Clinical trial NCT06306404: Sleeping Through Menopause
Official title: The Role of Online Sleep Intervention and Hormone Therapy on Sleep, Climacteric Symptoms and Mood in the Perimenopause
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE4
Conditions: Menopause
Insomnia
Lead sponsor: VU University of Amsterdam
Sponsor class: OTHER
First posted: 2024-03-12
Enrollment: 222
Sex: FEMALE
Minimum age (years): 40
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The perimenopause is known as a vulnerable period for some women, with noticeable somatic and psychological issues. Aside from climacteric symptoms, insomnia and depression are common. About half of women during the peri-menopausal period experience sleep problems like problems falling asleep, awakening during the night and being unable to return to sleep. This is often attributed to vasomotor symptoms, but this is not the only reason of poor sleep. Also, the peri-menopausal period is a critical time for the occurrence of new onset and recurrent depressions. It has been suggested that fluctuations in estradiol may increase the risk for depression by altering neuronal functions in the brain. But there are also indications that the risk for depression increases by indirect effects, such as the increase in insomnia. Poor sleep has increasingly been recognized as the key modifiable factor affecting mental issues like depression. While antidepressants and psychotherapies continue to be the treatments of choice for depression, and Cognitive Behavioral Therapy for sleep (CBTi) for insomnia, preclinical and clinical data support the benefits of estrogen-based therapies to improve mood, sleep and other menopause-related symptoms. Transdermal estradiol patches, which provide a stable release of estradiol and lead to more stable blood levels, have been suggested to have a positive effect on sleep and depressive symptoms in randomized controlled trials. However, it is currently unclear if the relation between improvement in mood and estradiol patches is mediated by improvement in sleep problems, and if the effect of estradiol patches on sleep problems is more effective during peri-menopause than the current evidence-based sleep interventions of CBTi, preferably in combination with Circadian Rhythm Support (CRS). The aim of the study is to pinpoint the determinants of complaints about sleep and mood and how they respond to Menopausal Hormone Treatment (MHT) with and without the addition of a guided eHealth sleep intervention that combines CBTi + CRS.

Measurements will be conducted at baseline (T0), 2 months (T1) and 4 months (T3), with questionnaires, sleep measurements (EEG sleepband and actigraph) and skin conductance (to measure hot flushes). Participants will be recruited via www.slaapregister.nl and via OLVG outpatient clinic population of peri-menopausal women seeking help for climacteric complaints (like hot flushes, feeling bloated, increase in weight), including sleep problems. The participants are adults between 40-55 years old, with an Insomnia Severity Index score ≥10 and Climacteric Green Scale score ≥ 13.They have the self-considered capability to complete online questionnaires and diaries in Dutch.

The intervention will be MHT (estradiol transdermal patches 50 mcg (Systen), in combination with 200 mg progesterone (Utrogestan tablets for 2 weeks, adjusted to the menstrual cycle to prevent endometrium carcinoma according to the international MHT guidelines), with and without the addition of a guided eHealth sleep intervention that combines CBTi + CRS.

Detailed description: The primary outcome measure is insomnia severity (Bastien et al., 2001). Secondary outcomes address five domains: depressive symptoms, symptoms of other mental health symptoms, climacteric symptoms, daytime functioning and well-being and other sleep measurements. The severity of mental health complaints characterizing different diagnostic dimensions, as well as well-being and daytime functioning including health behaviours and use of care, all assessed by online survey or clinical interview at T0, T1 (2 months) and T2 (4 months).

Climacteric symptoms are assessed with the Green Climacteric Scale at T0, T1, T2. Hot flashes are measured with ambulatory sternal skin conductance monitoring (Purplexus). The other sleep measures include other indicators of sleep and overnight alleviation of distress assessed from the Carney Consensus Sleep Diary, kept online for a week; rest-activity rhythm and activity-based sleep estimates obtained with an actigraph at 7 baseline nights (T0), 7 post-interventions nights (T1) and 7 follow-up nights (T2); objective sleep efficiency, REM sleep fragmentation and heartrate with an ambulatory headband EEG at 5 baseline nights (T0), 5 post-interventions nights (T1) and 5 follow-up nights (T2).

Eligibility criteria: Inclusion Criteria:

* Age between 40-55 years old
* Insomnia severity index score =\>10
* Green Climacteric Score =\>13
* Self-considered capability of completing online questionnaires and diaries in Dutch/English
* Presence of a menstruation (whether regular or not) and the last menstruation must be less than 12 months ago

Exclusion Criteria:

* CBTi treatment in past year
* Bipolar disorder or psychotic disorder
* Contra-indication for Hormone Replacement Therapy
* Alcohol or drugs dependency (scores of ≥ 20 on the AUDIT and ≥25 on the DUDIT)
* Women using thyroid medication, lamotrigine, aromatase, tamoxifen, because of interaction effects with MHT
* Use of drugs known to interfere with cytochrome P450 enzyme (CYP) 3A4
* Known hypersensitivity to the excipients in the estradiol patch: acrylate copolymer, polyethylene terephthalate, alfa-tocopherol, soy allergy (component of progesterone capsule).
* All women on hormonal contraceptives will be excluded.
* All women already on MHT will be excluded.

Primary outcomes:
measure: The primary outcome variable is the difference between the groups in the within-subject change in insomnia severity at T1 (2 months) and T2 (4 months) relative to T0 (baseline).
timeFrame: month 2 vs. month 4
Secondary outcomes:
Other outcomes:
Locations:
Study officials:
affiliation: OLVG and Amsterdam UMC, VU
name: Birit Broekman, Prof.
role: PRINCIPAL_INVESTIGATOR
affiliation: Netherlands Institute for Neuroscience
name: Eus van Someren, Prof.
role: PRINCIPAL_INVESTIGATOR
References: