Ganaxolone Treatment in Children With Fragile X Syndrome

Study Overview
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Brief Summary
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This Phase 2 proof-of-concept study is a double-blind, randomized, placebo-controlled, crossover study to investigate ganaxolone treatment in children with fragile x syndrome (FXS). The objective of the study is to assess the safety, tolerability and efficacy of ganaxolone in the treatment of anxiety and attention in subjects with FXS.

Detailed Description
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This is a single center study conducted at University of California Davis (UCD) MIND Institute. Children with FXS between the ages of 6-17 years, inclusive will be randomized at a 1:1 ratio to receive ganaxolone or placebo treatment for 6 weeks, discontinue treatment and washout for 2 weeks, and then cross over to the opposite treatment for another 6 weeks.

Official Title
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A Controlled, Double-blind, Crossover Trial of Ganaxolone in Children With Fragile X Syndrome

Conditions
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Fragile x Syndrome

Intervention / Treatment
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* Drug: Ganaxolone
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: molecular documentation of FMR1 full mutation ages 6-17 yrs, inclusive sexually active subjects are required to use a medically acceptable form of birth control Exclusion Criteria: non-English or Spanish speaking subjects concomitant systemic steroid, vigabatrin, felbamate and ketoconazole changes in medications within last 2 months clinically unstable medical disease, progressive CNS disease/disorder history of recurrent status epilepticus unwilling to withhold grapefruit or grapefruit juice for the duration of the study actively suicidal

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ganaxolone then Placebo<br>Participants first received ganaxolone. They were first titrated up to the 12 milligram per kilogram (mg/kg) three times daily (tid) during a 2-week titration phase, then maintained on that dose for an additional 4 weeks. After a washout period of 2 weeks, participants received placebo for a duration of 6 weeks (from week 8 to 14). | Drug: Ganaxolone<br>* oral suspension, given in 3 divided doses<br>Drug: Placebo<br>* oral suspension, given in 3 divided doses<br>|
| Experimental: Placebo then Ganaxolone<br>Participants first received placebo. They were first titrated up to the 12 mg/kg tid during a 2-week titration phase, then maintained on that dose for an additional 4 weeks. After a washout period of 2 weeks, participants received ganaxolone for a duration of 6 weeks (from week 8 to 14). | Drug: Ganaxolone<br>* oral suspension, given in 3 divided doses<br>Drug: Placebo<br>* oral suspension, given in 3 divided doses<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Global Impression-Improvement (CGI-I) Scale | The CGI-I scale is a clinician-rated 7-point scale used to assess how much the participant's illness had improved or worsened relative to a Baseline state at the beginning of the intervention. It was rated as: 1. very much improved; 2. much improved; 3. minimally improved; 4. no change; 5. minimally worse; 6. much worse; 7. very much worse. Higher scores indicated worse condition. | Week 14 (End of Treatment) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pediatric Anxiety Rating Scale (PARS) Total Score | Pediatric Anxiety Rating Scale (PARS) is a clinician administered measure of anxiety in children and adolescents. The PARS is comprised of a 50-item symptom checklist used to determine the presence or absence of specific anxiety symptoms during the prior week and 7 severity/impairment items, each scored from 0 to 5. The score on the 7 items allows the clinician to rate symptom severity and associated impairment on a range from 0 to 35, with higher scores reflecting greater symptom severity and associated impairment. | Week 14 (End of Treatment) | 
| Visual Analogue Scale (VAS) | A semi-structured VAS design was employed, providing two of the three behaviors to be assessed as anxiety and attention, chosen by caregiver(s) of one additional behavior from a bank of five. This bank included sociability, attention, aggression, language, and hyperactivity/impulsivity. Parents mark on a visual line measuring 10 centimeters (cm) with worst behavior at 0 cm and best behavior at 10 cm. For each behavior the caregiver is instructed to mark their impression of behavior at Baseline visit and again at each visit. The calculated distance in cm between the baseline and each visit marks thereby demonstrates whether each behavior improved, worsened, or stayed the same during the study, and by how much. Shown here is the least square mean distance and its corresponding standard error in cm from the worst behavior side, at baseline. Smaller the value, worser the behavior. | Week 14 (End of Treatment) | 
| Anxiety, Depression, and Mood Scale (ADAMS) | The ADAMS is a 28-item behavior-based informant instrument rated by the parent(s), legal authorized guardian(s), or consistent caregiver(s). The scale is composed of 5 factors, which addresses Manic/Hyperactive Behavior, Depressed Mood, Social Avoidance, General Anxiety, and Obsessive/Compulsive Behavior. Items are scored on a 0-3 Likert scale that combines frequency and severity ratings (where 0=behavior has not occurred or is not a problem, 3=behavior occurs a lot or is a severe problem). Each subscale score is calculated separately; the scale range for Manic/Hyperactive Behavior is 0-15; for Depressed Mood, 0-21; for Social Avoidance, 0-21; for General Anxiety, 0-21; for Obsessive Behavior, 0-9. There is an overlapped item between Manic/Hypertension Behavior and General Anxiety; hence, the subscale ranges appear to reflect scores for 29 items instead of 28 items. | Week 14 (End of Treatment) | 
| Aberrant Behavior Checklist (ABC) | The ABC is a 58-item parent rated from 0 (not at all a problem) to 3 (the problem is severe in degree with 6 subscales: Irritability (includes agitation, aggression, and self-injury, 15 items) with range of scores from 0-45; Social Withdrawal/Lethargy (16 items) with range of scores from 0-48; Stereotypy (7 items) with range of scores from 0-21; Hyperactivity (16 items) with range of scores from 0-48; Inappropriate Speech (4 items) with range of scores from 0-12 and Social avoidance (4 items) with range of scores from 0-12. Higher scores indicated greater severity. Social Withdrawal and Lethargy are reporting the same scale and Social Avoidance is a subscale of Social Withdrawal; hence, the subscale ranges appear to reflect scores for 62 items instead of 58 items. | Week 14 (End of Treatment) | 
| Swanson, Nolan, and Pelham-IV Questionnaire (SNAP-IV) | The SNAP-IV is a revision of the Swanson, Nolan, and Pelham (SNAP) Questionnaire. The SNAP-IV: ADHD Inattention Subscale (items 1-9) scores the intensity of each item during the last seven days on a 0 to 3 scale (0=not at all, 1=just a little, 2=pretty much, 3=very much). Possible scores ranged from 0-27; higher scores indicated a greater intensity. The SNAP-IV ADHD Hyperactivity/Impulsivity Subscale (items 10-18) scores the intensity of each item in the last seven days on a 0 to 3 scale (0=not at all, 1=just a little, 2=pretty much, 3=very much). Possible scores ranged from 0-27; higher scores indicated a greater intensity. SNAP-IV ADHD Combined Scale score (inattention + hyperactivity/impulsivity) ranged from 0-54. A low score of 0 indicates less inattention + hyperactivity/impulsivity. A high score of 54 indicates more inattention + hyperactivity. | Week 14 (End of Treatment) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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fragile x syndrome, ganaxolone, anxiety, attention, pediatric