Neurophysiological and Acute Pharmacological Studies in FXS Patients
Study Details
Study Description
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.
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
|
Early Phase 1 |
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Experimental: 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. |
Drug: Acamprosate
two 666mg pills
Drug: Lovastatin
two 20mg pills
Drug: Minocycline
two 135mg pills
Drug: Placebo
placebo pill
Drug: Baclofen
one 30mg pill
|
Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- 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.
Eligibility Criteria
Criteria
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.
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | Cincinnati Children's Hospital Medical Center | Cincinnati | Ohio | United States | 45229 |
Sponsors and Collaborators
- Children's Hospital Medical Center, Cincinnati
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Investigators
- Principal Investigator: Craig A Erickson, M.D., Children's Hospital Medical Center, Cincinnati
Study Documents (Full-Text)
More Information
Publications
None provided.- CIN001 - {LAM}
- U54HD082008
Study Results
Participant Flow
Recruitment Details | |
---|---|
Pre-assignment Detail | 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. |
Arm/Group Title | All Study Participants |
---|---|
Arm/Group 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 arm was replaced by baclofen. Remaining participants (n=13) received baclofen and 5 participants were re-enrolled to receive baclofen. |
Period Title: Overall Study | |
STARTED | 29 |
Placebo | 27 |
Acamprosate | 16 |
Lovastatin | 29 |
Minocycline | 27 |
Baclofen | 18 |
COMPLETED | 5 |
NOT COMPLETED | 24 |
Baseline Characteristics
Arm/Group Title | All Study Participants |
---|---|
Arm/Group Description | 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. |
Overall Participants | 29 |
Age (Count of Participants) | |
<=18 years |
0
0%
|
Between 18 and 65 years |
29
100%
|
>=65 years |
0
0%
|
Age (years) [Mean (Standard Deviation) ] | |
Mean (Standard Deviation) [years] |
24.71
(8.56)
|
Sex: Female, Male (Count of Participants) | |
Female |
9
31%
|
Male |
20
69%
|
Ethnicity (NIH/OMB) (Count of Participants) | |
Hispanic or Latino |
0
0%
|
Not Hispanic or Latino |
29
100%
|
Unknown or Not Reported |
0
0%
|
Race (NIH/OMB) (Count of Participants) | |
American Indian or Alaska Native |
0
0%
|
Asian |
0
0%
|
Native Hawaiian or Other Pacific Islander |
0
0%
|
Black or African American |
2
6.9%
|
White |
25
86.2%
|
More than one race |
1
3.4%
|
Unknown or Not Reported |
1
3.4%
|
Region of Enrollment (participants) [Number] | |
United States |
29
100%
|
Woodcock Johnson Test of Cognitive Abilities - Auditory Attention Task (scores on a scale) [Mean (Standard Deviation) ] | |
Mean (Standard Deviation) [scores on a scale] |
30.89
(4.92)
|
Outcome Measures
Title | Change in EEG Relative Gamma Power |
---|---|
Description | 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 |
Outcome Measure Data
Analysis Population Description |
---|
Missing 1 placebo, 1 lovastatin who contributed data with excessive movement or other artifact, or were unable to complete the task. |
Arm/Group Title | Placebo | Acamprosate | Lovastatin | Minocycline | Baclofen |
