Treating Leg Symptoms in Women With X-linked Adrenoleukodystrophy

• ClinicalTrials.gov Identifier: NCT05003648
• Recruitment Status: Recruiting
• First Posted: August 12, 2021
• Last Update Posted: April 6, 2023
• Sponsor: Massachusetts General Hospital
• Collaborator: European Leukodystrophy Association
• Information provided by (Responsible Party): Florian Eichler, Massachusetts General Hospital

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Adrenoleukodystrophy; Restless Legs Syndrome	Drug: Pramipexole; Drug: Placebo	Phase 4

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 24 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Treating Leg Symptoms in Women With X-linked Adrenoleukodystrophy: A Key to Improving Sleep and Gait Performance
• Estimated Study Start Date: April 1, 2023
• Estimated Primary Completion Date: April 1, 2024
• Estimated Study Completion Date: November 1, 2024

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: Placebo; Participants will be on the placebo arm for 2 months and will then cross over to the pramipexole arm for 2 months	Drug: Placebo; Matching placebo
Active Comparator: Pramipexole; Participants will be on the pramipexole arm for 2 months and will then cross over to the placebo arm for 2 months	Drug: 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.

Outcome Measures

Primary Outcome Measures :

1. Change in the International Restless Legs Severity (IRLS) score [ Time Frame: pre-intervention, week 8, week 17 ]
   Change in IRLS score before and after pramipexole treatment. Scores range from 0 to 40, with higher scores representing more severe RLS symptoms.
2. Prevalence of Restless Leg Syndrome in Women with X-linked Adrenoleukodystrophy [ Time Frame: pre-intervention ]
   The prevalence of RLS in women with ALD will be assessed using the Hening Telephone Diagnostic Interview (HTDI), an objective tool to diagnose RLS.

Secondary Outcome Measures :

1. Change in the 36-Item Short Form Survey (SF-36) score [ Time Frame: pre-intervention, week 8, week 17 ]
   Change in SF-36 score before and after pramipexole treatment. Scores range from 0 to 100, with higher scores representing better quality of life.
2. Change in the Generalized Anxiety Disorder Assessment (GAD-7) score [ Time Frame: pre-intervention, week 8, week 17 ]
   Change in GAD-7 score before and after pramipexole treatment. Scores range from 0 to 21, with higher scores representing more severe levels of anxiety.
3. Change in the Patient Health Questionnaire (PHQ-9) score [ Time Frame: pre-intervention, week 8, week 17 ]
   Change in the PHQ-9 score before and after pramipexole treatment. Scores range from 0 to 27, with higher scores representing more severe depression.
4. Improvement in RLS symptoms measured by the Clinical Global Impression - Improvement (CGI-I) scale [ Time Frame: week 8 and week 17 ]
   Improvement in the patient's illness after pramipexole treatment as determined by the physician. Scores range from 1 (very much improved) to 7 (very much worse).
5. Change in the Expanded Disability Status Scale (EDSS) score [ Time Frame: pre-intervention, week 8, week 17 ]
   Change in EDSS score before and after pramipexole treatment. Scores range from 0 (no disability) to 10 (death).
6. Change in the Multiple Sclerosis Walking Scale (MSWS-12) score [ Time Frame: pre-intervention, week 8, week 17 ]
   Change in MSWS-12 score before and after pramipexole treatment. Scores range from 0 to 100, with higher scores representing more severe walking impairment.
7. Change in the Suggested Immobilization Test (SIT) [ Time Frame: pre-intervention, week 8, week 17 ]
   Change in the sensory and motor aspects of RLS before and after pramipexole treatment, assessed using the SIT.
8. Change in sleep/wake parameters measured by actigraphy [ Time Frame: pre-intervention, week 8, week 17 ]
   Change in sleep/wake parameters including Total Sleep time, Sleep Latency, and Wake after Sleep Onset before and after pramipexole treatment. Parameters will be objectively measured using wrist-worn actigraphy.
9. Change in the Utah Early Neuropathy Scale (UENS) score [ Time Frame: pre-intervention, week 8, week 17 ]
   Change in UENS score before and after pramipexole treatment. Scores range from 0 to 42, with higher scores representing more severe neuropathy.
10. Change in the Timed Up and Go (TUG) Test [ Time Frame: pre-intervention, week 8, week 17 ]
    Change in the amount of time it takes for the patient to get up from an armchair, walk 3 m, turn around, walk back, and sit down again before and after pramipexole treatment. Higher scores represent more severe balance impairment.
11. Change in the 6 Minute Walk (6MW) Test [ Time Frame: pre-intervention, week 8, week 17 ]
    Change in the maximum distance a patient can walk in 6 minutes before and after pramipexole treatment. Higher scores represent better walking ability.
12. Change in quality of sleep and leg movements per hour of sleep measured by Polysomnography [ Time Frame: pre-intervention, week 8, week 17 ]
    Change in quality of sleep and indices of periodic leg movements before and after pramipexole treatment. These variables will be assessed using Polysomongraphy and will be measured at the Boston site only.
13. Change in the 13-item Spasticity Screening Tool score [ Time Frame: pre-intervention, week 8, week 17 ]
    Change in the Spasticity Screening Tool before and after pramipexole treatment. Scores range from 0 to 52, with higher scores representing more severe spasticity symptoms.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Contacts

Contact: Natalie Grant; 6176433799; nrgrant@mgh.harvard.edu

Locations

United States, Massachusetts

Massachusetts General Hospital; Not yet recruiting

Boston, Massachusetts, United States, 02114

Contact: Natalie Grant 617-643-3799 nrgrant@mgh.harvard.edu

Principal Investigator: Florian S Eichler, MD

Netherlands

University Medical Center of Amsterdam; Recruiting

Amsterdam, Netherlands

Contact: Marc Engelen, MD, PhD +31-20-5667508 m.engelen@amsterdamumc.nl

Principal Investigator: Marc Engelen, MD, PhD

Sponsors and Collaborators

Massachusetts General Hospital

European Leukodystrophy Association

Investigators

• Principal Investigator: Florian S Eichler, MD; Massachusetts General Hospital

More Information

• Responsible Party: Florian Eichler, Associate Professor of Neurology, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT05003648
• Other Study ID Numbers: 2021P001543
• First Posted: August 12, 2021
• Last Update Posted: April 6, 2023
• Last Verified: April 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided
• Plan Description: De-identified data will be shared between the two collaborating sites (Massachusetts General Hospital and University Medical Center of Amsterdam). We do not currently have a plan to share this data with other researchers.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Restless Legs Syndrome; Adrenoleukodystrophy; Neurologic Manifestations; Nervous System Diseases; Neurobehavioral Manifestations; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Parasomnias; Mental Disorders; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Hereditary Central Nervous System Demyelinating Diseases; Leukoencephalopathies; Demyelinating Diseases; Mental Retardation, X-Linked; Intellectual Disability; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Heredodegenerative Disorders, Nervous System; Metabolism, Inborn Errors; Peroxisomal Disorders; Metabolic Diseases; Adrenal Insufficiency; Adrenal Gland Diseases; Endocrine System Diseases; Pramipexole; Antioxidants