Acamprosate in Youth With Fragile X Syndrome

• Sponsor: Indiana University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01300923
• Collaborator: (none)
• Enrollment: 14
• Location: 1
• Arms: 2
• Duration (Months): 13
• Patients Per Site Per Month: 1.1

Study Details

Study Description

Brief Summary

Fragile X syndrome (FXS) is the most common inherited form of developmental disability. FXS is inherited from the carrier parent, most often the mothers. FXS is associated with severe interfering behavioral symptoms which include anxiety related symptoms, attention deficit hyperactivity, and aggressive behaviors. Approximately 25-33% of individuals with FXS also meet criteria for autistic disorder. The hypothesis of this study is that treatment with acamprosate will reduce inattention/hyperactivity, language impairment, irritability, social deficits, and cognitive delay in youth with FXS. The purpose of this study is to investigate the effectiveness and tolerability of acamprosate in youth with Fragile X Syndrome and to assess the potential psychophysiological differences between FXS and autism spectrum disorders.

Condition or Disease	Intervention/Treatment	Phase
Fragile X Syndrome; Autism Spectrum Disorders	Drug: Acamprosate	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 14 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Pilot Study of Acamprosate in Youth With Fragile X Syndrome
• Study Start Date: Aug 1, 2010
• Actual Primary Completion Date: Sep 1, 2011
• Actual Study Completion Date: Sep 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Acamprosate The maximum dose of acamprosate to be used in this study is 1998 mg per day for those subjects weighing greater than 60kg and 1332 mg per day for those less weighing less than 60kg.	Drug: Acamprosate; Other Names: Campral
No Intervention: Autism Spectrum Disorder This baseline comparison group will participated in only the psychophysiological and biomarker portion of subject characterization.

Outcome Measures

Primary Outcome Measures

1. Clinical Global Impression- Severity Scale (CGI-S) [Week 10]

   The Clinical Global Impression - Severity scale (CGI-S) is a 7-point scale that requires the clinician to rate the severity of the patient's illness at the time of assessment, relative to the clinician's past experience with patients who have the same diagnosis. Considering total clinical experience, a patient is assessed on severity of mental illness at the time of rating 1, normal, not at all ill; 2, borderline mentally ill; 3, mildly ill; 4, moderately ill; 5, markedly ill; 6, severely ill; or 7, extremely ill.

Secondary Outcome Measures

1. The Aberrant Behavior Checklist (ABC) [Week 10]

   The Aberrant Behavior Checklist (ABC) is a 58-item rating scale used to assess maladaptive behaviors across five original subscales: Irritability (15 items from 0-45), Social Withdrawal (16 items from 0-48), Stereotypy (7 items from 0-21), Hyperactivity (16 items from 0-48), Inappropriate Speech (4 items from 0-12). Additionally, Social Avoidance, a newly developed four-item subscale (from 0-12) of the ABC that captures core social avoidance aspects of Fragile X Syndrome is reported. All items on the ABC are rated from 0 (not at all a problem) to 3 (the problem is severe in degree). Higher scores indicate greater maladaptive behaviors. Differences between Baseline and Week 10 are used as an indicator of change.

2. Social Responsiveness Scale [Week 10]

   The 65-item SRS is a standardized measure of the core symptoms of autism. Each item is scored on a 4-point Likert scale. The score of each individual item is summed to create a total raw score. A total scores results are as follows: 0-62: Within normal limits 63-79: Mild range of impairment 80-108: Moderate range of impairment 109-149: Severe range of impairment

3. Children's Yale-Brown Obsessive Compulsive Scale Modified for PDD [Week 10]

   The Children's Yale-Brown Obsessive Compulsive Scales-Modified (CY-BOCS) is a 5-item, semi-structured clinician rating scale modified designed to rate the current severity of repetitive behavior in children and adolescents with PDD. Once the current repetitive behaviors are identified, they are separately rated on 5 items: Time Spent, Interference, Distress, Resistance, and Control. Each of these items is scored on a 5-point scale form 0 (least symptomatic) to 4 (most symptomatic). The CY-BOCS yields a Total Score from 0 to 20 and is sensitive to change.

4. ADHD Rating Scale 4th Edition [Week 10]

   The ADHD Rating Scale is an 18-item scale directly derived from DSM-IV criteria for Attention Deficit Hyperactivity Disorder. The ADHD Rating Scale-IV is completed by the parent and scored by a clinician. The scale consists of 2 subscales: inattention (9 items) and hyperactivity-impulsivity (9 items). If 3 or more items are skipped, the clinician should use extreme caution in interpreting the scale. The total score can range from 0 to 54, with a higher score indicating greater severity.

