Treatment of Fragile-X Associated Tremor/Ataxia Syndrome (FXTAS) With Allopregnanolone

Study Overview
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Brief Summary
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The purpose of this study is to examine the safety and efficacy of Allopregnanolone as a possible treatment for symptoms of Fragile X-associated Tremor/Ataxia Syndrome (FXTAS).

Detailed Description
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This study includes a screening visit with several assessments, followed by an open-label medication trial of Allopregnanolone for 12 weeks and an end-point evaluation to assess for changes. Assessments include blood draws for genetic and safety laboratory testing, neurological and physical exam and medical history, cognitive testing, and motor testing. Study record was updated in October 2018 to include adverse events and outcome measure reporting. Study record was updated in November 2018 in response to requests to (1) specify time frame of reported outcome measures, (2) clarify that the RASS was a safety monitoring tool, not a prespecified outcome measure, and as such will not be reported as an outcome measure, and (3) upload a version of the study protocol and statistical analysis plan with the required title page and statistical analysis plan information.

Official Title
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Treatment of Fragile-X Associated Tremor/Ataxia Syndrome (FXTAS) With Allopregnanolone

Conditions
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Fragile X-associated Tremor/Ataxia Syndrome

Intervention / Treatment
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* Drug: Allopregnanolone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Fragile X premutation carrier status (55 to 200 CGG repeats in FMR1), Diagnosis of FXTAS including an intention tremor and/or ataxia and/or deficits on the BDS-2 demonstrating executive function deficits. Exclusion Criteria other genetic problems in addition to the premutation a history of significant brain trauma significant substance abuse inability to follow the protocol liver or kidney disease heart failure active cancer other serious systemic disease current use of phenytoin

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 85 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Allopregnanolone<br>Subjects will receive an intravenous infusion of Allopregnanolone at escalating doses of 2mg, 4mg, and 6mg once weekly over a three week period. The highest dose tolerated without sedation will be held stable for the remaining weekly infusions, for a total of 12 infusions. | Drug: Allopregnanolone<br>* Allopregnanolone is an endogenous inhibitory pregnane neurosteroid. It is synthesized from progesterone, and is a potent positive allosteric modulator of the action of γ-aminobutyric acid at GABAA receptor. Subjects will receive up to 12 infusions in the study. Subjects will all begin with 2.0 mg dosage. If tolerated, the next infusion will be 4.0 mg, and if that is tolerated, the next infusion will be 6.0 mg. Subject infusions will remain stable at the highest dosage tolerated for the remainder of the study. Each infusion will consist of 2.0 mg, 4.0 mg, or 6.0 mg aliquots of the 0.5 mg/ml allopregnanolone in 6% sulfobutylether-β-cyclodextrin with 0.9% sodium chloride injection solution.<br>* Other names: brexanolone;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| California Verbal Learning Test II (CVLT2) Trial 1-5 Free Recall Total Raw Score | California Verbal Learning Test II (CVLT2) is an assessment measuring working memory. Trials 1-5 measure the total number of words remembered after 5 repeated trials and are summed to generate a raw score (called Trial 1-5 Free Recall Total Raw Score) ranging from 0 to 80, with higher scores reflecting better working memory. Mean and standard deviation for raw score at baseline/pre-treatment and at 14 weeks/post-treatment are presented here. | Baseline/pre-treatment and 14 weeks/post-treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Behavioral Dyscontrol Scale - 2 (BDS-2) Total Score | The BDS-2 is a validated 9-item assessment measuring the ability to regulate purposeful, goal-directed activity and to engage in activities of daily living, with focus on motor items. Each of the 9 items is scored on a scale of 0 to 3, resulting in a summed total score ranging from 0 to 27. Higher scores reflect fewer errors and stronger ability to regulate motor activities. Mean and standard deviation for total score at baseline/pre-treatment and at 14 weeks/post-treatment are presented here. | Baseline/pre-treatment and 14 weeks/post-treatment | 
| CATSYS Dot-to-Dot Tremor Intensity (CATSYS DTD TI) | The CATSYS system is a portable device recording various measures of neuromotor control, including tremor. The CATSYS Dot-to-Dot Tremor Intensity (DTD TI) protocol quantifies tremor by having a participant hold a tremor pen as they would an ordinary pen, with the elbow joint bent at a right angle and free of body contact, and the pen positioned approximately 4 inches from the navel. Subjects are instructed to use the pen first to tap the center of two circular stickers, approximately 0.5 inch in diameter, placed on opposite ends of the bottom portion of the computer monitor; then, subjects are instructed to trace a line across the table using the tremor pen. The pen is connected to a computer with sensors that measure tremor intensity (TI) in units of meters per second (m/s). Larger values reflect greater tremor intensity. Mean right-hand and left-hand TI and standard deviation at baseline/pre-treatment and at 14 weeks/post-treatment are reported here. | Baseline/pre-treatment and 14 weeks/post-treatment | 
| Hippocampal Volume, as Measured by Structural MRI | Patients will undergo structural Magnetic Resonance Imaging (MRI) at baseline/pre-treatment and at 14 weeks/post-treatment. The MRI is interpreted by a trained clinician and hippocampal volume in cubic centimeters is measured and recorded. Larger values reflect greater volumes of the hippocampus, and greater hippocampal volume post-treatment may be indicative of increased neurogenesis. Mean hippocampal volume and standard deviation at baseline/pre-treatment and post-treatment is reported here. | Baseline/pre-treatment and 14 weeks/post-treatment |