Fragile X Syndrome
Conditions
Brief summary
The aim of this study is to utilize neurophysiologic assessments, behavioral measures and clinical measures to assess how much deficits associated with Fragile X Syndrome from pre-dose to post-dose using pharmacology.
Interventions
DRUGAcamprosate
two 666mg pills
DRUGLovastatin
two 20mg pills
DRUGMinocycline
two 135mg pills
DRUGPlacebo
placebo pill
DRUGBaclofen
one 30mg pill
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Children's Hospital Medical Center, Cincinnati
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
This study was designed as a 4-intervention crossover, with all study participants receiving all possible interventions. These were originally placebo, acamprosate, minocycline, and lovastatin. Midway through the study (n=16) it was determined that acamprosate was undetectable in serum and this intervention was replaced by baclofen. Remaining participants (n=13) received baclofen and 5 participants were re-enrolled to receive baclofen or a second round of placebo, so investigators and participants would remain blinded to drug status during the baclofen visit. The second round of placebo was not analyzed.
Eligibility
Sex/Gender
ALL
Age
15 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
* Subjects ages 15-55, with fragile X syndrome (FXS) who completed the study entitled Mechanisms and brain circuits underlying fragile X syndrome (IRB # 2015-8425). FXS is defined as full FMR1 mutations (\>200 CGG repeats) confirmed by genetic testing. * General good health as determined by physical exam, medical history and laboratory work up.
Exclusion criteria
* Subjects with a history of intolerance to acamprosate, lovastatin, or minocycline will be excluded. * Subjects will also be excluded if they have taken any investigational drug within 3 months, have a history of substance abuse or dependence within 6 months, or significant psychiatric or central nervous system neurological disease unrelated to FXS. * Uncontrolled seizures impact EEG data as do anticonvulsants, barbiturates, lithium and benzodiazepines and are exclusions (within 5 half-lives). Those taking other psychiatric medications must be on stable doses for 4 weeks before any testing. * For female subjects of child bearing potential, a positive urine pregnancy test. * Potential subjects with a creatinine clearance \< 50 mL/min will be excluded. * Identified medical issues, inability to tolerate study procedures or study drug per the discretion of the Principal Investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in EEG Relative Gamma Power | Pre-dose, 4-hour post-dose | EEG relative gamma power at rest was calculated as the percent of power in the gamma frequencies relative to the sum of power in all frequency bands, averaged across electrodes, and calculated separately at pre-dose and post-dose timepoints. To assess the impact of drug, the pre-dose relative gamma power was subtracted from post-dose relative gamma power. Higher numbers indicate more relative gamma power post-dose; lower numbers indicate more relative gamma power pre-dose. |
| Clinical Global Impressions-Improvement | 4-hour post-dose | The Clinical Global Impressions - Improvement (CGI-I) requires the clinician to assess how much the patient's illness has changed relative to pre-dose, from 1 (very much improved) to 7 (very much worse). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Woodcock Johnson Test of Cognitive Abilities - Auditory Attention Task | 4-hour post-dose | Woodcock Johnson Test of Cognitive Abilities III Auditory Attention subscale. Participants must identify orally presented words amid increasingly intense background noise. The scores for this subtask range from 0-50, with higher scores indicating a better outcome. Raw scores for this subscale are reported (rather than standard scores, or age- or grade-equivalents). |
| Change From Pre-dose in the Repeatable Battery for the Assessment of Neuropsychological Status at 4 Hours Post Dose | Pre-dose, 4-hour post dose | Four 10-item lists of unrelated words were presented orally to the examinee who was then required to immediately recall words presented, at both pre-dose and post-dose timepoints. The impact of drug was assessed by subtracting the number of words remembered post-dose from the number of words remembered pre-dose. Lower numbers indicate more words remembered post-dose; higher numbers indicate more words remembered pre-dose. |
| Test of Attentional Performance for Children (KiTAP) Test of Alertness | Predose, 4-hour post-dose | Computerized task where an examinee is required to push a key when a target stimulus is presented on the screen. Scores are presented as change in median reaction time (RT), in milliseconds. |
Countries
United States
Participant flow
Pre-assignment details
Participants engaged in a baseline visit to gather preliminary data and ensure study compliance. Participants were then randomly assigned to different sequences for receiving acamprosate, lovastatin, minocycline, baclofen, and placebo. There was a 2-week washout period between visits.
