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

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).

Study Overview

• Status: Completed
• Conditions: Fragile X-associated Tremor/Ataxia Syndrome
• Intervention / Treatment: Drug: Allopregnanolone

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Sacramento, California, United States, 95817
      • UC Davis MIND Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Allopregnanolone; 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; 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.; Other Names: 5α-pregnan-3α-ol-20-one; 3α,5α-tetrahydroprogesterone; brexanolone

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Randi J. Hagerman, MD
• Investigators: Principal Investigator: Randi J Hagerman, MD, UC Davis MIND Institute

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2015
• Primary Completion (Actual): December 1, 2016
• Study Completion (Actual): December 1, 2017

Study Registration Dates

• First Submitted: November 5, 2015
• First Submitted That Met QC Criteria: November 10, 2015
• First Posted (Estimate): November 13, 2015

Study Record Updates

• Last Update Posted (Actual): December 6, 2018
• Last Update Submitted That Met QC Criteria: November 13, 2018
• Last Verified: November 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Disease; Dyskinesias; Cerebellar Diseases; Syndrome; Ataxia; Tremor; Cerebellar Ataxia; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Anesthetics; GABA Modulators; GABA Agents; Neurosteroids; Brexanolone; Pregnanolone
• Other Study ID Numbers: 720668

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes