InsomniaPhase 4NCT07542756
A SMART Approach to Evaluating the Benefits of Common Prescription and OTC Medications for Insomnia
A Phase 4 study testing Sleep Hygiene Education, Melatonin IR, 3 mg and Melatonin IR, 5 mg in people with Insomnia and Insomnia Disorder, run by University of Pennsylvania at 1 site in United States.
Trial summary
The purpose of this study is to assess the relative effectiveness, safety, and durability of the most commonly used prescription (zolpidem, trazodone) and over-the-counter (OTC) (melatonin, diphenhydramine) medications for insomnia, as well as a less commonly used prescription that may have a better risk/benefit… Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- Insomnia, Insomnia Disorder, Chronic Insomnia
- What is being tested?
- Sleep Hygiene Education, Melatonin IR, 3 mg and Melatonin IR, 5 mg
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 1,200 participants
- Where
- 1 siteUnited States
- Study dates
- 1 May 2026to 1 Jan 2032
- Phase
- Phase 4
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Adults aged 18-80 years.
- Meet DSM-5 criteria for Insomnia Disorder.
- Score ≥15 on the Insomnia Severity Index (ISI).
- Sleep initiation and/or maintenance complaints: ≥30 minutes in duration, occurring ≥3 nights/week, with a duration of ≥3 months.
- Willingness to discontinue use of all sleep-related medications prior to enrollment.
- Completion of a 2-week washout period before starting any study medication.
- Willingness to provide clinician assent for participation.
Who cannot join
- Patients will be ineligible if they meet any of the following criteria: self-reported daytime napping (≥1 hour per day on ≥3 days per week); a history of suicidal attempts or current ideation, acute or chronic psychiatric or medical condition not controlled by therapy (according to their primary care physician), or current alcohol or drug misuse; or the diagnoses of (or high risk for) other sleep disorders, including circadian rhythm disorders (phase advance or phase delay syndromes), shift work related sleep disorder ("day sleepers" who work ~11pm to 7am) and those with rotating shiftwork schedules. To determine eligibility, all subjects will be screened using a multitier process including: an online screener; an intake interview; a review of the subjects EMR; and, finally, the receipt of the patient's PCP's assent. The following provides additional listing and details (AD) for the Exclusion Criteria:
- General Considerations
- Age < 18 or > 80 years old
- Inadequate English language comprehension
- Minimal facility with smartphones, computers, i-Pads, or the internet.
- Women's Health Given the potential for teratogenic effects with at least trazodone (FDA Class C), women intending to become pregnant, or who are pregnant, or who are breastfeeding will not be eligible for the study. Women will be asked to confirm the use of birth control using self-report and, if applicable, by providing evidence of contraceptive medication (e.g., prescription or pill pack). We will perform a urine pregnancy test at baseline for female participants who are of reproductive age to confirm eligibility. At study enrollment, participants will be told to alert the study team and stop taking study medications if they become pregnant. Participants will be asked to test for pregnancy in the event of a missed cycle.
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- Medical and Psychiatric Considerations
- Acute or unstable psychiatric conditions
- Unstable medical condition, significant medical disorder, or acute illness (as determined by their PCP), within one month prior to the study period.
- Significant liver or kidney problems
- Pheochromocytoma or porphyria (contraindicated for trazodone)
- Epilepsy or Seizure Disorder (contraindicated for trazodone)
- Glaucoma or urinary retention (contraindicated for doxepin)
- Increased ocular pressure (contraindicated for diphenhydramine)
- Diagnosis of alcohol or substance use disorder within 2 years prior to the screening visit
- Inability to refrain from drinking alcohol or substance use for at least 3 consecutive days
- Sleep Disorders and Sleep Habits
- Any lifetime history of (diagnosis of) breathing disorders, including COPD and sleep apnea.