---|---|---|---|---|---|
Arm/Group Description | Placebo: placebo pill | Acamprosate: two 666mg pills | Lovastatin: two 20mg pills | Minocycline: two 135mg pills | Baclofen: one 30mg pill |
Measure Participants | 26 | 16 | 28 | 27 | 18 |
Mean (Standard Deviation) [percent of power in gamma frequencies] |
0.0024
(.0265)
|
-0.0077
(0.0252)
|
-0.0039
(0.0225)
|
0.0019
(0.0235)
|
-0.0160
(0.0346)
|
Title | Clinical Global Impressions-Improvement |
---|---|
Description | 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 |
Outcome Measure Data
Analysis Population Description |
---|
CGI-I was not collected for one participant on their minocycline day and another participant on their baclofen day. |
Arm/Group Title | Placebo | Acamprosate | Lovastatin | Minocycline | Baclofen |
---|---|---|---|---|---|
Arm/Group Description | Placebo: placebo pill | Acamprosate: two 666mg pills | Lovastatin: two 20mg pills | Minocycline: two 135mg pills | Baclofen: one 30mg pill |
Measure Participants | 27 | 16 | 29 | 26 | 17 |
Mean (Standard Deviation) [score on a scale] |
3.70
(.61)
|
3.88
(.62)
|
3.97
(.50)
|
3.81
(.49)
|
3.94
(.43)
|
Title | Woodcock Johnson Test of Cognitive Abilities - Auditory Attention Task |
---|---|
Description | 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 |
Outcome Measure Data
Analysis Population Description |
---|
Data is missing from 2 placebo, 1 acamprosate, 1 lovastatin, 2 minocycline, and 1 baclofen. |
Arm/Group Title | Placebo | Acamprosate | Lovastatin | Minocycline | Baclofen |
---|---|---|---|---|---|
Arm/Group Description | Placebo: placebo pill | Acamprosate: two 666mg pills | Lovastatin: two 20mg pills | Minocycline: two 135mg pills | Baclofen: one 30mg pill |
Measure Participants | 25 | 15 | 28 | 25 | 17 |
Mean (Standard Deviation) [score on a scale] |
32.84
(5.77)
|
33.07
(5.48)
|
32.93
(5.31)
|
33.24
(6.04)
|
33
(5.17)
|
Title | Change From Pre-dose in the Repeatable Battery for the Assessment of Neuropsychological Status at 4 Hours Post Dose |
---|---|
Description | 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 |
Outcome Measure Data
Analysis Population Description |
---|
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/Group Title | Placebo | Acamprosate | Lovastatin | Minocycline | Baclofen |
---|---|---|---|---|---|
Arm/Group Description | Placebo: placebo pill | Acamprosate: two 666mg pills | Lovastatin: two 20mg pills | Minocycline: two 135mg pills | Baclofen: one 30mg pill |
Measure Participants | 25 | 15 | 28 | 26 | 17 |
Mean (Standard Deviation) [number of words remembered] |
-.20
(4.23)
|
-1.47
(5.17)
|
-1.25
(3.85)
|
-.69
(5.58)
|
-.88
(3.35)
|
Title | Test of Attentional Performance for Children (KiTAP) Test of Alertness |
---|---|
Description | 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 |
Outcome Measure Data
Analysis Population Description |
---|
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/Group Title | Placebo | Acamprosate | Lovastatin | Minocycline | Baclofen |
---|---|---|---|---|---|
Arm/Group Description | Placebo: placebo pill | Acamprosate: two 666mg pills | Lovastatin: two 20mg pills | Minocycline: two 135mg pills | Baclofen: one 30mg pill |
Measure Participants | 25 | 14 | 27 | 26 | 18 |
