Trazodone Dose Tolerance and APAP Adherence (TrazoDose)

Randomized Controlled Trial of Trazodone Dose Tolerance and APAP Adherence

Trazodone may help obstructive sleep apnea patients to stick to their therapy, but optimal dosing is unknown. This study looks at what dose of trazodone has the best balance of potential benefits to side-effects in people with obstructive sleep apnea who are either starting on positive airway pressure therapy or not adherent to it. Participants will be randomly assigned to one of three groups: trazodone 50 mg, trazodone 100 mg, or placebo for 14 days. The investigators will monitor side-effects and adherence to positive airway pressure therapy.

Study Overview

• Status: Suspended
• Conditions: Sleep Apnea, Obstructive
• Intervention / Treatment: Drug: Placebo; Drug: Trazodone

Detailed Description

Clinical Significance: Trazodone is an often-used medication in clinical sleep medicine. However, there is a dearth of information on side-effects with doses typically used for sleep. In addition, a significant proportion of the VA population have obstructive sleep apnea for which the primary treatment is positive airway therapy. However, many patients have difficulty adhering to this treatment long-term. Increased adherence to this modality has been shown to improve risk for cardiovascular and neurologic co-morbidity associated with obstructive sleep apnea. This project explores both the tolerability and safety of common doses of trazodone used in clinical sleep practice as well explores potential effects on positive airway pressure therapy adherence.

Objectives: This project seeks to determine the tolerability and multi-domain effect on sleep and mood of a 14 day course of trazodone at either 50 mg or 100 mg or placebo.

Research Plan: This is a three-group, randomized, double-blind, placebo-controlled trial with prospective data collection of VA outpatient sleep clinic patients with obstructive sleep apnea with who are non-adherent or newly started on auto-titrating positive airway pressure therapy. Evaluation focuses on medication tolerability as measured by number of days before study drug discontinuation by the participant, the Treatment Satisfaction Questionnaire for Medication, the side-effect profile at the two doses (50mg and 100mg) compared to placebo as well as longitudinal collection of adherence data and standardized questionnaires on sleepiness, insomnia, depression, anxiety, and self-efficacy. The investigators also plan to longitudinally monitor coefficient of variation of breath-to-breath tidal volume, a measure of respiratory mechanics which may be affected by trazodone use. Study participants will have 2 visits at baseline and 2 weeks after randomization.

Methodology: This study will be conduced in the Louis Stokes Cleveland Medical Center - Wade Park Sleep Clinic, a tertiary institutional referral facility. Participants must be adults with obstructive sleep apnea prescribed auto-titrating positive airway therapy who are either newly initiated or do not fulfill standard criteria for adherence and do not have allergy to trazodone; current use of trazodone, monoamine oxidase inhibitors, or sedative hypnotics; alcohol or drug abuse; severe psychiatric disease; epilepsy; significant cardiac disease; liver disease; pregnancy; hypotension; or predisposition to priapism. Study staff will interview the potential participant and do a review of the medical record for exclusion criteria before consent is obtained. The investigators expect to recruit 45 participants into the study with a 20% attrition rate before completion. Hypothesis about the tolerability of trazodone and effect on positive airway therapy adherence was prespecified.

• Study Type: Interventional
• Enrollment (Anticipated): 45
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Louis Stokes Cleveland VA Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Louis Stokes Cleveland VA Sleep Medicine clinic patient
• AHI greater than or equal to 5
• obstructive sleep apnea
• new initiation or nonadherence to APAP

Exclusion Criteria:

• schizophrenia
• bipolar disorder
• current use of trazodone or sedative hypnotics
• allergy to trazodone
• current use of tricyclic antidepressants or monoamine oxidase inhibitors
• current alcohol or drug abuse
• heart failure
• heart attack in past 3 months
• congenital long QT, ventricular arrhythmia (including Torsades de Pointes), bradycardia, or digoxin therapy
• use of amiodarone, sotalol, dofetilide, or dronedarone
• epilepsy
• liver disease
• pregnancy (or planning pregnancy)
• right of priapism: history of priapism, sickle cell disease, Farby disease

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; pill filled with inert material	Drug: Placebo; take at bedtime for 14 days
Active Comparator: Trazodone 50mg	Drug: Trazodone; take at bedtime for 14 days; Other Names: Desyrel; oleptro
Active Comparator: Trazodone 100mg	Drug: Trazodone; take at bedtime for 14 days; Other Names: Desyrel; oleptro

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Discontinuation rate by participant	Did the participant discontinue trazodone at a higher rate than placebo?	14-16 days post-randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
3 month APAP adherence	APAP use in last 30 days (of the 3 month period) as measured by (1) average hours/day and (2) percent days with 4 or more hours use	3 months post-randomization assessing 30 days before this 3 month period
Respiratory patterning	Variation of breath to breath tidal volume obtained from plethysmography (a stretchy band around the chest x 20 minutes while wearing APAP)	14-16 days post-randomization
Medication Satisfaction	Treatment Satisfaction Questionnaire for Medications version II overall and subscale scores	14-16 days post-randomization
side-effect profile	participant-reported side effects of study drug	14-16 days post-randomization
sleepiness	Epworth Sleepiness Scale	14-16 days post-randomization
insomnia	Insomnia Severity Index	14-16 days post-randomization
general self-efficacy	General Self-Efficacy Scale	14-16 days post-randomization
depression	Clinically Useful Depression Outcome Scale (CUDOS)	14-16 days post-randomization
anxiety	Clinically Useful Anxiety Outcome Scale (CUXOS)	14-16 days post-randomization

Collaborators and Investigators

• Sponsor: Louis Stokes VA Medical Center
• Investigators: Principal Investigator: Kingman P Strohl, MD, Louis Stokes Cleveland VA Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): February 13, 2017
• Primary Completion (Anticipated): September 1, 2020
• Study Completion (Anticipated): December 1, 2020

Study Registration Dates

• First Submitted: October 11, 2016
• First Submitted That Met QC Criteria: October 24, 2016
• First Posted (Estimate): October 26, 2016

Study Record Updates

• Last Update Posted (Actual): May 11, 2020
• Last Update Submitted That Met QC Criteria: May 7, 2020
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Keywords: adherence; obstructive sleep apnea; trazodone; positive airway pressure
• Additional Relevant MeSH Terms: Nervous System Diseases; Respiratory Tract Diseases; Apnea; Respiration Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Sleep Apnea Syndromes; Sleep Apnea, Obstructive; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Tranquilizing Agents; Psychotropic Drugs; Serotonin Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Antidepressive Agents; Anti-Anxiety Agents; Antidepressive Agents, Second-Generation; Trazodone
• Other Study ID Numbers: 16025-H17

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

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