- Shift work related sleep disorder (work ~11pm to 7am and "day sleeper") and rotating shiftwork schedules
- Circadian rhythm disorders (phase advance or phase delay syndromes)
- Self-reported usual daytime napping ≥1 hour per day (3 or more days per week)
- Medications and Concomitant meds
- Known hypersensitivity or contraindication to study drugs
- Known hypersensitivity or contraindication to drugs of the same class as the study treatments
- Known hypersensitivity or contraindication to any excipients of the study drug formulation
- Treatment with CNS active drugs prohibited by the protocol for five half-lives of the respective drug (or 2 weeks)
- Lifestyle
- Heavy tobacco use (≥1 pack of cigarettes a day or inability to refrain from smoking during the night)
- Not able or willing to stop treatment with moderate or strong cytochrome P450 3A4 (CYP3A4) inhibitors
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site, 1 recruiting
- Recruiting
University of Pennsylvania
Philadelphia, Pennsylvania, 19104
Michael L Perlis, PhD, 215-746-3577, mperlis@upenn.edu
About this study
Official title: Sequential Multiple Assignment Randomized Trial Comparing Commonly Prescribed and Over the Counter Medications for the Treatment of Insomnia in Adults
The purpose of this study is to assess the relative effectiveness, safety, and durability of the most commonly used prescription (zolpidem, trazodone) and over-the-counter (OTC) (melatonin, diphenhydramine) medications for insomnia, as well as a less commonly used prescription that may have a better risk/benefit profile (doxepin).
Read the detailed description
Nearly 50% of primary care patients report symptoms of insomnia (e.g., problems initiating and/or maintaining sleep). Such sleep-related difficulties can presage new onset comorbid illness, as well as exacerbate, and be exacerbated by, existing comorbid illnesses. Accordingly, effectively treating insomnia in primary care patients is an untapped means towards the promotion of better public health.
Research Question:
While cognitive behavioral therapy for insomnia (CBT-I) is considered the first-line treatment, most patients (particularly those in primary care) do not have access to this form of therapy.
Instead, the majority of treated patients are using over-the-counter medications (OTCs), including melatonin and diphenhydramine (e.g., Benadryl), or are prescribed hypnotics (most commonly trazodone or zolpidem [e.g., Ambien]). Surprisingly, little is known about the absolute or relative effectiveness and safety of these commonly used medications, and of the often used medications, only Ambien is approved/recommended by the FDA and professional medical or sleep medicine societies. There are also limited data on which of these medical strategies has the best risk/benefit profile or is most acceptable to patients. The investigators' recent evaluation of FDA-approved medications for insomnia suggests doxepin, which is less commonly prescribed, has the most optimal risk/benefit profile. Multiple agencies have called for rigorous comparative effectiveness studies addressing these knowledge gaps, including the Agency for Healthcare Research and Quality (AHRQ), the National Institutes of Health (NIH), and the Patient-Centered Outcomes Research Institute (PCORI). Moreover, the investigators' feedback from stakeholders shows that the need for such data is not just a professional practice concern, but shared by primary care patients and clinicians. Thus, evidence-based guidance on the management of insomnia with OTC and prescriptive medications is urgently needed.
Protocol Synopsis:
The investigators propose to conduct a large-scale, double blinded, placebo-controlled sequential multiple assignment randomized trial (SMART) comparing the relative effectiveness and safety of over-the counter medications commonly used by patients to treat their insomnia (i.e., diphenhydramine and melatonin) and prescriptive medications that are either commonly prescribed by clinicians (i.e., zolpidem and trazodone) or less commonly used, but may have a more optimal risk/benefit profile (i.e., doxepin). All conditions will use a nightly dosing strategy and include sleep hygiene education. To better align with current practice, participants who tolerate an initial lower medication dose but do not exhibit a treatment response will increase to a higher dose after 2 weeks. Treatment responders at 1 month will be followed for up to 6 months to understand longer-term maintenance of treatment benefits. The SMART design will re-randomize treatment non-responders at 1 month to an alternative arm (with each successive treatment non-response), providing all participants the opportunity to secure a treatment response with one of the study medications. To maintain blinding, participants will be instructed to take each medication (including placebo) 30 minutes prior to bed and all medications will be manufactured by a central Pharmacy to appear identical. All participants will be further instructed to be in bed for a period of 7-9 hours to both promote safety and potentially increase medication effects on early morning awakening and total sleep time.
