Treating Leg Symptoms in Women With X-linked Adrenoleukodystrophy

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Brief Title

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

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.
    

Study Phase

Phase 4

Study Type

Interventional


Primary Outcome

Change in the International Restless Legs Severity (IRLS) score

Secondary Outcome

 Change in the 36-Item Short Form Survey (SF-36) score

Condition

Adrenoleukodystrophy

Intervention

Pramipexole

Study Arms / Comparison Groups

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

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

24

Start Date

September 2021

Completion Date

April 2022

Primary Completion Date

March 2022

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
      

Gender

Female

Ages

18 Years - 75 Years

Accepts Healthy Volunteers

No

Contacts

Florian S Eichler, MD, 6176433799, [email protected]

Location Countries

Netherlands

Location Countries

Netherlands

Administrative Informations


NCT ID

NCT05003648

Organization ID

2021P001543


Responsible Party

Principal Investigator

Study Sponsor

Massachusetts General Hospital

Collaborators

 European Leukodystrophy Association

Study Sponsor

Florian S Eichler, MD, Principal Investigator, Massachusetts General Hospital


Verification Date

August 2021