Comparing Digital Therapy, Trazodone, and Daridorexant for Menopause-Related Insomnia Symptoms

CELESTE: Comparative Effectiveness Study of behavioraL and Drug-rElated inSomnia Therapies for pEri- and Post-menopausal People

The goal of this clinical trial is to learn how three current insomnia therapies (trazodone, daridorexant, cognitive behavioral therapy for insomnia) compare with each other in peri- and post-menopausal women. It will also learn about the safety of the treatments. The main questions it aims to answer are:

Which commonly used insomnia therapies are most effective and safe for improving insomnia symptoms in peri- and post-menopausal people?

How well do the treatments work for people from different backgrounds, who are at different stages of menopause, and who have different conditions common during menopause (e.g., sleep apnea, mood disturbance, etc.)?

What medical problems do participants have when using these treatments?

Participants will:

Be asked to take trazodone every night, take daridorexant every night, or participate in an online behavioral program for insomnia, for a total of 12 months.

Participate in a total of one in-person visit and 7 virtual visits (phone calls) over the 12 months.

Wear (and keep) a Fitbit and fill out a daily sleep diary for at least 4 weeks over the 12 months.

Fill out online surveys 4 times over the 12 months.

Insomnia, or trouble sleeping, is common. It affects about 1 in 10 adults. People with insomnia are not happy with how long or how well they sleep. Insomnia has been linked to a higher risk of depression, heart disease, memory problems, and lower quality of life. It can also lead to missing work and having accidents. Sleep problems like insomnia are also common or people going through perimenopause and post-menopause.

CBT-I teaches people to change behaviors and thoughts that make it hard to sleep. Daridorexant is an FDA-approved medicine for insomnia. Trazodone is FDA-approved to treat depression, but many doctors also prescribe it to help with sleep. This is called off-label use, which means it is used for a purpose the FDA has not officially approved. Studies show that trazodone is one of the most common medicines prescribed for insomnia in the United States.

We do not yet know how well CBT-I, trazodone, and daridorexant compare, especially for people in perimenopause and post-menopause. Throughout the duration of the study, the participant will be given one of the three therapies.

This study takes about 12 months to complete for each participant.

The following visits and procedures will happen:

Consent telephone or virtual call

Screening Visit: Baseline surveys, urine pregnancy test, electrocardiogram, height and weight assessment. The 7 days after this visit, the participant will also be asked to wear their Fitbit for 24 hours every day, fill out diaries in the morning and night, and wear a home sleep apnea test for one night.

Randomization Call: The participant will be randomized (like a flip of a coin) to receive one of the three insomnia therapies (CBT-I, trazodone, or daridorexant) a week after their baseline visit.

1-week and 4-weeks Call: Quick phone call with study staff for any study treatment adjustments.

3-Months and 6-Months Call/Visit: Fill out surveys. At 6-months, weight will be measured. During the visit window, the participant will also be asked to wear their Fitbit for 24 hours every day and fill in a sleep diary in the morning and night for a total of 7 days.

9-Months Call: Quick phone call with study staff to see if there are any issues.

12-Months Call/Visit: Fill out surveys. During the visit window, the participant will also be asked to wear their Fitbit for 24 hours every day and fill in a sleep diary in the morning and night for a total of 7 days. The Fitbit is for the participant to keep and does not have to be returned.

Inclusion Criteria:

• Age 40-62 years
• Assigned female sex at birth
• In peri- or early menopause, following the STRAW criteria of self-report of irregular menstrual cycle or within 5 years from the last menstrual period. When menstrual markers are absent or unreliable (e.g., hysterectomy; endometrial ablation), participants must be older than 45 years old and report hot flashes
• Insomnia severity index score > 10 at screening
• Insomnia started or worsened during peri- or early menopause
• English or Spanish speaking (Spanish-only speaking individuals will be recruited after full development of Spanish-facing materials, which may lag initial study start)

Exclusion Criteria:

• Untreated, previously diagnosed severe sleep apnea (self-report; chart review; clinician assessment)
• Untreated, previously diagnosed moderate-severe restless legs syndrome (self-report; chart review)
• Severe daytime sleepiness (Epworth Sleepiness Scale > 15) at screening
• Sleep schedule issues that would impact effectiveness of the interventions (e.g., night shift workers with >1 night shift/week; main sleep period outside of 8pm - 11am)
• Regular use of hypnotics > 2 nights/week
• Limited internet access
• Pregnant or lactating or positive urine pregnancy test at baseline visit
• Prolonged QTc interval (>460 ms) (by study baseline electrocardiogram (EKG) or EKG report in medical record)
• History of the following health conditions: Uncontrolled hypertension; clinically significant heart disease such as arrhythmias requiring medication, cardiomyopathies, heart failure, clinically significant valvular heart disease, or severe coronary artery disease (unstable angina, myocardial infarction in the prior 6 months); hypersomnia or narcolepsy; bipolar disorder, severe depression, or psychosis ; seizure within the past year; use of opioids or substance use disorder; known allergy or contraindication to trazodone or daridorexant (self-report and chart review); known severe chronic liver disease (e.g. cirrhosis); end-stage renal disease on hemodialysis; other severe medical comorbidity (e.g. likely hospitalization within next 6 months or medical conditions that increase risk of participation at a study clinician's discretion)
• Use of medications such as those that: Have known potential for significantly prolonging the QT interval (i.e. antiarrhythmics such as amiodarone, sotalol, quinidine, procainamide, dofetilide, and ibutilide), are strong CYP3A4 inhibitors, or are moderate or strong CYP3A4 inducers
• Use of one of the interventions in the past 6 months
• Other conditions determined by the PI or study clinician to preclude study participation