- Being tested
- Sleep Hygiene Education, Melatonin IR, 3 mg, Melatonin IR, 5 mg, Diphenhydramine, 25 mg, Diphenhydramine, 50 mg
- Keywords
- Sleep, Insomnia, Zolpidem, Diphenhydramine, Doxepin, Melatonin, Trazodone, Placebo
- Medical subject headings
- Sleep Initiation and Maintenance Disorders
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Sleep Hygiene EducationOther
Also called Sleep Hygiene
Standard behavioral and environmental recommendations aimed at promoting healthy sleep
Melatonin IR, 3 mgDietary supplement
Also called Acetyl-5-methoxytryptamine
Immediate release formulation of melatonin, once nightly 30 minutes prior to bed
Melatonin IR, 5 mgDietary supplement
Also called Acetyl-5-methoxytryptamine
Immediate release formulation of melatonin, once nightly 30 minutes prior to bed
Diphenhydramine, 25 mgDrug
Also called Benadryl
Diphenhydramine 25 mg, once nightly 30 minutes prior to bed. Note: Given the strong recommendation against the use of diphenhydramine in older adults (i.e., the Beers Criteria), participants ≥64 years of age will not be randomized to the diphenhydramine arm.
Diphenhydramine, 50 mgDrug
Also called Benadryl
Diphenhydramine, 50 mg, once nightly 30 minutes prior to bed. Note: Given the strong recommendation against the use of diphenhydramine in older adults (i.e., the Beers Criteria), participants ≥64 years of age will not be randomized to the diphenhydramine arm.
Doxepin, 3 mgDrug
Also called Silenor
Doxepin, 3 mg, once nightly 30 minutes prior to bed
Doxepin, 6 mgDrug
Also called Silenor
Doxepin, 6 mg, once nightly 30 minutes prior to bed
Trazodone, 50 mgDrug
Also called Desyrel
Trazodone, 50 mg, once nightly 30 minutes prior to bed
Trazodone, 100 mgDrug
Also called Desyrel
Trazodone, 100 mg, once nightly 30 minutes prior to bed
PlaceboDrug
Also called Inactive Drug, Inert Capsule
Placebo, once nightly 30 minutes prior to bed
Zolpidem, 5 mgDrug
Also called Ambien
Zolpidem, 5 mg, once nightly 30 minutes prior to bed
Zolpidem, 10 mgDrug
Also called Ambien
Zolpidem, 10 mg, once nightly 30 minutes prior to bed
| Study group | Role | What they receive |
|---|---|---|
| Melatonin | Experimental | Nightly 30 minutes prior to bed (3 or 5 mg) Receives: Other: Sleep Hygiene Education; Dietary Supplement: Melatonin IR, 3 mg; Dietary Supplement: Melatonin IR, 5 mg |
| Placebo | Placebo comparator | Nightly 30 minutes prior to bed Receives: Other: Sleep Hygiene Education; Drug: Placebo |
| Diphenhydramine | Experimental | Nightly 30 minutes prior to bed (25 or 50 mg). Note: Given the strong recommendation against the use of diphenhydramine in older adults (i.e., the Beers Criteria), participants ≥64 years of age will not be randomized to the diphenhydramine arm. Receives: Other: Sleep Hygiene Education; Drug: Diphenhydramine, 25 mg; Drug: Diphenhydramine, 50 mg |
| Zolpidem | Experimental | Nightly 30 minutes prior to bed (5 or 10 mg) Receives: Other: Sleep Hygiene Education; Drug: Zolpidem, 5 mg; Drug: Zolpidem, 10 mg |
| Doxepin | Experimental | Nightly 30 minutes prior to bed (3 or 6 mg) Receives: Other: Sleep Hygiene Education; Drug: Doxepin, 3 mg; Drug: Doxepin, 6 mg |
| Trazodone | Experimental | Nightly 30 minutes prior to bed (50 or 100 mg) Receives: Other: Sleep Hygiene Education; Drug: Trazodone, 50 mg; Drug: Trazodone, 100 mg |
What is being measured
The primary outcome is the main question the study is designed to answer.
