NCT07542756 · University of Pennsylvania
A SMART Approach to Evaluating the Benefits of Common Prescription and OTC Medications for Insomnia
What this study is about
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).
View original scientific description
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).
Interventions
OTHER
Sleep Hygiene Education
Standard behavioral and environmental recommendations aimed at promoting healthy sleep
DIETARY_SUPPLEMENT
Melatonin IR, 3 mg
Immediate release formulation of melatonin, once nightly 30 minutes prior to bed
DIETARY_SUPPLEMENT
Melatonin IR, 5 mg
Immediate release formulation of melatonin, once nightly 30 minutes prior to bed
DRUG
Diphenhydramine, 25 mg
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.
DRUG
Diphenhydramine, 50 mg
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.
DRUG
Doxepin, 3 mg
Doxepin, 3 mg, once nightly 30 minutes prior to bed
DRUG
Doxepin, 6 mg
Doxepin, 6 mg, once nightly 30 minutes prior to bed
DRUG
Trazodone, 50 mg
Trazodone, 50 mg, once nightly 30 minutes prior to bed
DRUG
Trazodone, 100 mg
Trazodone, 100 mg, once nightly 30 minutes prior to bed
DRUG
Placebo
Placebo, once nightly 30 minutes prior to bed
DRUG
Zolpidem, 5 mg
Zolpidem, 5 mg, once nightly 30 minutes prior to bed
DRUG
Zolpidem, 10 mg
Zolpidem, 10 mg, once nightly 30 minutes prior to bed
Primary outcome measures
Relative treatment response rates during acute (1-month) treatment phase
Time frame: From treatment initiation to 1 month after treatment initiation
Defined as an at least 8-point reduction on the Insomnia Severity Index (ISI)
Relative safety and tolerability based on side effects during acute (1-month) treatment phase
Time frame: From treatment initiation to 1 month after treatment initiation
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)
Relative effects on daytime symptoms and function during acute (1-month) treatment phase
Time frame: From treatment initiation to 1 month after treatment initiation
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
Durability of treatment response during longer-term maintenance (1-6 months) treatment phase
Time frame: From the start of the 2nd month after treatment initiation to 6 months after treatment initiation
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
Relative safety and tolerability based on side effects during longer-term maintenance (1-6 months) phase
Time frame: From the start of the 2nd month after treatment initiation to 6 months after treatment initiation
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)
Durability of effects on daytime symptoms and function during longer-term maintenance (1-6 months) phase
Time frame: From the start of the 2nd month after treatment initiation to 6 months after treatment initiation
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
Who can participate
This study lists these criteria on ClinicalTrials.gov. A study coordinator reviews eligibility during screening — this page does not determine whether you qualify.
Inclusion criteria
- 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.
Exclusion criteria
- 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. 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
Where
- Philadelphia, Pennsylvania
Collaborators
Patient-Centered Outcomes Research Institute
Related conditions & keywords
Frequently asked questions
What is a clinical trial?
A clinical trial is a research study that tests new medical treatments, drugs, devices, or procedures to determine their safety and effectiveness. Trials are carefully designed and monitored to protect participants while advancing medical knowledge.
Is it safe to participate?
Clinical trials follow strict safety guidelines and ethical standards. Trials must be reviewed and approved, and participants are closely monitored by medical professionals throughout the study. You can withdraw at any time if you choose.
Will I be compensated?
Many clinical trials offer compensation for your time, travel expenses, and inconvenience. The specific compensation varies by study and will be discussed during the screening process. All study-related medical care is typically provided at no cost to participants.
Will I receive a placebo instead of treatment?
When effective treatment exists, participants typically receive either the standard treatment plus the study intervention, or the standard treatment plus placebo. You would not be denied effective care. Placebos are primarily used when no proven treatment is available, or in addition to standard care. Your trial consent form will clearly explain what treatments you may receive.
Can I leave a trial if I change my mind?
Absolutely. Participation in clinical trials is completely voluntary. You have the right to withdraw from the study at any time, for any reason, without penalty or loss of benefits to which you are otherwise entitled.
How long does a clinical trial last?
Trial duration varies widely depending on the study design and purpose. Some trials last just a few weeks, while others may continue for months or years. The study coordinator will provide specific timeline information during your screening call.
Data: ClinicalTrials.gov · synced Jun 5, 2026 · Source of record for eligibility and locations