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants Participants received, in random order, a single dose of placebo, acamprosate, lovastatin, minocycline, or baclofen, with a two-week washout period between doses. Midway through the study (n=16) it was determined that acamprosate was undetectable in serum and this intervention was replaced by baclofen. Remaining participants (n=13) received baclofen and 5 participants were re-enrolled to receive baclofen or a second round of placebo, so investigators and participants would remain blinded to drug status during the baclofen visit. The second round of placebo was not analyzed. | 29 |
| Total | 29 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Participant declined to re-enroll for baclofen | 8 |
| Overall Study | Participant was not offered acamprosate; acamprosate was discontinued and replaced with baclofen | 13 |
| Overall Study | Withdrawal by Subject | 3 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 29 Participants |
| Age, Continuous | 24.71 years STANDARD_DEVIATION 8.56 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 29 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 25 Participants |
| Region of Enrollment United States | 29 participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 20 Participants |
| Woodcock Johnson Test of Cognitive Abilities - Auditory Attention Task | 30.89 scores on a scale STANDARD_DEVIATION 4.92 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 27 | 0 / 16 | 0 / 29 | 0 / 27 | 0 / 18 |
| other Total, other adverse events | 3 / 27 | 7 / 16 | 4 / 29 | 4 / 27 | 4 / 18 |
| serious Total, serious adverse events | 0 / 27 | 0 / 16 | 0 / 29 | 0 / 27 | 0 / 18 |
Outcome results
Primary
Change in EEG Relative Gamma Power
EEG relative gamma power at rest was calculated as the percent of power in the gamma frequencies relative to the sum of power in all frequency bands, averaged across electrodes, and calculated separately at pre-dose and post-dose timepoints. To assess the impact of drug, the pre-dose relative gamma power was subtracted from post-dose relative gamma power. Higher numbers indicate more relative gamma power post-dose; lower numbers indicate more relative gamma power pre-dose.
Time frame: Pre-dose, 4-hour post-dose
Population: Missing 1 placebo, 1 lovastatin who contributed data with excessive movement or other artifact, or were unable to complete the task.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in EEG Relative Gamma Power | 0.0024 percent of power in gamma frequencies | Standard Deviation 0.0265 |
| Acamprosate | Change in EEG Relative Gamma Power | -0.0077 percent of power in gamma frequencies | Standard Deviation 0.0252 |
| Lovastatin | Change in EEG Relative Gamma Power | -0.0039 percent of power in gamma frequencies | Standard Deviation 0.0225 |
| Minocycline | Change in EEG Relative Gamma Power | 0.0019 percent of power in gamma frequencies | Standard Deviation 0.0235 |
| Baclofen | Change in EEG Relative Gamma Power | -0.0160 percent of power in gamma frequencies | Standard Deviation 0.0346 |
Primary
Clinical Global Impressions-Improvement
The Clinical Global Impressions - Improvement (CGI-I) requires the clinician to assess how much the patient's illness has changed relative to pre-dose, from 1 (very much improved) to 7 (very much worse).
Time frame: 4-hour post-dose
Population: CGI-I was not collected for one participant on their minocycline day and another participant on their baclofen day.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Clinical Global Impressions-Improvement | 3.70 score on a scale | Standard Deviation 0.61 |
| Acamprosate | Clinical Global Impressions-Improvement | 3.88 score on a scale | Standard Deviation 0.62 |
| Lovastatin | Clinical Global Impressions-Improvement | 3.97 score on a scale | Standard Deviation 0.5 |
| Minocycline | Clinical Global Impressions-Improvement | 3.81 score on a scale | Standard Deviation 0.49 |
| Baclofen | Clinical Global Impressions-Improvement | 3.94 score on a scale | Standard Deviation 0.43 |
Secondary
Change From Pre-dose in the Repeatable Battery for the Assessment of Neuropsychological Status at 4 Hours Post Dose
Four 10-item lists of unrelated words were presented orally to the examinee who was then required to immediately recall words presented, at both pre-dose and post-dose timepoints. The impact of drug was assessed by subtracting the number of words remembered post-dose from the number of words remembered pre-dose. Lower numbers indicate more words remembered post-dose; higher numbers indicate more words remembered pre-dose.
