Medications for PTSD-Related Insomnia

(NAP Trial)

Recruiting at 24 trial locations

Overseen By Larry Albers, MD

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: VA Office of Research and Development

Must not be taking: Sleep medications

Disqualifiers: Bipolar, Schizophrenia, TBI, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

774 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if the medications trazodone, eszopiclone (Lunesta), gabapentin (Neurontin), or a placebo can improve sleep issues related to PTSD (posttraumatic stress disorder). Many Veterans with PTSD experience insomnia, which includes difficulty falling or staying asleep. The trial seeks Veterans with PTSD linked to military service who have ongoing sleep problems. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications listed in Appendix A. If you're taking one of these medications to help with sleep, you can participate if you stop taking it for a period of time (called a washout period) under your doctor's care.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that eszopiclone is usually well-tolerated. In one study, participants taking eszopiclone for three weeks showed more improvement in PTSD symptoms than those taking a placebo. Another study found it safe and tolerable for individuals with PTSD-related sleep problems.

For trazodone, research suggests it is safe in low doses for insomnia. It is often used to address sleep issues and has been reported to effectively treat sleep disturbances in PTSD.

These studies indicate that both eszopiclone and trazodone are generally safe with few side effects, making them promising options for managing sleep issues linked to PTSD. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for PTSD-related insomnia because they offer different approaches to managing sleep disturbances. Eszopiclone is unique because it targets the GABA receptors in the brain, potentially helping patients fall asleep faster. Gabapentin, on the other hand, is believed to help by reducing nighttime anxiety and hyperarousal, which are common in PTSD. Trazodone is an antidepressant that is often used off-label for its sedative effects, providing a dual benefit for those with PTSD by potentially improving both mood and sleep. These treatments could offer new hope compared to traditional options like benzodiazepines or other sedative-hypnotics, which can have issues with dependency and tolerance.

What evidence suggests that this trial's treatments could be effective for PTSD-related insomnia?

Research has shown that eszopiclone, which participants in this trial may receive, can significantly improve sleep and reduce PTSD symptoms compared to a placebo. It addresses sleep problems and nightmares in individuals with PTSD. Trazodone, another treatment option in this trial, effectively enhances sleep, with 92% of users falling asleep more easily and 78% staying asleep longer. Although not part of this trial, Gabapentin has shown promise in improving sleep issues and other PTSD symptoms; one study found that 77% of patients noticed improvements. Overall, evidence supports the effectiveness of these medications in treating sleep problems related to PTSD. ^{1 2 3 5 6}

Who Is on the Research Team?

John H. Krystal, MD

Principal Investigator

VA Connecticut Healthcare System West Haven Campus, West Haven, CT

Are You a Good Fit for This Trial?

This trial is for veterans aged 18-75 with PTSD-related insomnia, who have a significant level of sleep disturbance and PTSD symptoms. Participants must be able to give informed consent, adhere to lifestyle guidelines, and allow phone interview recordings. They should not have severe medical conditions or substance dependence, nor be involved in other clinical studies.

Inclusion Criteria

Total CAPS-5 score 23

Primary DSM-5 diagnosis of PTSD, assessed by structured interview using the CAPS-5

Allow digital recording of phone interviews

Exclusion Criteria

A comorbid current or lifetime diagnosis of certain psychiatric disorders

Under criminal investigation or pending legal charges with potential incarceration

Participants with narcolepsy

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive trazodone hydrochloride, eszopiclone, or placebo for insomnia symptoms in PTSD, with dose titration over the initial 3 weeks and continued treatment until week 12

12 weeks

Interim Analysis

Mid-point interim analysis to evaluate treatment efficacy and potentially drop arms meeting futility criteria

1 week

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Eszopiclone
• Gabapentin
• Placebo
• Trazodone

Trial Overview The study tests if trazodone, eszopiclone, or gabapentin can improve sleep for those with PTSD-related insomnia. It's a comparison against a placebo over approximately 17 weeks. Patients are randomly assigned to one of the medications or placebo without knowing which they receive.

How Is the Trial Designed?

Group I: Trazodone Active Control 1 Intervention

Participants who are assigned to take trazodone, an active study medication.

Group II: Eszopiclone Active Control 1 Intervention

Participants who are assigned to take eszopiclone, an active study medication.

Group III: Placebo Placebo Group 1 Intervention

Participants who are assigned to take a placebo, a non-active study medication.

Eszopiclone is already approved in United States, Canada, European Union for the following indications:

Approved in United States as Lunesta for:

• Insomnia

Approved in Canada as Lunesta for:

• Insomnia

Approved in European Union as Lunesta for:

• Insomnia

Who Is Running the Clinical Trial?

VA Office of Research and Development

Lead Sponsor

Trials

1,691

Recruited

3,759,000+

Published Research Related to This Trial

In a 12-week study involving 25 participants with PTSD and insomnia, both eszopiclone (ESZ) and placebo showed significant improvements in PTSD symptoms, but there were no significant differences between the two treatments.

While ESZ did not demonstrate a specific advantage over placebo in improving sleep or PTSD symptoms, there was a notable correlation between sleep improvement and overall PTSD symptom reduction in the ESZ group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Double-blind randomized controlled study of the efficacy, safety and tolerability of eszopiclone vs placebo for the treatment of patients with post-traumatic stress disorder and insomnia. Dowd, SM., Zalta, AK., Burgess, HJ., et al.[2021]

In a 12-week study involving 10 Vietnam combat veterans with chronic PTSD, nefazodone treatment significantly reduced PTSD and depressive symptoms, indicating its efficacy as a therapeutic option.

Nefazodone also improved both subjective and objective sleep quality, leading to longer total sleep time and better sleep maintenance, which is crucial for veterans suffering from sleep disturbances related to PTSD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of nefazodone on subjective and objective sleep quality in posttraumatic stress disorder. Neylan, TC., Lenoci, M., Maglione, ML., et al.[2019]

Prazosin and Image Rehearsal Therapy (IRT) are both highly recommended (Level A) for treating PTSD-associated nightmares and nightmare disorder, respectively, indicating strong evidence for their efficacy.

Venlafaxine is not recommended for PTSD-associated nightmares, while clonidine may be considered, highlighting the importance of selecting appropriate treatments based on available evidence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Best practice guide for the treatment of nightmare disorder in adults. Aurora, RN., Zak, RS., Auerbach, SH., et al.[2022]

In a study analyzing veterans with PTSD, it was found that the severity of insomnia and nightmares significantly influenced the prescription of sleep medications, with trazodone prescribed for insomnia and prazosin for nightmares.

Over time, there was a shift in prescribing patterns, with veterans more likely to receive trazodone and prazosin, and less likely to be prescribed benzodiazepines, indicating a move towards potentially safer sleep medication options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Symptom Presentation and Prescription of Sleep Medications for Veterans With Posttraumatic Stress Disorder. Greenbaum, MA., Neylan, TC., Rosen, CS.[2018]

The NAP Study is a large-scale clinical trial involving 1224 veterans with PTSD, comparing the efficacy of three insomnia medications (trazodone, eszopiclone, and gabapentin) against a placebo over 12 weeks, aiming to find effective treatments for PTSD-related insomnia.

The study features an adaptive design that allows for real-time adjustments based on interim results, potentially enhancing the statistical power of the remaining treatment comparisons and guiding future research on biomarkers for treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Design of the National Adaptive Trial for PTSD-related Insomnia (NAP Study), VA Cooperative Study Program (CSP) #2016. Krystal, JH., Chow, B., Vessicchio, J., et al.[2022]

This review highlights that sleep disorders like insomnia and nightmares are prevalent in PTSD and significantly affect quality of life, yet the pharmacological treatment options remain under-researched.

Promising results have been found for medications such as the atypical antipsychotic olanzapine and the alpha1-adrenoceptor antagonist prazosin, but more randomized controlled trials with larger participant groups are needed to confirm their efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacotherapy for disordered sleep in post-traumatic stress disorder: a systematic review. van Liempt, S., Vermetten, E., Geuze, E., et al.[2022]

In a 12-week open-label trial with 10 combat-related PTSD patients, nefazodone was well tolerated and led to significant improvements in most PTSD symptoms, sleep quality, and anger management, with all patients rated as much improved by the end of the study.

The treatment showed moderate to large effect sizes for symptom improvement, although self-reported depression did not show significant change, indicating nefazodone's potential effectiveness in managing PTSD symptoms, particularly sleep disturbances.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Open trial of nefazodone for combat-related posttraumatic stress disorder. Hertzberg, MA., Feldman, ME., Beckham, JC., et al.[2019]

In a retrospective review of 30 PTSD patients treated with gabapentin, 77% experienced moderate or greater improvement in sleep duration and a reduction in nightmares, suggesting gabapentin may effectively address sleep disturbances associated with PTSD.

While gabapentin was generally well-tolerated, with sedation and mild dizziness as common side effects, further controlled studies are necessary to confirm its efficacy in treating insomnia and other PTSD symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gabapentin in PTSD: a retrospective, clinical series of adjunctive therapy. Hamner, MB., Brodrick, PS., Labbate, LA.[2019]

Veterans with PTSD show low rates of insomnia diagnoses (3.5-5.6%) but high rates of sedative-hypnotic prescriptions (44.2-49.0%), indicating a potential under-diagnosis of insomnia.

Younger Veterans and those without breathing-related sleep disorders are more likely to be diagnosed with insomnia, while those with greater service connection and substance use disorders are more likely to be prescribed sedative-hypnotics, highlighting the need for policy changes to prioritize behavioral treatments over medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Characterization of Insomnia among Veterans with PTSD: Identifying Risk Factors for Diagnosis and Treatment with Sedative-Hypnotics. Bramoweth, AD., Luther, J., Hanusa, BH., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7099286/

Double-blind randomized controlled study of the efficacy, ... The data from insomnia focused CBT appears to improve sleep but no other symptoms of PTSD. However, the data from Imagery Rehearsal therapy for the treatment ...

2. psychiatrist.com psychiatrist.com/jcp/eszopiclone-treatment-posttraumatic-stress-disorder/

Eszopiclone for the Treatment of Posttraumatic Stress ... Results: Three weeks of eszopiclone pharmacotherapy was associated with significantly greater improvement than placebo on PTSD symptom measures ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT00120250

Eszopiclone for Sleep Disturbance and Nightmares in Post ... The investigators hypothesize that eszopiclone will be significantly more effective than placebo and well tolerated for PTSD-related sleep disturbance, ...

4. jcsm.aasm.org jcsm.aasm.org/doi/pdf/10.5664/jcsm.11008

Breathing new life into PTSD-related sleep disorders! Eszopiclone for the treatment of posttraumatic stress disorder and associated insomnia: a randomized, double- blind, placebo-controlled ...

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1551714421002767

Design of the National Adaptive Trial for PTSD-related ... Small clinical trials have produced mixed results in terms of reducing insomnia and improving PTSD symptoms [15,16].

6. clinicaltrials.gov clinicaltrials.gov/study/NCT01605253

Study Details | NCT01605253 | Eszopiclone for the ... The purpose of this study is to determine if eszopiclone relative to placebo (sugar pill) is effective and tolerable for people with posttraumatic stress ...