Insomnia, Restless Legs Syndrome, Sleep Disorder
Conditions
Keywords
Suvorexant
Brief summary
The investigators aim to determine the effect of suvorexant on actigraphically-derived total sleep time in patients with effectively treated restless legs syndrome with persistent insomnia in a two-arm, double-blind, randomized placebo-controlled crossover 2.5-month trial.
Detailed description
Restless Legs Syndrome (RLS) is a sensory-motor neurological disorder characterized by an irresistible urge to move the legs. Persistent difficulties with all phases of sleep are common in patients whose RLS symptoms are resolved with treatment. Multiple potential causes for treatment-refractory sleep disturbance exist, including activating effects of dopamine agonists (which are first-line RLS treatments), conditioned insomnia and poor sleep habits as a result of chronic RLS-related sleep disturbance, and comorbid medical and psychiatric illness. Suvorexant provides an important therapeutic option to treat insomnia in the context of RLS. It has demonstrated long-term efficacy, particularly in shortening the duration of nocturnal awakenings and increasing total sleep time. Similarly, it has a comparatively benign side effect profile compared to many other agents typically prescribed to treat insomnia. The investigators aim to determine the effect of suvorexant on actigraphically-derived total sleep time, as well as actigraphically-derived wake after sleep onset, Insomnia Severity Index score, subjective sleep endpoints, and RLS symptom severity.
Interventions
DRUGSuvorexant
10-mg or 20-mg suvorexant capsules
OTHERPlacebo
Matching placebo capsules
Sponsors
Massachusetts General Hospital
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
The participant, investigator, and clinical research coordinator will remain masked throughout the duration of the study.
Intervention model description
Subjects will be randomized in a 1:1 ratio to suvorexant 10-20 mg or equivalent placebo for four weeks followed by crossover (after a 2-week washout) to the alternate treatment.
Eligibility
Sex/Gender
ALL
Age
25 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
1. Men or women of any ethnic origin 2. Written informed consent is obtained 3. Speaks and writes in English 4. A willingness and ability to comply with study procedures 5. Age 25-85 years 6. Diagnosis of RLS via Cambridge-Hopkins RLS questionnaire 7. International Restless Legs Syndrome Study Group scale score (IRLS) \< 15 8. RLS treatment with a dopaminergic agonist or an alpha-2-delta agent 9. No changes in RLS medication in the previous month 10. DSM-5 criteria for Insomnia Disorder 11. Report a total sleep time ≤ 7 hours and wake after sleep onset (WASO) \> 45 minutes on 7 or more of the 14 nightly sleep logs during both the initial 2-week screening period and the two-week screening run-in period. WASO does not decrease by more than 50% on the 2-week sleep diary obtained between the screening visit and the randomization visit
Exclusion criteria
1. Diagnosis of moderate/severe obstructive sleep apnea (AHI \> 30) not using continuous positive airway pressure therapy (CPAP) (can be included if CPAP adherent), or other untreated primary sleep disorders (e.g. narcolepsy) 2. Shift workers 3. Unwillingness to not use sedative-hypnotics (other than suvorexant) during the study period 4. Unwillingness to maintain stable RLS medication during the study unless medically indicated 5. Current use of an opiate medication 6. Unwillingness to not take stimulants (e.g. caffeine) after 4:00 pm during the study 7. Current major depressive episode, by report and as indicated by the Patient Health Questionnaire (PHQ-9) 8. Lifetime history of bipolar disorder, psychosis, or other serious psychiatric illness 9. Current alcohol/substance use disorder 10. BMI ≥ 40 kg/m\^2 11. Renal or hepatic disease judged to interfere with drug metabolism and excretion 12. Pregnancy or breastfeeding 13. Malignancy within past 2 years 14. Surgery within past 3 months 15. Neurological disorder or cardiovascular disease raising safety concerns about use of suvorexant and/or judged to interfere with ability to assess efficacy of the treatment 16. Medical instability considered to interfere with study procedures 17. Concomitant medications with drug interaction or co-administration concerns 18. Contraindications or allergic responses to suvorexant 19. History of being treated with suvorexant 20. Travel across two time-zones during the week prior to enrollment 21. Greater than 6 cups of coffee per day
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Actigraphically-Derived Total Sleep Time | 2 weeks | Change in mean total sleep time (between baseline and end of treatment, for each treatment period), as measured by actigraphy. Participants wear an actigraph watch, which assesses periods of activity and rest to determine the total amount of sleep during one sleep period. Total sleep time excludes sleep onset latency and nighttime awakenings. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Actigraphically-Derived Wake After Sleep Onset | 2 weeks | Change in wake after sleep onset (between baseline and end of treatment, for each treatment period), as measured by actigraphy. Participants wear an actigraph watch, which assesses periods of activity and rest to determine the total wake time after sleep onset, during nighttime awakenings. |
| Insomnia Severity Index | 2 weeks | Change in ISI score between baseline and end of treatment, for each treatment period. The ISI is a validated tool to measure insomnia severity, on a scale of 0-28, with a higher score representing greater insomnia severity. |
Countries
United States
Participant flow
Pre-assignment details
Prior to signing an Informed Consent Form (ICF), participants complete Sleep Diaries. If eligible, they sign the ICF, followed by additional Sleep Diaries. During this second period, 8 enrolled participants were excluded from the study for the following reasons: sleep no longer met criteria (4), RLS was too severe (2), sleep apnea (1), no RLS (1). Four participants withdrew from the study due to: unrelated surgery (2), no longer interested (1), lost to follow-up (1).
