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

Official title

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

Overview

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).

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.

Interventions

• Drug Trazodone
  50mg of trazodone administered for 4 weeks.
• Drug Placebo
  Placebo administered for 4 weeks.

Primary outcome measures

• Change in total sleep duration between the treatment arms [Time frame: Baseline and End of study, up to 12 weeks]
• Change in Slow Wave Sleep (SWS) duration between the treatment arms [Time frame: Baseline and End of study, up to 12 weeks]
• Change in SWS intensity between the treatment arms [Time frame: Baseline and End of study, up to 12 weeks]
• Change in sleep onset latency between the treatment arms [Time frame: Baseline and End of study, up to 12 weeks]
• Change in sleep fragmentation between the treatment arms [Time frame: Baseline and End of study, up to 12 weeks]
• Change in self reported sleep measure Pittsburgh Sleep Quality Index (PSQI) between treatment arms [Time frame: Baseline and End of study, up to 12 weeks]
• Change in self reported sleep measure Epworth Sleepiness Score (ESS) between treatment arms [Time frame: Baseline and End of study, up to 12 weeks]

Secondary outcome measures (2)

• Change in memory performance between treatment arms [Time frame: 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 [Time frame: Baseline and End of study, up to 12 weeks]

Eligibility criteria

Inclusion criteria

• Mild Cognitive Impairment (MCI) as defined by Albert et al.2 including subjective memory complaint and/or objective evidence of memory problems;
• Clinical Dementia Rating (CDR) of 0.5 with a Memory Box score of >=0.5;
• Evidence of sleep complaints with Pittsburgh Sleep Quality Index score of >5 (a well-validated cutoff observed in >40% of older persons);
• 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;
• Visual and auditory acuity adequate for neuropsychological testing;
• Good general health with no disease expected to interfere with the study;
• Able to have Magnetic Resonance Imaging (MRI) scan;
• Availability of knowledgeable informant (KI)
• Buschke Selective Reminding Test or more standard deviations below age-education norms

Exclusion criteria

• Less than 55 years of age to reduce likelihood of including individuals with frontotemporal dementia or non-dementia MCI;
• Too frail or medically unstable to undergo study procedures;
• 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;
• Dementia;
• Cognitive complaints and deficits better explained by other medical/neurologic conditions;
• Delirium;
• Allergic to trazodone;
• Taking sleep medications including trazodone;
• Current substance abuse;
• Current major depressive, manic, or acute psychotic episode;
• 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:
• Lack of available KI;
• Prior diagnosis of Q wave T wave Corrected for heart rate (QTc) > 470 msec (females) or > 450 msec (males);
• Inability to provide informed consent

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Crossover

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

United States · 1 center

• Johns Hopkins Hospital — Baltimore

Publications

• Eyob E, Shaw JS, Bakker A, Munro C, Spira A, Wu M, Rabinowitz JA, Peters M, Wanigatunga S, Zipunnikov V, Thompson R, Burhanullah MH, Leoutsakos JM, Rosenberg P, Greenberg B. A Randomized-Controlled Trial Targeting Cognition in Early Alzheimer's Disease by Improving Sleep with Trazodone (REST). J Alzheimers Dis. 2024;101(s1):S205-S215. doi: 10.3233/JAD-230635. PMID 39422935

Identifiers

NCT: NCT05282550 · IRB00301426 · R01AG071522

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