Fragile x Syndrome
Conditions
Keywords
fragile x syndrome, ganaxolone, anxiety, attention, pediatric
Brief summary
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
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.
Interventions
DRUGGanaxolone
oral suspension, given in 3 divided doses
DRUGPlacebo
oral suspension, given in 3 divided doses
Sponsors
University of California, Davis
U.S. Army Medical Research and Development Command
Marinus Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
6 Years to 17 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Global Impression-Improvement (CGI-I) Scale | Week 14 (End of Treatment) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pediatric Anxiety Rating Scale (PARS) Total Score | Week 14 (End of Treatment) | 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. |
| Visual Analogue Scale (VAS) | Week 14 (End of Treatment) | 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. |
| Anxiety, Depression, and Mood Scale (ADAMS) | Week 14 (End of Treatment) | 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. |
| Aberrant Behavior Checklist (ABC) | Week 14 (End of Treatment) | 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. |
| Swanson, Nolan, and Pelham-IV Questionnaire (SNAP-IV) | Week 14 (End of Treatment) | 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. |
Countries
Belgium, United States
Participant flow
Recruitment details
A total of 48 participants from the University of California at Davis Medical Center site and 11 participants from a Belgium site between November 1, 2012 and November 1, 2016 were enrolled in the study.
Pre-assignment details
59 participants were randomized in the study.
Participants by arm
| Arm | Count |
|---|---|
| Ganaxolone, Then Placebo Participants received ganaxolone 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, they received placebo for a duration of 6 weeks (from week 8 to 14). | 30 |
| Placebo, Then Ganaxolone Participants received placebo 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, they received ganaxolone for a duration of 6 weeks (from week 8 to 14). | 29 |
| Total | 59 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Treatment Period 1 (Week 1 to Week 6) | Adverse Event | 3 | 0 |
| Treatment Period 1 (Week 1 to Week 6) | Consent Withdrawn | 1 | 0 |
| Treatment Period 2 (Week 8 to Week 14) | Adverse Event | 1 | 1 |
| Treatment Period 2 (Week 8 to Week 14) | Other | 0 | 2 |
Baseline characteristics
| Characteristic | Placebo, Then Ganaxolone | Total | Ganaxolone, Then Placebo |
|---|---|---|---|
| Age, Continuous | 11.33 Years STANDARD_DEVIATION 3.368 | 10.95 Years STANDARD_DEVIATION 3.299 | 10.58 Years STANDARD_DEVIATION 3.245 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 10 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 23 Participants | 48 Participants | 25 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 4 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 3 Participants | 5 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 23 Participants | 45 Participants | 22 Participants |
| Sex: Female, Male Female | 6 Participants | 9 Participants | 3 Participants |
| Sex: Female, Male Male | 23 Participants | 50 Participants | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 59 | 0 / 54 |
| other Total, other adverse events | 49 / 59 | 46 / 54 |
| serious Total, serious adverse events | 0 / 59 | 0 / 54 |
Outcome results
Primary
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.
Time frame: Week 14 (End of Treatment)
Population: Intention-to-Treat (ITT) Population consisted of all participants who received medication and who had at least one post-Baseline assessment. Only those participants with data available at the specified data points were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Ganaxolone | Clinical Global Impression-Improvement (CGI-I) Scale | 3.4 Scores on a scale | Standard Error 0.13 |
| Placebo | Clinical Global Impression-Improvement (CGI-I) Scale | 3.5 Scores on a scale | Standard Error 0.13 |
Comparison: Null hypothesis of no treatment difference in CGI-I will be assessed using a linear mixed-effects model for repeated measures, accounting for treatment (ganaxolone versus placebo) and period at a significant level of 0.05. A sample size of 30 participants in each arm/group was planned in the study will have 90% power to detect a modest effect size of 0.6 at level 0.05 in CGI-I. With a possible dropout rate of 15%, the power for testing the effect size becomes 84%.p-value: 0.4475Linear mixed-effect
Secondary
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.
Time frame: Week 14 (End of Treatment)
Population: ITT Population. Only those participants with data available at the specified data points were analyzed.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Ganaxolone | Aberrant Behavior Checklist (ABC) | Total - Subscale I (Irritability) | 15.7 Scores on a scale | Standard Error 0.87 |
| Ganaxolone | Aberrant Behavior Checklist (ABC) | Total - Subscale II (Social Withdrawal/Lethargy) | 5.6 Scores on a scale | Standard Error 0.53 |
| Ganaxolone | Aberrant Behavior Checklist (ABC) | Total - Subscale III - (Stereotypy) | 5.7 Scores on a scale | Standard Error 0.4 |
| Ganaxolone | Aberrant Behavior Checklist (ABC) | Total - Subscale IV (Hyperactivity) | 11.3 Scores on a scale | Standard Error 0.65 |
| Ganaxolone | Aberrant Behavior Checklist (ABC) | Total - Subscale V (Inappropriate Speech) | 5.1 Scores on a scale | Standard Error 0.32 |
| Ganaxolone | Aberrant Behavior Checklist (ABC) | Total - Subscale VI (Social Avoidance) | 2.4 Scores on a scale | Standard Error 0.22 |
| Placebo | Aberrant Behavior Checklist (ABC) | Total - Subscale V (Inappropriate Speech) | 5.3 Scores on a scale | Standard Error 0.31 |
| Placebo | Aberrant Behavior Checklist (ABC) | Total - Subscale I (Irritability) | 16.1 Scores on a scale | Standard Error 0.86 |
| Placebo | Aberrant Behavior Checklist (ABC) | Total - Subscale IV (Hyperactivity) | 12.3 Scores on a scale | Standard Error 0.62 |
| Placebo | Aberrant Behavior Checklist (ABC) | Total - Subscale II (Social Withdrawal/Lethargy) | 5.7 Scores on a scale | Standard Error 0.54 |
| Placebo | Aberrant Behavior Checklist (ABC) | Total - Subscale VI (Social Avoidance) | 2.8 Scores on a scale | Standard Error 0.21 |
| Placebo | Aberrant Behavior Checklist (ABC) | Total - Subscale III - (Stereotypy) | 6.4 Scores on a scale | Standard Error 0.39 |
Secondary
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.