Participants by arm
| Arm | Count |
|---|---|
| Treatment --> Placebo This group will receive suvorexant during the first 4-week phase, and placebo during the second 4-week phase.
Suvorexant: 10-mg or 20-mg suvorexant capsules
Placebo: Matching placebo capsules | 18 |
| Placebo --> Treatment This group will receive placebo during the first 4-week phase, and suvorexant during the second 4-week phase.
Suvorexant: 10-mg or 20-mg suvorexant capsules
Placebo: Matching placebo capsules | 16 |
| Total | 34 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Treatment 2 | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Placebo --> Treatment | Treatment --> Placebo |
|---|---|---|---|
| Age, Continuous | 62.7 years STANDARD_DEVIATION 9.7 | 59.3 years STANDARD_DEVIATION 10.9 | 65.7 years STANDARD_DEVIATION 7.7 |
| BMI | 28.1 kg/m^2 STANDARD_DEVIATION 8 | 27.0 kg/m^2 STANDARD_DEVIATION 4.8 | 29.0 kg/m^2 STANDARD_DEVIATION 10.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 34 Participants | 16 Participants | 18 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Insomnia Severity Index (ISI) | 15.1 units on a scale (0-28) STANDARD_DEVIATION 3.9 | 14.2 units on a scale (0-28) STANDARD_DEVIATION 3.8 | 16 units on a scale (0-28) STANDARD_DEVIATION 3.9 |
| International Restless Legs Syndrome Study Group Rating Scale (IRLS) | 8.2 units on a scale (0-40) STANDARD_DEVIATION 5.2 | 8.1 units on a scale (0-40) STANDARD_DEVIATION 4.5 | 8.3 units on a scale (0-40) STANDARD_DEVIATION 5.9 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 34 Participants | 16 Participants | 18 Participants |
| Region of Enrollment United States | 34 Participants | 16 Participants | 18 Participants |
| Sex: Female, Male Female | 24 Participants | 12 Participants | 12 Participants |
| Sex: Female, Male Male | 10 Participants | 4 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 34 | 0 / 32 |
| other Total, other adverse events | 18 / 34 | 12 / 32 |
| serious Total, serious adverse events | 0 / 34 | 0 / 32 |
Outcome results
Primary
Actigraphically-Derived Total Sleep Time
Change in mean total sleep time (between baseline and end of treatment, for each treatment period), as measured by actigraphy. Participants wear an actigraph watch, which assesses periods of activity and rest to determine the total amount of sleep during one sleep period. Total sleep time excludes sleep onset latency and nighttime awakenings.
Time frame: 2 weeks
Population: Two participants in the Treatment --\> Placebo arm of the study withdrew prior to treatment period 2.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment --> Placebo | Actigraphically-Derived Total Sleep Time | Treatment 1 | 5.03 Minutes | Standard Deviation 40.8 |
| Treatment --> Placebo | Actigraphically-Derived Total Sleep Time | Treatment 2 | 7.60 Minutes | Standard Deviation 53.01 |
| Placebo --> Treatment | Actigraphically-Derived Total Sleep Time | Treatment 1 | 11.44 Minutes | Standard Deviation 24.16 |
| Placebo --> Treatment | Actigraphically-Derived Total Sleep Time | Treatment 2 | 17.96 Minutes | Standard Deviation 32.04 |
Secondary
Actigraphically-Derived Wake After Sleep Onset
Change in wake after sleep onset (between baseline and end of treatment, for each treatment period), as measured by actigraphy. Participants wear an actigraph watch, which assesses periods of activity and rest to determine the total wake time after sleep onset, during nighttime awakenings.
Time frame: 2 weeks
Population: Two participants in the Treatment --\> Placebo arm withdrew from the study prior to treatment period 2.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment --> Placebo | Actigraphically-Derived Wake After Sleep Onset | Treatment 2 | -1.05 Minutes | Standard Deviation 15.59 |
| Treatment --> Placebo | Actigraphically-Derived Wake After Sleep Onset | Treatment 1 | 0.88 Minutes | Standard Deviation 14.26 |
| Placebo --> Treatment | Actigraphically-Derived Wake After Sleep Onset | Treatment 2 | -1.20 Minutes | Standard Deviation 12.05 |
| Placebo --> Treatment | Actigraphically-Derived Wake After Sleep Onset | Treatment 1 | -0.67 Minutes | Standard Deviation 19.53 |
Secondary
Insomnia Severity Index
Change in ISI score between baseline and end of treatment, for each treatment period. The ISI is a validated tool to measure insomnia severity, on a scale of 0-28, with a higher score representing greater insomnia severity.
Time frame: 2 weeks
Population: Two participants in the Treatment --\> Placebo arm withdrew from the study prior to treatment period 2.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Treatment --> Placebo | Insomnia Severity Index | Treatment 1 | -4.78 units on a scale | Standard Deviation 4.62 |
| Treatment --> Placebo | Insomnia Severity Index | Treatment 2 | -4.29 units on a scale | Standard Deviation 5.3 |
| Placebo --> Treatment | Insomnia Severity Index | Treatment 2 | -5.69 units on a scale | Standard Deviation 6.87 |
| Placebo --> Treatment | Insomnia Severity Index | Treatment 1 | -1.25 units on a scale | Standard Deviation 5.3 |