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

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01433354
• Collaborator: (none)
• Enrollment: 119
• Locations: 28
• Arm: 1
• Duration (Months): 34
• Patients Per Site: 4.3
• 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 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.

Condition or Disease	Intervention/Treatment	Phase
Fragile X Syndrome	Drug: AFQ056	Phase 2/Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 119 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 and Tolerability of AFQ056 in Adolescent Patients With Fragile X Syndrome
• Study Start Date: Nov 1, 2011
• Actual Primary Completion Date: Sep 1, 2014
• Actual Study Completion Date: Sep 1, 2014

Arms and Interventions

Arm

Intervention/Treatment

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.

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.

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 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years to 18 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Sacramento	California	United States	95817
2	Novartis Investigative Site	Decatur	Georgia	United States	30033
3	Novartis Investigative Site	Chicago	Illinois	United States	60612
4	Novartis Investigative Site	Boston	Massachusetts	United States	02115
5	Novartis Investigative Site	Omaha	Nebraska	United States	68198-5575
6	Novartis Investigative Site	Staten Island	New York	United States	10314
7	Novartis Investigative Site	Nashville	Tennessee	United States	37212
8	Novartis Investigative Site	Westmead	New South Wales	Australia	2145
9	Novartis Investigative Site	Parkville	Victoria	Australia	3052
10	Novartis Investigative Site	Bruxelles		Belgium	1200
11	Novartis Investigative Site	Leuven		Belgium	3000
12	Novartis Investigative Site	Glostrup		Denmark	2600
13	Novartis Investigative Site	Bron Cedex		France	69677
14	Novartis Investigative Site	Mainz		Germany	55131
15	Novartis Investigative Site	München		Germany	80639
16	Novartis Investigative Site	Tübingen		Germany	72076
17	Novartis Investigative Site	Würzburg		Germany	97070
18	Novartis Investigative Site	Ramat Gan		Israel	52621
19	Novartis Investigative Site	Genova	GE	Italy	16147
20	Novartis Investigative Site	Padova		Italy	35128
21	Novartis Investigative Site	Rotterdam		Netherlands	3015 CE
22	Novartis Investigative Site	Málaga	Andalucia	Spain	29009
23	Novartis Investigative Site	Sabadell	Barcelona	Spain	08208
24	Novartis Investigative Site	Sant Cugat	Cataluña	Spain	08190
25	Novartis Investigative Site	Spånga		Sweden	16374
26	Novartis Investigative Site	Lausanne		Switzerland
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: NCT01433354
• Other Study ID Numbers: CAFQ056B2278; 2011-002379-40
• First Posted: Sep 13, 2011
• Last Update Posted: Mar 24, 2016
• Last Verified: Feb 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 centres in 13 countries.
Pre-assignment Detail	A total of 120 patients were enrolled, of which 119 received the study medication. Category 1 patients received AFQ056 in the core study and enrolled in the extension within 7 days of the core study; Category 2 included all other patients who were enrolled into the extension study

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.
Period Title: Overall Study
STARTED	119
COMPLETED	0
NOT COMPLETED	119

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	119
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	15.2 (1.75)
Sex: Female, Male (Count of Participants)
Female	13 10.9%
Male	106 89.1%

