Clinical trial NCT05003648: Treating Leg Symptoms in Women With X-linked Adrenoleukodystrophy
Official title: Treating Leg Symptoms in Women With X-linked Adrenoleukodystrophy: A Key to Improving Sleep and Gait Performance
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Adrenoleukodystrophy
Restless Legs Syndrome
Lead sponsor: Massachusetts General Hospital
Sponsor class: OTHER
Collaborators: name: European Leukodystrophy Association
First posted: 2021-08-12
Enrollment: 24
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

Eligibility criteria: PHASE 1 (PREVALENCE STUDY)

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

Exclusion Criteria:

1. Inflammatory brain demyelination

PHASE 2 (CROSS-OVER STUDY)

Inclusion Criteria:

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. 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

Primary outcomes:
measure: Change in the International Restless Legs Severity (IRLS) score
timeFrame: pre-intervention, week 8, week 17
measure: Prevalence of Restless Leg Syndrome in Women with X-linked Adrenoleukodystrophy
timeFrame: pre-intervention
Secondary outcomes:
measure: Change in the 36-Item Short Form Survey (SF-36) score
timeFrame: pre-intervention, week 8, week 17
measure: Change in the Generalized Anxiety Disorder Assessment (GAD-7) score
timeFrame: pre-intervention, week 8, week 17
measure: Change in the Patient Health Questionnaire (PHQ-9) score
timeFrame: pre-intervention, week 8, week 17
measure: Improvement in RLS symptoms measured by the Clinical Global Impression - Improvement (CGI-I) scale
timeFrame: week 8 and week 17
measure: Change in the Expanded Disability Status Scale (EDSS) score
timeFrame: pre-intervention, week 8, week 17
measure: Change in the Multiple Sclerosis Walking Scale (MSWS-12) score
timeFrame: pre-intervention, week 8, week 17
measure: Change in the Suggested Immobilization Test (SIT)
timeFrame: pre-intervention, week 8, week 17
measure: Change in sleep/wake parameters measured by actigraphy
timeFrame: pre-intervention, week 8, week 17
measure: Change in the Utah Early Neuropathy Scale (UENS) score
timeFrame: pre-intervention, week 8, week 17
measure: Change in the Timed Up and Go (TUG) Test
timeFrame: pre-intervention, week 8, week 17
measure: Change in the 6 Minute Walk (6MW) Test
timeFrame: pre-intervention, week 8, week 17
measure: Change in quality of sleep and leg movements per hour of sleep measured by Polysomnography
timeFrame: pre-intervention, week 8, week 17
measure: Change in the 13-item Spasticity Screening Tool score
timeFrame: pre-intervention, week 8, week 17
Other outcomes:
Locations:
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Amsterdam
country: Netherlands
facility: University Medical Center of Amsterdam
Study officials:
affiliation: Massachusetts General Hospital
name: Florian S Eichler, MD
role: PRINCIPAL_INVESTIGATOR
References: