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

Sponsor

Johns Hopkins University (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05282550

Collaborator

National Institute on Aging (NIA) (NIH)

100

Enrollment

Location

Arms

Anticipated Duration (Months)

1.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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).

Condition or Disease	Intervention/Treatment	Phase
AMCI - Amnestic Mild Cognitive Impairment Sleep Disturbance	Drug: Trazodone Drug: Placebo	Phase 2

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 Design

Study Type:

Interventional

Anticipated Enrollment :

100 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Intervention Model Description:

We will administer trazodone and placebo for 4 weeks each with a 4-week washout.We will administer trazodone and placebo for 4 weeks each with a 4-week washout.

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

Study drug will be compounded by the Investigational Drug Service (IDS) at Johns Hopkins Bayview Medical Center. The IDS will prepare blind medication using opaque capsules and randomly assign eligible participants to treatment order (ie, starting with trazodone vs. placebo treatment).

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Oct 1, 2022

Anticipated Primary Completion Date :

Mar 1, 2027

Anticipated Study Completion Date :

May 1, 2028

Arms and Interventions

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.

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.

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

Change in memory performance between treatment arms [Baseline and End of study, up to 12 weeks]
Comparison of means for memory performance from baseline measured in percent correct between trazodone and placebo arm.
Change in hippocampal activation on Function Magnetic Resonance Imaging (fMRI) measures during memory functioning between treatment arms [Baseline and End of study, up to 12 weeks]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

55 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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)

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