and Serious Adverse Events (SAEs).
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Prior to Ext First Dose	AFQ056 25mg Bid	AFQ056 50mg Bid	AFQ056 75mg Bid	AFQ056 100mg Bid	AFQ056 Total
Arm/Group Description
Measure Participants	40	147	148	141	135	148
At least one AE	9 6.1%	49 NaN	47 NaN	50 NaN	112 NaN	138 NaN
At least one severe AE	1 0.7%	1 NaN	2 NaN	5 NaN	18 NaN	24 NaN
Any serious or significant AE	0 0%	1 NaN	0 NaN	1 NaN	6 NaN	7 NaN
SAE	0 0%	1 NaN	0 NaN	1 NaN	6 NaN	7 NaN
Discontinued due to SAE	0 0%	1 NaN	0 NaN	1 NaN	1 NaN	3 NaN
Discontinued due to non serious AE	0 0%	4 NaN	5 NaN	4 NaN	11 NaN	22 NaN

Adverse Events

Arm/Group Title	Prior to Ext.First Dose		AFQ056 25 mg Bid		AFQ056 50 mg Bid		AFQ056 75 mg Bid		AFQ056 100 mg Bid		AFQ056 Total
Arm/Group Description	Prior to Ext.first dose		AFQ056 25 mg bid		AFQ056 50 mg bid		AFQ056 75 mg bid		AFQ056 100 mg bid
All Cause Mortality
	Prior to Ext.First Dose		AFQ056 25 mg Bid		AFQ056 50 mg Bid		AFQ056 75 mg Bid		AFQ056 100 mg Bid		AFQ056 Total
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Prior to Ext.First Dose		AFQ056 25 mg Bid		AFQ056 50 mg Bid		AFQ056 75 mg Bid		AFQ056 100 mg Bid		AFQ056 Total
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/40 (0%)		1/147 (0.7%)		0/148 (0%)		1/141 (0.7%)		6/135 (4.4%)		7/148 (4.7%)
Investigations
Hepatic enzyme increased	0/40 (0%)		0/147 (0%)		0/148 (0%)		0/141 (0%)		1/135 (0.7%)		1/148 (0.7%)
Nervous system disorders
Epilepsy	0/40 (0%)		0/147 (0%)		0/148 (0%)		0/141 (0%)		1/135 (0.7%)		1/148 (0.7%)
Psychiatric disorders
Aggression	0/40 (0%)		0/147 (0%)		0/148 (0%)		1/141 (0.7%)		2/135 (1.5%)		3/148 (2%)
Agitation	0/40 (0%)		0/147 (0%)		0/148 (0%)		0/141 (0%)		2/135 (1.5%)		2/148 (1.4%)
Hallucination, auditory	0/40 (0%)		0/147 (0%)		0/148 (0%)		0/141 (0%)		1/135 (0.7%)		1/148 (0.7%)
Hallucination, visual	0/40 (0%)		1/147 (0.7%)		0/148 (0%)		0/141 (0%)		1/135 (0.7%)		1/148 (0.7%)
Panic attack	0/40 (0%)		0/147 (0%)		0/148 (0%)		0/141 (0%)		1/135 (0.7%)		1/148 (0.7%)
Other (Not Including Serious) Adverse Events
	Prior to Ext.First Dose		AFQ056 25 mg Bid		AFQ056 50 mg Bid		AFQ056 75 mg Bid		AFQ056 100 mg Bid		AFQ056 Total
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/40 (15%)		26/147 (17.7%)		28/148 (18.9%)		36/141 (25.5%)		88/135 (65.2%)		117/148 (79.1%)
Gastrointestinal disorders
Diarrhoea	0/40 (0%)		1/147 (0.7%)		1/148 (0.7%)		1/141 (0.7%)		7/135 (5.2%)		10/148 (6.8%)
Vomiting	0/40 (0%)		1/147 (0.7%)		2/148 (1.4%)		2/141 (1.4%)		14/135 (10.4%)		18/148 (12.2%)
General disorders
Asthenia	0/40 (0%)		1/147 (0.7%)		0/148 (0%)		5/141 (3.5%)		8/135 (5.9%)		9/148 (6.1%)
Fatigue	0/40 (0%)		1/147 (0.7%)		2/148 (1.4%)		3/141 (2.1%)		3/135 (2.2%)		9/148 (6.1%)
Infections and infestations
Nasopharyngitis	3/40 (7.5%)		2/147 (1.4%)		4/148 (2.7%)		3/141 (2.1%)		21/135 (15.6%)		27/148 (18.2%)
Upper respiratory tract infection	0/40 (0%)		4/147 (2.7%)		1/148 (0.7%)		3/141 (2.1%)		16/135 (11.9%)		24/148 (16.2%)
Nervous system disorders
Dizziness	1/40 (2.5%)		5/147 (3.4%)		4/148 (2.7%)		1/141 (0.7%)		5/135 (3.7%)		13/148 (8.8%)
Headache	0/40 (0%)		4/147 (2.7%)		3/148 (2%)		7/141 (5%)		14/135 (10.4%)		21/148 (14.2%)
Psychiatric disorders
Aggression	0/40 (0%)		6/147 (4.1%)		8/148 (5.4%)		5/141 (3.5%)		11/135 (8.1%)		22/148 (14.9%)
Agitation	0/40 (0%)		0/147 (0%)		1/148 (0.7%)		3/141 (2.1%)		10/135 (7.4%)		13/148 (8.8%)
Anxiety	0/40 (0%)		1/147 (0.7%)		3/148 (2%)		3/141 (2.1%)		10/135 (7.4%)		16/148 (10.8%)
Insomnia	1/40 (2.5%)		4/147 (2.7%)		3/148 (2%)		7/141 (5%)		12/135 (8.9%)		23/148 (15.5%)
Irritability	1/40 (2.5%)		0/147 (0%)		7/148 (4.7%)		4/141 (2.8%)		6/135 (4.4%)		15/148 (10.1%)
Respiratory, thoracic and mediastinal disorders
Cough	1/40 (2.5%)		4/147 (2.7%)		0/148 (0%)		2/141 (1.4%)		9/135 (6.7%)		16/148 (10.8%)

Limitations/Caveats

The sponsor decided to terminate this study prematurely, as the study treatment failed to demonstrate efficacy in target population in two other clinical studies: CAFQ056B2214 (NCT01357239) and CAFQ056A2212 (NCT01253629).

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety