DORA-HD

A trial of daridorexant, a medication to treat insomnia, in Huntington's disease gene carriers with disturbed sleep.

Research summary

Huntington's disease (HD) is a rare genetic disease characterised by problems with movement, mood, and thinking/memory. In addition to these symptoms, around 90% of people with HD also have difficulty staying asleep during the night. Many HD gene carriers are not aware they have this problem.

A growing body of scientific evidence suggests that this insomnia might be, making some of symptoms of HD worse, and might even be accelerating the disease process itself. Alongside this, another body of scientific evidence suggests that treating this insomnia has the potential to improve these symptoms, or even slow down disease progression. However, this has not yet been formally tested in people with HD.

Until now, if has been difficult to test this theory, as traditional sleep therapies tend to include unhealthy sleep and come with problematic side effects. However, a new class of insomnia treatments (called 'DORAs') has now emerged. These work very differently from traditional 'sleeping pills', as they act by reducing wakefulness, rather than by increasing sleepiness. In large scale trails in healthy adults and people with Alzheimer's who also have insomnia, DORAs taken for years or more have been shown to increase healthy sleep, with very little in the way of side effects such as daytime sleepiness, and no withdrawal symptoms or dependence/addiction.

As a result of these trial, one DORA called daridorexant can now be prescribed for insomnia in the UK. However, it has not yet been specifically trialled in HD gene carriers.

We are, therefore conducting this trial primarily to access whether daridorexant is an effective and safe means of treating insomnia in HD gene carriers has any beneficial effect on memory and thinking processes, mood, quality of life, and the progression of HD.

If the trial is successful, this will form the basis of larger trials designed to further test the effect of daridorexant in people with HD.

Main inclusion criteria

  • Age ≥ and ≤ 75 years;
  • Prodromal or early HD, as indicated by:
  1. CAG repeat ≥ 38
  2. Unified Hintington's Disease Rating Scale (UHDRS) Diagnostic Confidence Level (DCL) ≥2 PLUS UHDRS total motor score (TMS) of ≥4 OR Symbol Digit Modalities Task (SDMT) score below norm for age and education as defined in Tabrizi et al. 2022;
  • Fluent English speaker;
  • Written informed consent;
  • For participants of child-bearing potential: negative serum pregnancy test at the screening visit;
  • Contraceptive requirements followed as outlined in the protocol;
  • Evidence of sleep maintenance insomnia, as indicated by wake after sleep onset (WASO) > 30 minutes on at least 2 of 4 nights of screening home polysomnography (PSG). 

Main exclusion criteria

  • Lacking capacity to consent (including Mini Mental State Examination Score (MMSE) < 24);
  • Untreated obstructive sleep apnoea, defined by known clinical diagnosis based on PSG, or STOPBANG questionnaire score ≥ 5;
  • History of or current substance abuse/addiction/dependence (including alcohol);
  • History of attempted suicide or suicidal ideation with plan (i.e., active suicidal ideation) that required hospital visit and/or change in level of care within 12 months prior to screening;
  • Current suicidal ideation, demonstrated by the Columbia-Suicide Severity Rating Scale (C-SSRS) as per judgment of the investigator;
  • Current moderate or severe depression, as defined by Beck Depression Inventory-ll (BDI-l) or Montgomery- Ăsberg Depression Rating Scale (MADRS) score > 20;
  • Other neurodegenerative comorbidity
  • Daytime napping ≥ 1 hour ≥ 3 times a week;
  • Diagnosis of narcolepsy, restless legs syndrome or rapid eye movement sleep (REM) behaviour sleep disorder;
  • Inability to avoid night work or nocturnal care responsibilities during trial period;
  • Inability to avoid travel > 2 time zones during 2 weeks prior to PSG assessment;
  • Average daily caffeine intake ≥ 800mg;
  • Current use of sedative medication (benzodiazepines, Z-drugs or sedating antihistamines) - not including antipsychotics or sedating antidepressants;
  • Current use of strong CYP3A4 inhibitor or strong inducer medication;
  • Current use of digoxin;
  • Diagnosis or evidence of severe hepatic impairment;
  • Pregnant or breastfeeding, or planning pregnancy within the trial period;
  • Inability to undergo/tolerate magnetic resonance imaging (MRI) (e.g. due to claustrophobia or other condition that precludes MRI scans), blood sampling or PSG;
  • Received daridorexant or any other investigational drug within 30 days prior to the screening visit;
  • Received a huntingtin-lowering investigational therapy within the last 12 months prior the screening visit;
  • Any other condition or lifestyle factor which, in the opinion of the investigator, makes the patient inappropriate for entry into the trial;
  • Hypersensitivity to daridorexant or to any other excipients listed in section 6.1 of the SmPC.

 

Chief investigator

Dr Zanna Voysey

Contact details

Clinical Trials Coordinators: George Pettitt, Emma Cutting

Email: [email protected]