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 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.
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	AFQ056	Prior to Ext. First Dose	AFQ056 25 mg Bid	AFQ056 50 mg Bid	AFQ056 75 mg Bid	AFQ056 100 mg Bid
Arm/Group Description	Total
Measure Participants	119	31	119	118	116	108
At least one AE	110 92.4%	10 NaN	36 NaN	41 NaN	44 NaN	90 NaN
At least one severe AE	8 6.7%	0 NaN	1 NaN	1 NaN	1 NaN	5 NaN
Any serious or significant AE	4 3.4%	0 NaN	0 NaN	1 NaN	0 NaN	3 NaN
SAEs	4 3.4%	0 NaN	0 NaN	1 NaN	0 NaN	3 NaN
Discontinued due to AEs	6 5%	1 NaN	2 NaN	2 NaN	0 NaN	3 NaN
Discontinued due to SAEs	1 0.8%	0 NaN	0 NaN	0 NaN	0 NaN	1 NaN
Discontinued due to non serious AE	5 4.2%	1 NaN	2 NaN	2 NaN	0 NaN	2 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		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		Total
All Cause Mortality
	Prior to Ext.First Dose		AFQ056 25 mg Bid		AFQ056 50 mg Bid		AFQ056 75 mg Bid		AFQ056 100 mg Bid		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		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	0/31 (0%)		0/119 (0%)		1/118 (0.8%)		0/116 (0%)		3/108 (2.8%)		4/119 (3.4%)
Infections and infestations
Appendicitis	0/31 (0%)		0/119 (0%)		0/118 (0%)		0/116 (0%)		1/108 (0.9%)		1/119 (0.8%)
Respiratory tract infection	0/31 (0%)		0/119 (0%)		0/118 (0%)		0/116 (0%)		1/108 (0.9%)		1/119 (0.8%)
Injury, poisoning and procedural complications
Foreign body	0/31 (0%)		0/119 (0%)		1/118 (0.8%)		0/116 (0%)		0/108 (0%)		1/119 (0.8%)
Joint dislocation	0/31 (0%)		0/119 (0%)		0/118 (0%)		0/116 (0%)		1/108 (0.9%)		1/119 (0.8%)
Psychiatric disorders
Aggression	0/31 (0%)		0/119 (0%)		0/118 (0%)		0/116 (0%)		1/108 (0.9%)		1/119 (0.8%)
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		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	6/31 (19.4%)		23/119 (19.3%)		30/118 (25.4%)		33/116 (28.4%)		74/108 (68.5%)		103/119 (86.6%)
Gastrointestinal disorders
Diarrhoea	1/31 (3.2%)		2/119 (1.7%)		4/118 (3.4%)		0/116 (0%)		5/108 (4.6%)		12/119 (10.1%)
Vomiting	1/31 (3.2%)		2/119 (1.7%)		5/118 (4.2%)		0/116 (0%)		8/108 (7.4%)		13/119 (10.9%)
General disorders
Fatigue	0/31 (0%)		2/119 (1.7%)		2/118 (1.7%)		3/116 (2.6%)		5/108 (4.6%)		11/119 (9.2%)
Pyrexia	0/31 (0%)		0/119 (0%)		1/118 (0.8%)		2/116 (1.7%)		4/108 (3.7%)		7/119 (5.9%)
Infections and infestations
Ear infection	0/31 (0%)		2/119 (1.7%)		0/118 (0%)		1/116 (0.9%)		5/108 (4.6%)		8/119 (6.7%)
Gastroenteritis viral	0/31 (0%)		0/119 (0%)		2/118 (1.7%)		1/116 (0.9%)		5/108 (4.6%)		8/119 (6.7%)
Influenza	0/31 (0%)		1/119 (0.8%)		0/118 (0%)		2/116 (1.7%)		6/108 (5.6%)		8/119 (6.7%)
Nasopharyngitis	0/31 (0%)		7/119 (5.9%)		3/118 (2.5%)		8/116 (6.9%)		25/108 (23.1%)		35/119 (29.4%)
Upper respiratory tract infection	1/31 (3.2%)		3/119 (2.5%)		5/118 (4.2%)		3/116 (2.6%)		9/108 (8.3%)		17/119 (14.3%)
Investigations
Weight increased	1/31 (3.2%)		1/119 (0.8%)		0/118 (0%)		0/116 (0%)		5/108 (4.6%)		7/119 (5.9%)
Metabolism and nutrition disorders
Decreased appetite	2/31 (6.5%)		0/119 (0%)		2/118 (1.7%)		1/116 (0.9%)		0/108 (0%)		5/119 (4.2%)
Nervous system disorders
Headache	0/31 (0%)		4/119 (3.4%)		1/118 (0.8%)		4/116 (3.4%)		8/108 (7.4%)		15/119 (12.6%)
Psychomotor hyperactivity	0/31 (0%)		2/119 (1.7%)		3/118 (2.5%)		1/116 (0.9%)		3/108 (2.8%)		9/119 (7.6%)
Psychiatric disorders
Aggression	0/31 (0%)		3/119 (2.5%)		3/118 (2.5%)		4/116 (3.4%)		12/108 (11.1%)		19/119 (16%)
Agitation	0/31 (0%)		1/119 (0.8%)		1/118 (0.8%)		0/116 (0%)		4/108 (3.7%)		6/119 (5%)
Anxiety	0/31 (0%)		3/119 (2.5%)		1/118 (0.8%)		0/116 (0%)		11/108 (10.2%)		15/119 (12.6%)
Initial insomnia	0/31 (0%)		3/119 (2.5%)		2/118 (1.7%)		4/116 (3.4%)		9/108 (8.3%)		18/119 (15.1%)
Insomnia	1/31 (3.2%)		4/119 (3.4%)		10/118 (8.5%)		5/116 (4.3%)		12/108 (11.1%)		25/119 (21%)
Irritability	0/31 (0%)		3/119 (2.5%)		1/118 (0.8%)		3/116 (2.6%)		9/108 (8.3%)		15/119 (12.6%)
Respiratory, thoracic and mediastinal disorders
Cough	0/31 (0%)		1/119 (0.8%)		1/118 (0.8%)		4/116 (3.4%)		7/108 (6.5%)		12/119 (10.1%)
Epistaxis	0/31 (0%)		0/119 (0%)		2/118 (1.7%)		2/116 (1.7%)		3/108 (2.8%)		6/119 (5%)

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.