Time frame: Week 14 (End of Treatment)
Population: ITT Population. Only those participants with data available at the specified data points were analyzed.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Ganaxolone | Anxiety, Depression, and Mood Scale (ADAMS) | Depress Mood Total | 3.5 Scores on a scale | Standard Error 0.32 |
| Ganaxolone | Anxiety, Depression, and Mood Scale (ADAMS) | General Anxiety Total | 6.2 Scores on a scale | Standard Error 0.45 |
| Ganaxolone | Anxiety, Depression, and Mood Scale (ADAMS) | Social Avoidance Total | 5.8 Scores on a scale | Standard Error 0.42 |
| Ganaxolone | Anxiety, Depression, and Mood Scale (ADAMS) | Obsessive/Compulsive Behavior Total | 2.7 Scores on a scale | Standard Error 0.21 |
| Ganaxolone | Anxiety, Depression, and Mood Scale (ADAMS) | Manic/Hyperactive Behavior Total | 7.4 Scores on a scale | Standard Error 0.42 |
| Placebo | Anxiety, Depression, and Mood Scale (ADAMS) | Obsessive/Compulsive Behavior Total | 2.8 Scores on a scale | Standard Error 0.2 |
| Placebo | Anxiety, Depression, and Mood Scale (ADAMS) | Manic/Hyperactive Behavior Total | 7.8 Scores on a scale | Standard Error 0.4 |
| Placebo | Anxiety, Depression, and Mood Scale (ADAMS) | Depress Mood Total | 2.6 Scores on a scale | Standard Error 0.32 |
| Placebo | Anxiety, Depression, and Mood Scale (ADAMS) | Social Avoidance Total | 6.3 Scores on a scale | Standard Error 0.41 |
| Placebo | Anxiety, Depression, and Mood Scale (ADAMS) | General Anxiety Total | 7.0 Scores on a scale | Standard Error 0.44 |
Secondary
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.
Time frame: Week 14 (End of Treatment)
Population: ITT Population. Only those participants with data available at the specified data points were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Ganaxolone | Pediatric Anxiety Rating Scale (PARS) Total Score | 8.3 Scores on a scale | Standard Error 0.54 |
| Placebo | Pediatric Anxiety Rating Scale (PARS) Total Score | 9.2 Scores on a scale | Standard Error 0.54 |
Secondary
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.
Time frame: Week 14 (End of Treatment)
Population: ITT Population. Only those participants with data available at the specified data points were analyzed.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Ganaxolone | Swanson, Nolan, and Pelham-IV Questionnaire (SNAP-IV) | ADHD Inattention | 15.5 Scores on a scale | Standard Error 0.66 |
| Ganaxolone | Swanson, Nolan, and Pelham-IV Questionnaire (SNAP-IV) | ADHD Hyperactivity/Impulsive | 13.9 Scores on a scale | Standard Error 0.66 |
| Ganaxolone | Swanson, Nolan, and Pelham-IV Questionnaire (SNAP-IV) | ADHD Combined | 29.3 Scores on a scale | Standard Error 1.19 |
| Placebo | Swanson, Nolan, and Pelham-IV Questionnaire (SNAP-IV) | ADHD Inattention | 14.6 Scores on a scale | Standard Error 0.62 |
| Placebo | Swanson, Nolan, and Pelham-IV Questionnaire (SNAP-IV) | ADHD Hyperactivity/Impulsive | 12.6 Scores on a scale | Standard Error 0.64 |
| Placebo | Swanson, Nolan, and Pelham-IV Questionnaire (SNAP-IV) | ADHD Combined | 27.1 Scores on a scale | Standard Error 1.14 |
Secondary
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.
Time frame: Week 14 (End of Treatment)
Population: ITT Population. Only those participants with data available at the specified data points were analyzed
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Ganaxolone | Visual Analogue Scale (VAS) | Severity of Anxiety | 5.6 Centimeters (cm) | Standard Error 0.27 |
| Ganaxolone | Visual Analogue Scale (VAS) | Severity of Attention | 4.4 Centimeters (cm) | Standard Error 0.24 |
| Ganaxolone | Visual Analogue Scale (VAS) | Severity of Target Behavior 3 | 4.4 Centimeters (cm) | Standard Error 0.28 |
| Placebo | Visual Analogue Scale (VAS) | Severity of Anxiety | 5.0 Centimeters (cm) | Standard Error 0.26 |
| Placebo | Visual Analogue Scale (VAS) | Severity of Attention | 3.9 Centimeters (cm) | Standard Error 0.24 |
| Placebo | Visual Analogue Scale (VAS) | Severity of Target Behavior 3 | 3.9 Centimeters (cm) | Standard Error 0.27 |