5. Vineland Adaptive Behavior Scales-II (VABS-II) Communication Domain [Week 10]

   The VABS-II is a semi-structured interview designed to assess adaptive functioning in communication, daily living, socialization and motor skills. Recognizing that language is a major area of impairment in the study population, the Communication Domain (99 Items from 0-198), in particular the Expressive Subdomain (54 Items from 0-108) are of interest in this study. Items arranged in a developmental sequence are rated on a 3-point scale. Each item is scored from 0 (never performs the behavior) to 3 (usually performs the behavior independently). Higher scores indicate higher adaptive functioning. Differences between Baseline and Week 10 are used as an indicator of change.

6. Peabody Picture Vocabulary [Week 10]

   The Peabody Picture Vocabulary Test is one of the most commonly used assessment tests that measure verbal ability in standard American English vocabulary. This test has been nationally standardized using examinees from various age groups, from children to adults. Thus, the raw scores are equated to mental age, using the norms obtained from standardization. The total standard scores range from 40 (worse receptive vocabulary) to 160 (better receptive vocabulary). The scores can also be converted to percentile rank.

7. Brain-derived Neurotrophic Factor (BDNF) [Screen and Week 10]

   BDNF is a protein that supports the survival of existing neurons and growth and differentiation of new neurons and synapses.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 5 Years to 17 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male and female outpatients between the ages of 5 and 17 years.

• Confirmed diagnosis of Fragile X Syndrome based upon genetic testing.

• Stable dosing of all psychotropic medications for at least 2 weeks prior to baseline.

• Subjects with a stable seizure disorder or history of only childhood febrile seizures will be included.

• Clinical Global Impression-Severity Score of 4 (Moderately Ill) or greater.

• Must be in good physical health.

• Subjects of child bearing age of both genders will be required to utilize birth control as applicable.

Exclusion Criteria:

• Diagnosis of schizophrenia, another psychotic disorder, bipolar disorder or alcohol or other substance abuse based on Diagnostic and Statistical Manual Fourth Edition-Text Revised (DSM-IV-TR).

• A significant medical condition such as heart, liver, renal or pulmonary disease or unstable seizure disorder.

• Females with a positive urine pregnancy test

• Creatinine clearance of less than 30.

• Concomitant use of another glutamatergic agent (memantine,riluzole, d-cycloserine, amantadine topiramate, gabapentin, among others.

• Evidence of hypersensitivity to acamprosate or potentially serious adverse effect.

• Subjects 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 for any reason.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Riley Child and Adolescent Psychiatry Clinic - Riley Hospital for Children	Indianapolis	Indiana	United States	46202

Sponsors and Collaborators

• Indiana University

Investigators

• Principal Investigator: Craig A. Erickson, M.D., Indiana University School of Medicine - Department of Psychiatry

Study Documents (Full-Text)

None provided.

More Information

Publications

• Erickson CA, Wink LK, Ray B, Early MC, Stiegelmeyer E, Mathieu-Frasier L, Patrick V, Lahiri DK, McDougle CJ. Impact of acamprosate on behavior and brain-derived neurotrophic factor: an open-label study in youth with fragile X syndrome. Psychopharmacology (Berl). 2013 Jul;228(1):75-84. doi: 10.1007/s00213-013-3022-z. Epub 2013 Feb 24.

• Responsible Party: Indiana University
• ClinicalTrials.gov Identifier: NCT01300923
• Other Study ID Numbers: 1003-26
• First Posted: Feb 23, 2011
• Last Update Posted: Jul 30, 2019
• Last Verified: Jul 1, 2019

• Keywords provided by Indiana University: Fragile X Syndrome; Acamprosate
• Additional relevant MeSH terms: Fragile X Syndrome; Syndrome; Autism Spectrum Disorder; Acamprosate

Study Results

Participant Flow

Pre-assignment Detail	The psychophysiological measures proved non-feasible as subjects could not tolerate the procedures. The paradigms were tried on two subjects in the Autism Spectrum Disorder arm; however, the data that was collected was not usable. Subsequently, neurobiological characterization was halted.

Arm/Group Title	Acamprosate	Autism Spectrum Disorder (ADS)
Arm/Group Description	The maximum dose of acamprosate to be used in this study is 1998 mg per day for those subjects weighing greater than 60kg and 1332 mg per day for those less weighing less than 60kg. Acamprosate	This baseline comparison group will participated in only and biomarker portion of subject characterization.
Period Title: Overall Study
STARTED	12	2
COMPLETED	12	0
NOT COMPLETED	0	2

