Neurophysiological and Acute Pharmacological Studies in FXS Patients

Sponsor
Children's Hospital Medical Center, Cincinnati (Other)
Overall Status
Completed
CT.gov ID
NCT02998151
Collaborator
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (NIH)
29
1
1
58
0.5

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

Study Type:
Interventional
Actual Enrollment :
29 participants
Allocation:
Randomized
Intervention Model:
Crossover Assignment
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.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.
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Basic Science
Official Title:
Neurophysiological and Acute Pharmacological Studies in FXS Patients
Study Start Date :
Jan 1, 2016
Actual Primary Completion Date :
Nov 1, 2020
Actual Study Completion Date :
Nov 1, 2020

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

  1. 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.

  2. 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

  1. 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).

  2. 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.

  3. 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

Ages Eligible for Study:
15 Years to 55 Years
Sexes Eligible for Study:
All
Accepts 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.

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.
Responsible Party:
Children's Hospital Medical Center, Cincinnati
ClinicalTrials.gov Identifier:
NCT02998151
Other Study ID Numbers:
  • CIN001 - {LAM}
  • U54HD082008
First Posted:
Dec 20, 2016
Last Update Posted:
Nov 26, 2021
Last Verified:
Nov 1, 2021
Studies a U.S. FDA-regulated Device Product:
No
Additional relevant MeSH terms:

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

1. Primary Outcome
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)
2. Primary Outcome
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)
3. Secondary Outcome
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)
4. Secondary Outcome
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)
5. Secondary Outcome
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

[Not Specified]

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
Email craig.erickson@cchmc.org
Responsible Party:
Children's Hospital Medical Center, Cincinnati
ClinicalTrials.gov Identifier:
NCT02998151
Other Study ID Numbers:
  • CIN001 - {LAM}
  • U54HD082008
First Posted:
Dec 20, 2016
Last Update Posted:
Nov 26, 2021
Last Verified:
Nov 1, 2021