Relative treatment response rates during acute (1-month) treatment phase
Defined as an at least 8-point reduction on the Insomnia Severity Index (ISI)
Measured: From treatment initiation to 1 month after treatment initiation
Relative safety and tolerability based on side effects during acute (1-month) treatment phase
Percent of participants who experience 1 or more side effect(s), as well as the average number of events, incidence rate, and severity of events for each medication, as assessed by self-report (spontaneous and based on a weekly medical symptoms checklist)
Measured: From treatment initiation to 1 month after treatment initiation
Relative effects on daytime symptoms and function during acute (1-month) treatment phase
As measured by the Functional Outcomes of Sleep Questionnaire (FOSQ- 10). Min. score: 5, Max Score: 20 Lower score = more functional impairment Higher score = less functional impairment
Measured: From treatment initiation to 1 month after treatment initiation
Durability of treatment response during longer-term maintenance (1-6 months) treatment phase
Among initial treatment responders based on Insomnia Severity Index (ISI) and tolerability, the percent of subjects who continue to exhibit an ISI-based treatment response
Measured: From the start of the 2nd month after treatment initiation to 6 months after treatment initiation
Relative safety and tolerability based on side effects during longer-term maintenance (1-6 months) phase
Among initial treatment responders based on ISI and tolerability, percent of participants who experience 1 or more side effect(s), as well as the average number of events, incidence rate, and severity of events for each medication, as assessed by self-report (spontaneous and based on a weekly medical symptoms checklist)
Measured: From the start of the 2nd month after treatment initiation to 6 months after treatment initiation
Durability of effects on daytime symptoms and function during longer-term maintenance (1-6 months) phase
Among initial treatment responders based on Insomnia Severity Index (ISI) and tolerability, the relative improvements in on the Functional Outcomes of Sleep Questionnaire (FOSQ- 10). Min. score: 5, Max Score: 20. Lower score = more functional impairment, higher score = less functional impairment
Measured: From the start of the 2nd month after treatment initiation to 6 months after treatment initiation
Secondary outcomes (13)
Sleep Latency (SL)
Average self-reported Sleep Latency (SL), per sleep diary entries
Measured: From baseline (prior to treatment), to the end of 1 month of treatment (acute treatment phase) and from the start of the 2nd month after treatment initiation to 6 months after treatment initiation (longer-term maintenance phase in responders)
Wake After Sleep Onset (WASO)
Average self-reported Wake After Sleep Onset (WASO), per sleep diary entries
Measured: From baseline (prior to treatment), to the end of 1 month of treatment (acute treatment phase) and from the start of the 2nd month after treatment initiation to 6 months after treatment initiation (longer-term maintenance phase in responders)
Sleep Duration/Total Sleep Time (TST)
Average total sleep time (TST), calculated from daily sleep diaries
Measured: From baseline (prior to treatment), to the end of 1 month of treatment (acute treatment phase) and from the start of the 2nd month after treatment initiation to 6 months after treatment initiation (longer-term maintenance phase in responders)
Self-Reported Daytime Insomnia Symptoms
As measured by The Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ). Min. score: 0, Max score: 140. Lower score = less daytime insomnia symptoms/impairment, Higher score = more daytime insomnia symptoms/impairment
Measured: From baseline (prior to treatment), to the end of 1 month of treatment (acute treatment phase) and from the start of the 2nd month after treatment initiation to 6 months after treatment initiation (longer-term maintenance phase in responders)
Self-Reported Daytime Sleepiness
As measured by the Epworth Sleepiness Scale (ESS) Min. score: 0, Max score: 24 Lower score = less daytime sleepiness Higher score = more daytime sleepiness
Measured: From baseline (prior to treatment), to the end of 1 month of treatment (acute treatment phase) and from the start of the 2nd month after treatment initiation to 6 months after treatment initiation (longer-term maintenance phase in responders)
Self-Reported Fatigue
As measured by the Brief Fatigue Inventory (BFI). Min. score: 0, Max score: 10. Lower score = less fatigue, higher score = more fatigue
Measured: From baseline (prior to treatment), to the end of 1 month of treatment (acute treatment phase) and from the start of the 2nd month after treatment initiation to 6 months after treatment initiation (longer-term maintenance phase in responders)
Self-Reported Depression
As measured by the Patient Health Questionnaire (PHQ-9). Min. score: 0, max score: 27. Lower score = less depression, higher score = more depression
Measured: From baseline (prior to treatment), to the end of 1 month of treatment (acute treatment phase) and from the start of the 2nd month after treatment initiation to 6 months after treatment initiation (longer-term maintenance phase in responders)
Self-Reported Anxiety
As measured by the General Anxiety Disorder-7 (GAD-7). Min. score: 0, max score: 21. Lower score = less anxiety, higher score = more anxiety