Baseline Characteristics

Arm/Group Title	Acamprosate Treatment Group
Arm/Group Description	Twelve subjects received open-label acamprosate, mean final of 1,054 mg/day (range: 666-1,998 mg/day)
Overall Participants	12
Age (Count of Participants)
<=18 years	12 100%
Between 18 and 65 years	0 0%
>=65 years	0 0%
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	11.9
Sex: Female, Male (Count of Participants)
Female	2 16.7%
Male	10 83.3%
Region of Enrollment (participants) [Number]
United States	12 100%
Aberrant Behavior Checklist (units on a scale) [Mean (Standard Deviation) ]
ABC Irritability	9.9 (7.8)
ABC Social Withdrawal	8.8 (5.8)
ABC Stereotypy	6.8 (6.8)
ABC Hyperactivity	16.8 (9.1)
ABC Inappropriate Speech	5.2 (3.5)
ABC Social Avoidance	3.3 (2.6)
Clinical Global Impression -Severity (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	4.25 (0.45)
Children's Yale-Brown Obsessive Compulsive Scale Modified for PDD (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	11.1 (2.6)
Social Responsiveness Scale (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	91.3 (27.4)
ADHD Rating Scale 4th Edition (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	23.6 (10.6)
Peabody Picture Vocabulary Test (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	85.2 (32.0)
Vineland Adaptive Behavior Scales-II (VABS-II) Communication Domain (units on a scale) [Mean (Standard Deviation) ]
Communication Domain	63.4 (10.0)
Expressive Communication Domain	69.8 (23.0)
Brain-derived neurotropic factor (pg/mL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [pg/mL]	790.4 (1.3050)

Outcome Measures

1. Primary Outcome

Title	Clinical Global Impression- Severity Scale (CGI-S)
Description	The Clinical Global Impression - Severity scale (CGI-S) is a 7-point scale that requires the clinician to rate the severity of the patient's illness at the time of assessment, relative to the clinician's past experience with patients who have the same diagnosis. Considering total clinical experience, a patient is assessed on severity of mental illness at the time of rating 1, normal, not at all ill; 2, borderline mentally ill; 3, mildly ill; 4, moderately ill; 5, markedly ill; 6, severely ill; or 7, extremely ill.
Time Frame	Week 10

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Acamprosate Treatment Group
Arm/Group Description	Twelve subjects received open-label acamprosate, mean final of 1,054 mg/day (range: 666-1,998 mg/day).
Measure Participants	12
Mean (Standard Deviation) [units on a scale]	7.0 (8.9)

2. Secondary Outcome

Title	The Aberrant Behavior Checklist (ABC)
Description	The Aberrant Behavior Checklist (ABC) is a 58-item rating scale used to assess maladaptive behaviors across five original subscales: Irritability (15 items from 0-45), Social Withdrawal (16 items from 0-48), Stereotypy (7 items from 0-21), Hyperactivity (16 items from 0-48), Inappropriate Speech (4 items from 0-12). Additionally, Social Avoidance, a newly developed four-item subscale (from 0-12) of the ABC that captures core social avoidance aspects of Fragile X Syndrome is reported. All items on the ABC are rated from 0 (not at all a problem) to 3 (the problem is severe in degree). Higher scores indicate greater maladaptive behaviors. Differences between Baseline and Week 10 are used as an indicator of change.
Time Frame	Week 10

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Acamprosate Treatment Group
Arm/Group Description	Twelve subjects received open-label acamprosate, mean final of 1,054 mg/day (range: 666-1,998 mg/day)
Measure Participants	12
ABC Irritability	7.0 (8.9)
ABC Social Withdrawal	4.1 (6.5)
ABC Stereotypy	6.0 (6.3)
ABC Hyperactivity	11.0 (8.6)
ABC Inappropriate Speech	4.8 (3.4)
ABC Social Avoidance	1.6 (2.7)

3. Secondary Outcome

Title	Social Responsiveness Scale
Description	The 65-item SRS is a standardized measure of the core symptoms of autism. Each item is scored on a 4-point Likert scale. The score of each individual item is summed to create a total raw score. A total scores results are as follows: 0-62: Within normal limits 63-79: Mild range of impairment 80-108: Moderate range of impairment 109-149: Severe range of impairment
Time Frame	Week 10

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Acamprosate Treatment Group
Arm/Group Description	Twelve subjects received open-label acamprosate, mean final of 1,054 mg/day (range: 666-1,998 mg/day)
Measure Participants	12
Mean (Standard Deviation) [units on a scale]	76.4 (26.8)

4. Secondary Outcome

Title	Children's Yale-Brown Obsessive Compulsive Scale Modified for PDD
Description	The Children's Yale-Brown Obsessive Compulsive Scales-Modified (CY-BOCS) is a 5-item, semi-structured clinician rating scale modified designed to rate the current severity of repetitive behavior in children and adolescents with PDD. Once the current repetitive behaviors are identified, they are separately rated on 5 items: Time Spent, Interference, Distress, Resistance, and Control. Each of these items is scored on a 5-point scale form 0 (least symptomatic) to 4 (most symptomatic). The CY-BOCS yields a Total Score from 0 to 20 and is sensitive to change.
Time Frame	Week 10

