Treating Leg Symptoms in Women With X-linked Adrenoleukodystrophy

NCT ID: NCT05003648

Last Updated: 2024-04-03

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE4
• Total Enrollment: 24 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-04-01
• Study Completion Date: 2025-11-01

Brief Summary

The investigators recently observed that up to 25% of women with X-linked adrenoleukodystrophy (ALD) have moderate to severe Restless Leg Syndrome (RLS). In this study, the investigators aim to estimate the prevalence of RLS among women with ALD and to assess whether pramipexole improves RLS symptoms as well as sleep and gait measures in women with ALD.

Detailed Description

X-linked adrenoleukodystrophy (ALD) is a neurodegenerative disease caused by mutations in the ABCD1 peroxisomal half-transporter gene, resulting in accumulation of very long chain fatty acids (VLCFAs). As ALD is an X-linked disease, women were previously considered asymptomatic carriers. It is now known that even though adrenal insufficiency and cerebral disease occur in less than 1% of women, more than 80% eventually develop progressive spinal cord disease. Recently, the investigators observed that women are more frequently affected by movement disorders independent of the demyelinating brain disease seen in men. In a pilot study, the investigators found that up to 25% of women with ALD have moderate to severe Restless Leg Syndrome (RLS). RLS is a movement disorder characterized by a powerful urge to move the legs, usually accompanied by unpleasant dysesthesias, that is precipitated by rest, relieved by movement, and most pronounced in the evening or at night. Dopamine agonists such as pramipexole are efficacious and first-line FDA-approved treatments in low doses for primary (i.e., idiopathic) RLS and have been shown to improve both the primary symptoms of RLS (sensory discomfort, motor restlessness) as well as the associated sleep and quality of life impairments in RLS.

In the first phase of the study, the investigators will enroll 100 women with ALD at the two participating sites (Massachusetts General Hospital and University Medical Center Amsterdam). Participants will undergo structured phone interviews with both an expert in ALD and RLS to assess the presence of probable or definite RLS. Participants with probable or definite RLS will then undergo an additional phone call to determine RLS severity and assess eligibility for the second phase of the study. The objective of the first phase of the study is to determine the prevalence of RLS in women with ALD.

The second phase of the study will consist of a 4-month randomized, double-blind, placebo-controlled cross over study to assess whether pramipexole improves RLS symptoms as well as sleep and gait measures in women with ALD. The investigators will enroll 24 women with ALD and moderate to severe RLS. Participants will first be randomized 1:1 to 0.125-0.5 mg pramipexole or placebo. After the first two months, a switch-over visit will take place and include a battery of neurological assessments, walking measures, polysomnography, and questionnaires. At this visit, the crossover from pramipexole to placebo and from placebo to pramipexole will occur. The final study visit will occur 2 months after the switch-over visit and all study assessments will be repeated.

Conditions

Adrenoleukodystrophy; Restless Legs Syndrome

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Placebo

Participants will be on the placebo arm for 2 months and will then cross over to the pramipexole arm for 2 months

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Matching placebo

Pramipexole

Participants will be on the pramipexole arm for 2 months and will then cross over to the placebo arm for 2 months

Group Type: ACTIVE_COMPARATOR

Pramipexole

Intervention Type: DRUG

Participants will be started on 0.125 mg pramipexole for the first week. If this dose is well tolerated but not effective, the dose can be increased to 0.25 mg for the following week. If this dose is well tolerated but not effective, the dose can be further increased to 0.5 mg for the remainder of the 2-month period.

Interventions

Pramipexole

Participants will be started on 0.125 mg pramipexole for the first week. If this dose is well tolerated but not effective, the dose can be increased to 0.25 mg for the following week. If this dose is well tolerated but not effective, the dose can be further increased to 0.5 mg for the remainder of the 2-month period.

Intervention Type: DRUG

Placebo

Matching placebo

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Women of any ethnic origin.

2. Ability to provide verbal consent

3. A willingness and ability to comply with study procedures.

4. Age 18-75 years

5. Metabolically or genetically confirmed diagnosis of ALD

1. Participation in Phase 1

2. Ability to provide written informed consent

3. Women with ALD who have Restless Leg Syndrome (IRLS > 15)

Exclusion Criteria

1. Inflammatory brain demyelination

PHASE 2 (CROSS-OVER STUDY)

1. Pregnant. Research staff perform pregnancy tests upon visit to center.

2. Participants with active or unstable major psychiatric disorder other than ALD, who, in the investigators' judgement, require further treatment

3. Use of dopaminergic agonists or antagonists within the last 30 days

4. Alcohol use disorder within the last 30 days

5. History of being treated for restless legs syndrome, specifically with dopamine agonist medications

6. Methamphetamine or benzodiazepine dependence in the last 30 days

7. Neurological disorder or cardiovascular disease raising safety concerns about use of pramipexole and/or judged to interfere with ability to assess efficacy of the treatment

8. Medical instability considered to interfere with study procedures

9. Renal disease judged to interfere with drug metabolism and excretion

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

European Leukodystrophy Association

OTHER

Sponsor Role: collaborator

Massachusetts General Hospital

OTHER

Sponsor Role: lead

Responsible Party

Florian Eichler

Associate Professor of Neurology

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Florian S Eichler, MD

Role: PRINCIPAL_INVESTIGATOR

Massachusetts General Hospital

Locations

Massachusetts General Hospital

Boston, Massachusetts, United States

Site Status: RECRUITING

University Medical Center of Amsterdam

Amsterdam, , Netherlands

Site Status: RECRUITING

Countries

United States; Netherlands

Central Contacts

Riya Saxena

Role: CONTACT

rsaxena2@mgh.harvard.edu

603-674-6743

Facility Contacts

Riya Saxena

Role: primary

rsaxena2@mgh.harvard.edu

603-674-6743

Marc Engelen, MD, PhD

Role: primary

m.engelen@amsterdamumc.nl

+31-20-5667508

Other Identifiers

2021P001543

Identifier Type: -

Identifier Source: org_study_id