Measured: From baseline (prior to treatment), to the end of 1 month of treatment (acute treatment phase) and from the start of the 2nd month after treatment initiation to 6 months after treatment initiation (longer-term maintenance phase in responders)
Cognitive Dysfunction and Residual Sedation
As measured by the 90-second Digit Symbol Substitution Test (DSST). Min. score: 0, max score: 120. Lower score = more cognitive dysfunction \& residual sedation, higher score = less cognitive dysfunction \& residual sedation
Measured: From baseline (prior to treatment), to the end of 1 month of treatment (acute treatment phase) and from the start of the 2nd month after treatment initiation to 6 months after treatment initiation (longer-term maintenance phase in responders)
Attention/Fatigue
As measured by number of lapses and mean reaction time on a 3-minute Psychomotor Vigilance Test (PVT). Min. lapses: 0, max lapses: 45. Less lapses = better performance (better attention, less fatigue), more lapses = worse performance (worse attention, more fatigue). Min mean reaction time: 100 ms, max mean reaction time: 500 ms. Lower mean reaction time = better performance (better attention, less fatigue), higher mean reaction time = worse performance (worse attention, more fatigue)
Measured: From baseline (prior to treatment), to the end of 1 month of treatment (acute treatment phase) and from the start of the 2nd month after treatment initiation to 6 months after treatment initiation (longer-term maintenance phase in responders)
Self-Reported Quality of Life
As measured by The 12-item Short Form Survey (SF-12) Min: 0, Max: 100 (normed to population scores). Lower score = worse quality of life, higher score = better quality of life
Measured: From baseline (prior to treatment), to the end of 1 month of treatment (acute treatment phase) and from the start of the 2nd month after treatment initiation to 6 months after treatment initiation (longer-term maintenance phase in responders)
Self-Reported State Alertness Versus Sleepiness
As measured by the Karolinska Sleepiness Scale (KSS), a single-item measure of state alertness versus sleepiness, administered twice daily. The item is a Likert-scale with a range of 1 (extremely alert) to 9 (very sleepy), with lower scores representing higher levels of state alertness and higher scores representing higher levels of state sleepiness.
Measured: From baseline (prior to treatment), to the end of 1 month of treatment (acute treatment phase) and from the start of the 2nd month after treatment initiation to 6 months after treatment initiation (longer-term maintenance phase in responders)
Sleep Continuity, Activity and Caloric Expenditure
As measured by a Fitbit, a commercially-available wearable device that utilizes movement detection and heart rate measurements to make sleep/wake assessments every 60 seconds, as well as hourly measures of heart rate, diurnal activity levels, and inferential measures of caloric expenditure.
Measured: From baseline (prior to treatment), to the end of 1 month of treatment (acute treatment phase) and from the start of the 2nd month after treatment initiation to 6 months after treatment initiation (longer-term maintenance phase in responders)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Apr 2026
- Study start1 May 2026
- Primary completion1 Jan 2032 (estimated)
- Study completion1 Jan 2032 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for InsomniaStudies of the same condition, open and under way.
- More trials run by University of PennsylvaniaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Sequential
- Model description
- This study protocol is a double-blind, randomized, six-condition, placebo controlled, Sequential Multiple Assignment Randomized Trial (SMART) design. Given the strong recommendation against the use of diphenhydramine in older adults (i.e., the Beers Criteria), participants ≤63 years of age will be randomized to one of the six study medications and participants ≥64 years of age will be randomized to one of five study medications (excluding diphenhydramine). Primary analyses will evaluate effects on insomnia symptoms, side effects, and daytime function at one month. We will also leverage the SMART design to explore the effects of different treatment sequences.
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 1,200 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Pennsylvania
- Sponsor type
- University, hospital or other
- Collaborators
- Patient-Centered Outcomes Research Institute
- Responsible party
- Sponsor
- Investigators
- Michael L Perlis, PhD, Principal investigator, University of Pennsylvania
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07542756
- Sponsor's protocol ID
- 859970
- Other IDs
- BPS-2024C3-42200
- Status last verified
- Sep 2026
- First submitted
- 20 Mar 2026
- Last updated
- 16 Sep 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: Following the trial, the study's de-identified data will be made available for archival analyses (first to study site investigators and then to all interested clinical investigators) consistent with PCORI data sharing policies: "Data collected as part of this research project will be de-identified and such de-identified data to be used for secondary research purposes and shared with researchers not affiliated with the institution conducting the research project." All shared data sets will be de-identified and will only retain a code that indicates the order in which the patient was enrolled and their site of origination. PCORI must approve all sharing of information/data prior to its occurrence.