Targeting Cognition in Early Alzheimer's Disease by Improving Sleep With Trazodone (REST)

RCT Targeting Cognition in Early Alzheimer's Disease by Improving Sleep With Trazodone (REST)

To investigate the effect of trazodone on sleep, hippocampal-dependent memory and hippocampal excitability. The investigators hypothesize that trazodone will improve total sleep time and proportion of time in Slow Wave Sleep (SWS).

Study Overview

• Status: Recruiting
• Conditions: Sleep Disturbance; AMCI - Amnestic Mild Cognitive Impairment
• Intervention / Treatment: Drug: Trazodone; Drug: Placebo

Detailed Description

The REST trial is a randomized, placebo-controlled, double-blind crossover study of trazodone (50 mg at bedtime) in participants with Amnestic Mild Cognitive impairment (aMCI) and sleep complaints. The investigators will randomize 100 subjects and administer trazodone and placebo for 4 weeks each with a 4-week washout period in between. A 4-week washout period is more than sufficient due to trazodone's elimination half-life of 10-12 hours. The crossover design will facilitate recruitment and enable the use of the subjects as a control without requiring a parallel placebo arm.

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Barry Greenberg, PhD; Phone Number: 410-955-1696; Email: bgreen45@jhmi.edu
• Study Contact Backup: Name: Paul Rosenberg, MD; Phone Number: 410-550-9883; Email: prosenb9@jhmi.edu

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Recruiting
      • Johns Hopkins Hospital
      • Contact: Barry Greenberg, PhD; Phone Number: 410-955-1696; Email: bgreen45@jhmi.edu
      • Contact: Paul Rosenberg, MD; Phone Number: 410-550-9883; Email: prosenb9@jhmi.edu
      • Principal Investigator: Barry Greenberg, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 55 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Mild Cognitive Impairment (MCI) as defined by Albert et al.2 including subjective memory complaint and/or objective evidence of memory problems;
2. Clinical Dementia Rating (CDR) of 0.5 with a Memory Box score of >=0.5;
3. Evidence of sleep complaints with Pittsburgh Sleep Quality Index score of >5 (a well-validated cutoff observed in >40% of older persons);
4. Memory performance > 1.5 Standard Deviation (SD) below age-and education-matched control subjects on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) List Recall;
5. Visual and auditory acuity adequate for neuropsychological testing;
6. Good general health with no disease expected to interfere with the study;
7. Able to have Magnetic Resonance Imaging (MRI) scan;
8. Availability of knowledgeable informant (KI)

Exclusion Criteria:

