Sequenced Therapies for Comorbid and Primary Insomnias

• Sponsor: Jack Edinger, PhD (Other)
• Overall Status: Completed
• CT.gov ID: NCT01651442
• Collaborator: National Institutes of Health (NIH) (NIH), National Institute of Mental Health (NIMH) (NIH)
• Enrollment: 211
• Locations: 2
• Arms: 6
• Actual Duration (Months): 55
• Patients Per Site: 105.5
• Patients Per Site Per Month: 1.9

Study Details

Study Description

Brief Summary

Chronic insomnia is a prevalent disorder associated with increased health care costs, impaired functioning, and an increased risk for developing serious psychiatric disorders. Cognitive-behavioral therapies (CBTs) and benzodiazepine receptor agonist (BzRA) medications are the most widely supported approaches for insomnia management. Unfortunately, few studies have compared the psychological/behavioral therapies and BzRAs for insomnia treatment. Moreover, insomnia treatment studies have been limited by small, highly screened study samples, fixed-dose and fixed-agent pharmacotherapy strategies that do not represent usual adjustable dosing practices, relatively short follow-up intervals, and reliance on self-report or polysomnographic (PSG) sleep parameters as outcomes, rather than on more clinically relevant indicators of remission. Finally, studies have yet to test the benefits of treatment sequencing for those who do not respond to initial their insomnia therapy. This multi-site project will address these limitations. Two study sites will enroll a total of 224 participants who meet broad criteria for a chronic insomnia disorder, and a sizeable portion (60%) of this sample will have insomnia occurring comorbid to a psychiatric disorder. Participants will be evaluated with clinical assessments and PSG, and then will be randomly assigned to first-stage therapy with an easy-to-administer behavioral insomnia therapy (BT) or zolpidem (most widely prescribed BzRA). Centrally trained therapists will administer therapies according to manualized, albeit flexible, treatment algorithms. Initial outcomes will be assessed after 6 weeks, and treatment remitters will be followed for the next 12 months on maintenance therapy. Those not achieving remission will be offered re-randomization to a second, 6-week treatment involving pharmacotherapy (zolpidem or trazodone) or psychological therapy (BT or cognitive therapy-CT). All participants will be re-evaluated 12 weeks after protocol initiation, and at 3-, 6-, 9-, and 12-month follow-ups while continuing their final treatment. Insomnia remission, defined categorically as a score < 8 on the Insomnia Severity Index, will serve as the primary outcome for treatment comparisons. Secondary outcomes will include sleep diary and PSG sleep measures; subjective ratings of sleep and daytime function; adverse events; dropout rates; and treatment acceptability. Our over-arching goal is to obtain new information that aids in the development of clinical guidelines for managing insomnia sufferers with and without comorbid psychiatric conditions.

Condition or Disease	Intervention/Treatment	Phase
Insomnia Comorbid to Psychiatric Disorder; Primary Insomnia	Behavioral: Behavioral Insomnia Therapy; Drug: Zolpidem; Drug: Trazodone; Behavioral: Cognitive Therapy	N/A

Study Design

• Study Type: Interventional
• Actual Enrollment: 211 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Sequenced Therapies for Comorbid and Primary Insomnias
• Actual Study Start Date: Aug 1, 2012
• Actual Primary Completion Date: Mar 1, 2017
• Actual Study Completion Date: Mar 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Non-drug Sleep Therapy 1	Behavioral: Behavioral Insomnia Therapy; Sleep hygiene, stimulus control, and sleep restriction presented in four sessions.
Active Comparator: Sleep Medication 1	Drug: Zolpidem; 5mg or 10mg
Active Comparator: Non-drug Sleep Therapy 2 Following Non-drug Sleep Therapy 1	Behavioral: Cognitive Therapy; Cognitive restructuring, constructive worry, behavioral experiments presented in four sessions.
Active Comparator: Sleep Medication 2 Following Sleep Medication 1	Drug: Trazodone; 50mg to 150mg
Active Comparator: Non-drug Sleep Therapy 1 Following Sleep Medication 1	Behavioral: Behavioral Insomnia Therapy; Sleep hygiene, stimulus control, and sleep restriction presented in four sessions.
Active Comparator: Sleep Medication 1 Following Non-drug Sleep Therapy 1	Drug: Zolpidem; 5mg or 10mg

Outcome Measures

Primary Outcome Measures

1. Percent of Participants Who Met Remission as Measured by the Insomnia Severity Index [6 weeks, 12 weeks, 3 months, 6 months, 9 months & 12 months]

   The Insomnia Severity Index (ISI) is a self-report questionnaire assessing the nature, severity, and impact of insomnia. Remission is determined to be a score less-than 8.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• a complaint of persistent (i.e., > 1 month) difficulties initiating or maintaining sleep despite adequate opportunity for sleep;

• a sleep onset latency or wake time after sleep onset > 30 minutes 3 or more nights per week during two weeks sleep diary monitoring;

• an Insomnia Severity Index (ISI) score > 10 indicating at least "mild" insomnia; and

• a score ≥ 2 on either the interference or distress item of the screening ISI, indicating the insomnia causes significant distress or impairment in social, occupational, or other areas of functioning. These criteria represent those provided in the DSM-IV-TR87, Research Diagnostic Criteria3 and the International Classification of Sleep Disorders4, and will ensure a sample with clinically relevant insomnia.