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Acamprosate Treatment Group
Arm/Group Description	Twelve subjects received open-label acamprosate, mean final of 1,054 mg/day (range: 666-1,998 mg/day)
Measure Participants	12
Mean (Standard Deviation) [units on a scale]	9.8 (4.1)

5. Secondary Outcome

Title	ADHD Rating Scale 4th Edition
Description	The ADHD Rating Scale is an 18-item scale directly derived from DSM-IV criteria for Attention Deficit Hyperactivity Disorder. The ADHD Rating Scale-IV is completed by the parent and scored by a clinician. The scale consists of 2 subscales: inattention (9 items) and hyperactivity-impulsivity (9 items). If 3 or more items are skipped, the clinician should use extreme caution in interpreting the scale. The total score can range from 0 to 54, with a higher score indicating greater severity.
Time Frame	Week 10

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Acamprosate Treatment Group
Arm/Group Description	Twelve subjects received open-label acamprosate, mean final of 1,054 mg/day (range: 666-1,998 mg/day)
Measure Participants	12
Mean (Standard Deviation) [units on a scale]	16.7 (8.0)

6. Secondary Outcome

Title	Vineland Adaptive Behavior Scales-II (VABS-II) Communication Domain
Description	The VABS-II is a semi-structured interview designed to assess adaptive functioning in communication, daily living, socialization and motor skills. Recognizing that language is a major area of impairment in the study population, the Communication Domain (99 Items from 0-198), in particular the Expressive Subdomain (54 Items from 0-108) are of interest in this study. Items arranged in a developmental sequence are rated on a 3-point scale. Each item is scored from 0 (never performs the behavior) to 3 (usually performs the behavior independently). Higher scores indicate higher adaptive functioning. Differences between Baseline and Week 10 are used as an indicator of change.
Time Frame	Week 10

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Acamprosate Treatment Group
Arm/Group Description	Twelve subjects received open-label acamprosate, mean final of 1,054 mg/day (range: 666-1,998 mg/day).
Measure Participants	12
Communication Domain	66.6 (11.2)
Expressive Communication	78.9 (21.2)

7. Secondary Outcome

Title	Peabody Picture Vocabulary
Description	The Peabody Picture Vocabulary Test is one of the most commonly used assessment tests that measure verbal ability in standard American English vocabulary. This test has been nationally standardized using examinees from various age groups, from children to adults. Thus, the raw scores are equated to mental age, using the norms obtained from standardization. The total standard scores range from 40 (worse receptive vocabulary) to 160 (better receptive vocabulary). The scores can also be converted to percentile rank.
Time Frame	Week 10

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Acamprosate Treatment Group
Arm/Group Description	Twelve subjects received open-label acamprosate, mean final of 1,054 mg/day (range: 666-1,998 mg/day)
Measure Participants	12
Mean (Standard Deviation) [units on a scale]	83.3 (32.0)

8. Secondary Outcome

Title	Brain-derived Neurotrophic Factor (BDNF)
Description	BDNF is a protein that supports the survival of existing neurons and growth and differentiation of new neurons and synapses.
Time Frame	Screen and Week 10

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Acamprosate Treatment Group
Arm/Group Description	Twelve subjects received open-label acamprosate, mean final of 1,054 mg/day (range: 666-1,998 mg/day)
Measure Participants	10
Mean (Standard Deviation) [pg/mL]	1,007.6 (1,493.2)

Adverse Events

Time Frame	Ten Weeks
Arm/Group Title	Acamprosate
Arm/Group Description	The maximum dose of acamprosate to be used in this study is 1998 mg per day for those subjects weighing greater than 60kg and 1332 mg per day for those less weighing less than 60kg.
All Cause Mortality
	Acamprosate
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Acamprosate
	Affected / at Risk (%)	# Events
Total	0/12 (0%)
Other (Not Including Serious) Adverse Events
	Acamprosate
	Affected / at Risk (%)	# Events
Total	9/12 (75%)
Gastrointestinal disorders
Diarrhea	1/12 (8.3%)	1
mild constipation	1/12 (8.3%)	1
Infections and infestations
Rhinitis	1/12 (8.3%)	1
Psychiatric disorders
Irritability	4/12 (33.3%)	4
Increased repetitive behavior	2/12 (16.7%)	2
Increased anxiety	1/12 (8.3%)	1
Insomnia	1/12 (8.3%)	1
Nightmares	1/12 (8.3%)	1
Renal and urinary disorders
Urinary Urgency	1/12 (8.3%)	1

Limitations/Caveats

Psychophysiological measures proved non-feasible as subjects could not tolerate the procedures. The paradigms were tried on 2 subjects in the ADS arm, as data collected was not usable. Subsequently, neurobiological characterization was halted.

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.