Time frame: Pre-dose, 4-hour post dose
Population: One participant is missing from placebo, acamprosate, lovastatin, and minocycline conditions due to being unable to repeat list words back to experimenter (nonverbal). Baclofen and placebo are each additionally missing one participant who did not complete the pre-dose or post-dose task.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Pre-dose in the Repeatable Battery for the Assessment of Neuropsychological Status at 4 Hours Post Dose | -.20 number of words remembered | Standard Deviation 4.23 |
| Acamprosate | Change From Pre-dose in the Repeatable Battery for the Assessment of Neuropsychological Status at 4 Hours Post Dose | -1.47 number of words remembered | Standard Deviation 5.17 |
| Lovastatin | Change From Pre-dose in the Repeatable Battery for the Assessment of Neuropsychological Status at 4 Hours Post Dose | -1.25 number of words remembered | Standard Deviation 3.85 |
| Minocycline | Change From Pre-dose in the Repeatable Battery for the Assessment of Neuropsychological Status at 4 Hours Post Dose | -.69 number of words remembered | Standard Deviation 5.58 |
| Baclofen | Change From Pre-dose in the Repeatable Battery for the Assessment of Neuropsychological Status at 4 Hours Post Dose | -.88 number of words remembered | Standard Deviation 3.35 |
Secondary
Test of Attentional Performance for Children (KiTAP) Test of Alertness
Computerized task where an examinee is required to push a key when a target stimulus is presented on the screen. Scores are presented as change in median reaction time (RT), in milliseconds.
Time frame: Predose, 4-hour post-dose
Population: One participant is missing from the placebo, acamprosate, lovastatin, and minocycline conditions due to being unable to participate in the task. An additional one participant each is missing from placebo, acamprosate, and lovastatin conditions due to uncollected data at either the pre-dose or post-dose timepoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Test of Attentional Performance for Children (KiTAP) Test of Alertness | 13.76 change in median RT in milliseconds | Standard Deviation 188.37 |
| Acamprosate | Test of Attentional Performance for Children (KiTAP) Test of Alertness | -28.64 change in median RT in milliseconds | Standard Deviation 137.21 |
| Lovastatin | Test of Attentional Performance for Children (KiTAP) Test of Alertness | 18.59 change in median RT in milliseconds | Standard Deviation 169.39 |
| Minocycline | Test of Attentional Performance for Children (KiTAP) Test of Alertness | 26.85 change in median RT in milliseconds | Standard Deviation 226.69 |
| Baclofen | Test of Attentional Performance for Children (KiTAP) Test of Alertness | -31.44 change in median RT in milliseconds | Standard Deviation 171.91 |
Secondary
Woodcock Johnson Test of Cognitive Abilities - Auditory Attention Task
Woodcock Johnson Test of Cognitive Abilities III Auditory Attention subscale. Participants must identify orally presented words amid increasingly intense background noise. The scores for this subtask range from 0-50, with higher scores indicating a better outcome. Raw scores for this subscale are reported (rather than standard scores, or age- or grade-equivalents).
Time frame: 4-hour post-dose
Population: Data is missing from 2 placebo, 1 acamprosate, 1 lovastatin, 2 minocycline, and 1 baclofen.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Woodcock Johnson Test of Cognitive Abilities - Auditory Attention Task | 32.84 score on a scale | Standard Deviation 5.77 |
| Acamprosate | Woodcock Johnson Test of Cognitive Abilities - Auditory Attention Task | 33.07 score on a scale | Standard Deviation 5.48 |
| Lovastatin | Woodcock Johnson Test of Cognitive Abilities - Auditory Attention Task | 32.93 score on a scale | Standard Deviation 5.31 |
| Minocycline | Woodcock Johnson Test of Cognitive Abilities - Auditory Attention Task | 33.24 score on a scale | Standard Deviation 6.04 |
| Baclofen | Woodcock Johnson Test of Cognitive Abilities - Auditory Attention Task | 33 score on a scale | Standard Deviation 5.17 |