A SMART Approach to Evaluating the Benefits of Common Prescription and OTC Medications for Insomnia

NCT07542756 | Recruiting Phase 4 DMC FDA Drug

• 2 other identifiers: 859970BPS-2024C3-42200
• Study Type: interventional
• Target: 1,200
• Locations: 1 country
• Sites: 1

Brief 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 profile (doxepin).

Conditions

Insomnia; Insomnia Disorder; Chronic Insomnia; Chronic Insomnia Disorder

Keywords

Sleep; Insomnia; Zolpidem; Diphenhydramine; Doxepin; Melatonin; Trazodone; Placebo

Outcome Measures

Primary Outcomes (6)

• Relative treatment response rates during acute (1-month) treatment phase

  Defined as an at least 8-point reduction on the Insomnia Severity Index (ISI)

  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)

  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

  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

  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)

  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

  From the start of the 2nd month after treatment initiation to 6 months after treatment initiation

Secondary Outcomes (13)

• Sleep Latency (SL)

  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)

  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)

  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

  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

  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)

Study Arms (6)

Melatonin

EXPERIMENTAL

Nightly 30 minutes prior to bed (3 or 5 mg)

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

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.

Other: Sleep Hygiene Education; Drug: Diphenhydramine, 25 mg; Drug: Diphenhydramine, 50 mg

Zolpidem

EXPERIMENTAL

Nightly 30 minutes prior to bed (5 or 10 mg)

Other: Sleep Hygiene Education; Drug: Zolpidem, 5 mg; Drug: Zolpidem, 10 mg

Doxepin

EXPERIMENTAL

Nightly 30 minutes prior to bed (3 or 6 mg)

Other: Sleep Hygiene Education; Drug: Doxepin, 3 mg; Drug: Doxepin, 6 mg

Trazodone

EXPERIMENTAL

Nightly 30 minutes prior to bed (50 or 100 mg)

Other: Sleep Hygiene Education; Drug: Trazodone, 50 mg; Drug: Trazodone, 100 mg

Interventions

Melatonin IR, 3 mg DIETARY_SUPPLEMENT

Immediate release formulation of melatonin, once nightly 30 minutes prior to bed

Also known as: Acetyl-5-methoxytryptamine

Melatonin

Melatonin IR, 5 mg DIETARY_SUPPLEMENT

Immediate release formulation of melatonin, once nightly 30 minutes prior to bed

Also known as: Acetyl-5-methoxytryptamine

Melatonin

Sleep Hygiene Education OTHER

Standard behavioral and environmental recommendations aimed at promoting healthy sleep

Also known as: Sleep Hygiene

Diphenhydramine; Doxepin; Melatonin; Placebo; Trazodone; Zolpidem

Diphenhydramine, 25 mg DRUG

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.

Also known as: Benadryl

Diphenhydramine

Diphenhydramine, 50 mg DRUG

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.

Also known as: Benadryl

Diphenhydramine

Doxepin, 3 mg DRUG

Doxepin, 3 mg, once nightly 30 minutes prior to bed

Also known as: Silenor

Doxepin

Doxepin, 6 mg DRUG

Doxepin, 6 mg, once nightly 30 minutes prior to bed

Also known as: Silenor

Doxepin

Trazodone, 50 mg DRUG

Trazodone, 50 mg, once nightly 30 minutes prior to bed

Also known as: Desyrel

Trazodone

Trazodone, 100 mg DRUG

Trazodone, 100 mg, once nightly 30 minutes prior to bed

Also known as: Desyrel

Trazodone

Placebo DRUG

Placebo, once nightly 30 minutes prior to bed

Also known as: Inactive Drug, Inert Capsule

Placebo

Zolpidem, 5 mg DRUG

Zolpidem, 5 mg, once nightly 30 minutes prior to bed

Also known as: Ambien

Zolpidem

Zolpidem, 10 mg DRUG

Zolpidem, 10 mg, once nightly 30 minutes prior to bed

Also known as: Ambien

Zolpidem

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• 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

Sponsors & Collaborators

• University of Pennsylvania: lead
• Patient-Centered Outcomes Research Institute: collaborator

Study Sites (1)

University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

RECRUITING

MeSH Terms

Conditions

Sleep Initiation and Maintenance Disorders

Interventions

Diphenhydramine; Doxepin; Trazodone; Zolpidem

Condition Hierarchy (Ancestors)

Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Nervous System Diseases; Mental Disorders

Intervention Hierarchy (Ancestors)

Ethylamines; Amines; Organic Chemicals; Benzhydryl Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Oxepins; Ethers, Cyclic; Ethers; Dibenzoxepins; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Piperazines; Heterocyclic Compounds, 1-Ring; Pyridones; Pyridines

Study Officials

• Michael L Perlis, PhD

  University of Pennsylvania

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Michael L Perlis, PhD

CONTACT

215-746-3577; mperlis@upenn.edu

Mark Seewald, MSW

CONTACT

215-746-4378; mark.seewald@pennmedicine.upenn.edu

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: To maintain blinding throughout the study, all medications, including placebo, will be manufactured to appear identical.
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: March 20, 2026
• First Posted: April 21, 2026
• Study Start: May 1, 2026
• Primary Completion (Estimated): January 1, 2032
• Study Completion (Estimated): January 1, 2032
• Last Updated: June 5, 2026

Record last verified: 2026-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF

Locations

US (1)