Treating Leg Symptoms in Women with X-linked Adrenoleukodystrophy: A Key to Improving Sleep and Gait Performance

X-linked adrenoleukodystrophy (ALD) is a neurodegenerative disease that affects
both men and women (Moser et al, 2001). 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
[Engelen et al 2014, Habekost et al 2014]. Although both men and women develop
spinal cord disease, there are differences. Our longitudinal study of the
myelopathy in women revealed that the rate of progression over close to 8 years
was small and generally not perceived as clinically relevant (Huffnagel et al,
2019), prompting a search for alternative approaches to improve quality of life
in women with ALD. Recently was observed that women are more frequently
affected by movement disorders independent of the demyelinating brain disease
seen in men. In a pilot study performed by Eichler telephone interviews with 20
female adults with ALD and found that 8/20 had evidence of Restless Leg
Syndrome (RLS). Restless Legs Syndrome (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 (Trenkwalder et al., 2018).
These symptoms contribute to the primary morbidity of RLS which is severe sleep
disturbance, interfering with both falling and staying asleep as well as
overall sleep quality due to RLS sensory-motor symptoms and the presence of
periodic limb movements of sleep (PLMS) (Winkelman et al., 2009; Fulda, 2015).
The severe restlessness and sleep disturbance produce substantial acute
psychological distress. Both idiopathic and secondary RLS are independently
associated with substantial long-term detrimental effects on health, cognition,
quality of life, psychiatric morbidity and all-cause mortality (Winkelman et
al., 2009, Li et al., 2013, 2018, Kendzerska et al., 2017; Zhuang et al.,
2019).

This study has been transitioned to CTIS with ID 2024-518989-27-00 check the CTIS register for the current data.

Objective:
Primary Aim (PHASE 1):
To determine the prevalence of RLS in women with ALD.
Secondary Aim (PHASE 2):
To determine whether in a blinded crossover study a 8-week pramipexole
treatment course will significantly reduce RLS symptoms compared to placebo by
self-report (IRLS) and objective leg movement activity using the Suggested
Immobilization Test (SIT) in women with ALD.

Study design:
Phase 1: observational study
Phase 2: cross-over placebo controlled intervention study

Intervention (if applicable): Study medication: pramipexole or placebo
capsules, 0.125 mg
Day 0-7: 0.125 mg, QD
Day 7-14: 0.125 mg, QD or BID
Day 14-60: 0.125 mg QD, 0.125 mg BID or 0.125mg QID

Pramipexole may be effective in restless legs syndrome.
Pramipexole is a well-known drug and adverse events are well characterized.

The burden of participation includes:
Phase 1:
- Remote: pre-screening visit (V1)
- Remote: RLS diagnostic visit (V2)
- Remote: RLS severity visit (V3)
Phase 2, part 1:
- In person: Initation of blined placeco-controled crossover study (V4)
- Remote: Follow-up visits (V5-V7)
Phase 2, part 2:
- In person: Switch-over visit (V8)
neurological assessments, polysomnography, questionnaires
- Remote: Follow-up visits (V9-V11)
- In person: Final study visit (V12)

Patients also have complete an online sleep diary and for the last 7 days of
the study period actigraphy will be recorded in the home setting.