1. Less than 55 years of age to reduce likelihood of including individuals with frontotemporal dementia or non-dementia MCI;
2. Too frail or medically unstable to undergo study procedures;
3. Prior diagnosis of Obstructive Sleep Apnea (OSA) or evidence of moderate-to-severe OSA on baseline Home Sleep Test (HST) as evidenced by an apnea/hypopnea index of >15;
4. Dementia;
5. Cognitive complaints and deficits better explained by other medical/neurologic conditions;
6. Delirium;
7. Allergic to trazodone;
8. Taking sleep medications including trazodone;
9. Current substance abuse;
10. Current major depressive, manic, or acute psychotic episode;
11. Prior diagnosis of significant systemic illness or unstable medical condition which could lead to difficulty complying with the study protocol or represent alternate primary cause of memory problems beyond Alzheimer's Disease (AD) pathology:
12. Lack of available KI;
13. Prior diagnosis of Q wave T wave Corrected for heart rate (QTc) > 470 msec (females) or > 450 msec (males);
14. Inability to provide informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Trazodone First; Trazodone (50 mg at bedtime) and then placebo after a 4-week washout period.	Drug: Trazodone; 50mg of trazodone administered for 4 weeks.; Other Names: Desyrel; Drug: Placebo; Placebo administered for 4 weeks.
Placebo Comparator: Placebo First; Placebo and then Trazodone (50 mg at bedtime) after a 4-week washout period.	Drug: Trazodone; 50mg of trazodone administered for 4 weeks.; Other Names: Desyrel; Drug: Placebo; Placebo administered for 4 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in total sleep duration between the treatment arms	Comparison of means of total sleep duration from baseline measured in minutes between trazodone and placebo arm.	Baseline and End of study, up to 12 weeks
Change in Slow Wave Sleep (SWS) duration between the treatment arms	Comparison of means of SWS from baseline measured in minutes between trazodone and placebo arm.	Baseline and End of study, up to 12 weeks
Change in SWS intensity between the treatment arms	Comparison of means of SWS intensity measured from baseline in volts squared between trazodone and placebo arm.	Baseline and End of study, up to 12 weeks
Change in sleep onset latency between the treatment arms	Comparison of means of sleep onset latency from baseline measured in minutes between trazodone and placebo arm.	Baseline and End of study, up to 12 weeks
Change in sleep fragmentation between the treatment arms	Comparison of means of sleep fragmentation from baseline measured in minutes between trazodone and placebo arm.	Baseline and End of study, up to 12 weeks
Change in self reported sleep measure Pittsburgh Sleep Quality Index (PSQI) between treatment arms	Comparison of means score for PSQI from baseline between trazodone and placebo arm. A higher score means a worse outcome.	Baseline and End of study, up to 12 weeks
Change in self reported sleep measure Epworth Sleepiness Score (ESS) between treatment arms	Comparison of means score for ESS from baseline between trazodone and placebo arm. A higher score means a worse outcome.	Baseline and End of study, up to 12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in memory performance between treatment arms	Comparison of means for memory performance from baseline measured in percent correct between trazodone and placebo arm.	Baseline and End of study, up to 12 weeks
Change in hippocampal activation on Function Magnetic Resonance Imaging (fMRI) measures during memory functioning between treatment arms	Comparison of means of hippocampal activation on fMRI measures calculated as a beta weight reflecting relative activation during memory functioning from baseline between trazodone and placebo arm. Higher activation suggests a worse outcome.	Baseline and End of study, up to 12 weeks

Collaborators and Investigators

• Sponsor: Johns Hopkins University
• Collaborators: National Institute on Aging (NIA)
• Investigators: Principal Investigator: Barry Greenberg, PhD, Johns Hopkins University

Study record dates

Study Major Dates

• Study Start (Actual): February 2, 2023
• Primary Completion (Estimated): July 30, 2027
• Study Completion (Estimated): June 30, 2028

Study Registration Dates

• First Submitted: March 8, 2022
• First Submitted That Met QC Criteria: March 8, 2022
• First Posted (Actual): March 16, 2022

Study Record Updates

• Last Update Posted (Estimated): September 18, 2025
• Last Update Submitted That Met QC Criteria: September 17, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: Cognition; Trazodone; Slow wave sleep; AMCI
• Additional Relevant MeSH Terms: Nervous System Diseases; Mental Disorders; Sleep Wake Disorders; Parasomnias; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Substandard Drugs; Pharmaceutical Preparations; Piperazines; Pyridones; Trazodone; Counterfeit Drugs
• Other Study ID Numbers: IRB00301426; R01AG071522 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The Executive Committee of the study, consisting of the study PIs and the Director of the Data Coordinating Center for this study will oversee the deidentified Individual Participant Data (IPD) sharing. This will include the review of requests for trial data and samples. The Executive Committee will assure that all investigators who receive data and/or specimens are qualified investigators, with research goals consistent with those stated in the consent form. A Material Transfer Agreement (MTA) and/or Data Use Agreement (DUA) will be in place with approved requestors before any transfer of bio-samples or data. Investigators receiving the data and/or samples will be required to cite the grant in any publications generated by the data and to send a copy of all publications to the study team.
• IPD Sharing Time Frame: 1 year after study completion
• IPD Sharing Access Criteria: Upon approval of data analytic strategy by study team
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No