Mean (Standard Deviation) [change in median RT in milliseconds] |
13.76
(188.37)
|
-28.64
(137.21)
|
18.59
(169.39)
|
26.85
(226.69)
|
-31.44
(171.91)
|
Adverse Events
Time Frame | Adverse events were collected up to four weeks after the final dosing visit. | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
Adverse Event Reporting Description | Participants were asked about adverse events in person 4 hours after each dose and at the end of each dosing visit, and via phone calls conducted one day after and 8 days after each dosing visit. Additionally, participants were contacted by phone 4 weeks after the final dosing visit. | |||||||||
Arm/Group Title | Placebo | Acamprosate | Lovastatin | Minocycline | Baclofen | |||||
Arm/Group Description | Placebo: placebo pill | Acamprosate: two 666mg pills | Lovastatin: two 20mg pills | Minocycline: two 135mg pills | Baclofen: one 30mg pill | |||||
All Cause Mortality |
||||||||||
Placebo | Acamprosate | Lovastatin | Minocycline | Baclofen | ||||||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 0/27 (0%) | 0/16 (0%) | 0/29 (0%) | 0/27 (0%) | 0/18 (0%) | |||||
Serious Adverse Events |
||||||||||
Placebo | Acamprosate | Lovastatin | Minocycline | Baclofen | ||||||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 0/27 (0%) | 0/16 (0%) | 0/29 (0%) | 0/27 (0%) | 0/18 (0%) | |||||
Other (Not Including Serious) Adverse Events |
||||||||||
Placebo | Acamprosate | Lovastatin | Minocycline | Baclofen | ||||||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 3/27 (11.1%) | 7/16 (43.8%) | 4/29 (13.8%) | 4/27 (14.8%) | 4/18 (22.2%) | |||||
Eye disorders | ||||||||||
Blurred vision | 0/27 (0%) | 0 | 1/16 (6.3%) | 1 | 0/29 (0%) | 0 | 0/27 (0%) | 0 | 0/18 (0%) | 0 |
Gastrointestinal disorders | ||||||||||
Nausea | 0/27 (0%) | 0 | 0/16 (0%) | 0 | 0/29 (0%) | 0 | 0/27 (0%) | 0 | 1/18 (5.6%) | 1 |
Stomach pain | 1/27 (3.7%) | 1 | 1/16 (6.3%) | 1 | 1/29 (3.4%) | 1 | 2/27 (7.4%) | 2 | 0/18 (0%) | 0 |
Diarrhea | 0/27 (0%) | 0 | 1/16 (6.3%) | 1 | 1/29 (3.4%) | 1 | 1/27 (3.7%) | 1 | 0/18 (0%) | 0 |
Nervous system disorders | ||||||||||
Headache | 0/27 (0%) | 0 | 3/16 (18.8%) | 3 | 0/29 (0%) | 0 | 3/27 (11.1%) | 3 | 0/18 (0%) | 0 |
Somnolence | 1/27 (3.7%) | 1 | 1/16 (6.3%) | 1 | 1/29 (3.4%) | 1 | 0/27 (0%) | 0 | 0/18 (0%) | 0 |
Psychiatric disorders | ||||||||||
Irritability | 0/27 (0%) | 0 | 1/16 (6.3%) | 1 | 1/29 (3.4%) | 1 | 0/27 (0%) | 0 | 2/18 (11.1%) | 2 |
Confusion | 0/27 (0%) | 0 | 1/16 (6.3%) | 1 | 0/29 (0%) | 0 | 0/27 (0%) | 0 | 0/18 (0%) | 0 |
Mania | 2/27 (7.4%) | 2 | 0/16 (0%) | 0 | 1/29 (3.4%) | 1 | 0/27 (0%) | 0 | 1/18 (5.6%) | 1 |
Respiratory, thoracic and mediastinal disorders | ||||||||||
Allergic rhinitis | 0/27 (0%) | 0 | 2/16 (12.5%) | 2 | 0/29 (0%) | 0 | 0/27 (0%) | 0 | 0/18 (0%) | 0 |
Sore throat | 0/27 (0%) | 0 | 0/16 (0%) | 0 | 0/29 (0%) | 0 | 0/27 (0%) | 0 | 1/18 (5.6%) | 1 |
Skin and subcutaneous tissue disorders | ||||||||||
Rash maculo-papular | 0/27 (0%) | 0 | 0/16 (0%) | 0 | 0/29 (0%) | 0 | 0/27 (0%) | 0 | 1/18 (5.6%) | 1 |
Limitations/Caveats
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.
Results Point of Contact
Name/Title | Dr. Craig Erickson |
---|---|
Organization | Cincinnati Children's Hospital Medical Center |
Phone | 513-636-0523 |
craig.erickson@cchmc.org |
- CIN001 - {LAM}
- U54HD082008