Exclusion Criteria:

Exclusion criteria will be minimal to retain a broadly representative sample that includes patients with primary and insomnia comorbid to a psychiatric disorder. Likewise, individuals with a comorbid medical condition will be excluded only if the medical condition is life-threatening or would contra-indicate using study medications. Exclusion criteria are

• an untreated psychiatric disorder (e.g., major depression) as these conditions have specific treatments and it would be inappropriate not to offer those treatments;

• a lifetime diagnosis of any psychotic or bipolar disorder as sleep restriction and medications for insomnia may precipitate mania and hallucinations;

• an imminent risk for suicide;

• alcohol or drug abuse within the past year, since BzRAs are cross-tolerant with alcohol;

• terminal or progressive physical illness (e.g., cancer, COPD), or neurological degenerative disease (e.g., dementia);

• current use of medications known to cause insomnia (e.g., steroids);

• sleep apnea (apnea/hypopnea index > 15), restless legs syndrome, periodic limb movement during sleep (PLMS with arousal > 15 per hour), or a circadian rhythm sleep disorder (e.g., advanced sleep phase syndrome);

• habitual bedtimes later than 2:00 AM or rising times later than 10:00 AM;

• consuming > 2 alcoholic beverages per day on a regular basis.

Individuals using sleep-aids (prescribed or over-the-counter) will be included if they are willing and able to discontinue medications at least 2 weeks before baseline assessment. Participants using alcohol as a sleep aid or alcohol after 7:00pm on a regular basis will be required to discontinue this practice at least two weeks prior to baseline assessment. Individuals using psychotropic medications (e.g., anxiolytics, antidepressants) will not be automatically excluded from the study. Those on stable dosages (for at least three months) of SSRI or SNRI medications and who show at least partial remission (via SCID) from their mood or anxiety disorder will be accepted in the study if they meet the selection criteria above. Patients using TCAs, MAOIs, or atypical antidepressants will be excluded even if in remission as the effects of these medications on sleep might confound interpretation of the findings. We will impose similar standards for those with MDD, dysthymia, panic disorder, phobia, and GAD. We realize that some decisions about enrollment may not always be easy to make, but we will rely on all available data and a consensus approach to guide our clinical decision making process

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Jewish Health	Denver	Colorado	United States	80206
2	Université Laval	Quebec City	Quebec	Canada

Sponsors and Collaborators

• Jack Edinger, PhD
• National Institutes of Health (NIH)
• National Institute of Mental Health (NIMH)

Investigators

• Principal Investigator: Jack Edinger, PhD, National Jewish Health
• Principal Investigator: Charles Morin, PhD, Universite Laval

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 25, 2014

More Information

Publications

None provided.

• Responsible Party: Jack Edinger, PhD, Principal Investigator, National Jewish Health
• ClinicalTrials.gov Identifier: NCT01651442
• Other Study ID Numbers: R01MH091053-01; R01MH091075
• First Posted: Jul 27, 2012
• Last Update Posted: Mar 29, 2021
• Last Verified: Aug 1, 2019

• Additional relevant MeSH terms: Sleep Initiation and Maintenance Disorders; Mental Disorders; Problem Behavior; Zolpidem; Trazodone

Study Results

Participant Flow

Arm/Group Title	Non-drug Sleep Therapy 1	Sleep Medication 1	Non-drug Sleep Therapy 2 Following Non-drug Sleep Therapy 1	Sleep Medication 2 Following Sleep Medication 1	Non-drug Sleep Therapy 1 Following Sleep Medication 1	Sleep Medication 1 Following Non-drug Sleep Therapy 1
Arm/Group Description	Behavioral Insomnia Therapy: Sleep hygiene, stimulus control, and sleep restriction presented in four sessions.	Zolpidem: 5mg or 10mg	Cognitive Therapy: Cognitive restructuring, constructive worry, behavioral experiments presented in four sessions.	Trazodone: 50mg to 150mg	Behavioral Insomnia Therapy: Sleep hygiene, stimulus control, and sleep restriction presented in four sessions.	Zolpidem: 5mg or 10mg
Period Title: Phase I Treatment
STARTED	104	107	0	0	0	0
COMPLETED	88	80	0	0	0	0
NOT COMPLETED	16	27	0	0	0	0
Period Title: Phase I Treatment
STARTED	0	0	27	27	27	27
COMPLETED	0	0	25	15	21	17
NOT COMPLETED	0	0	2	12	6	10

Baseline Characteristics

Arm/Group Title	Non-drug Sleep Therapy 1	Sleep Medication 1	Total
Arm/Group Description	Behavioral Insomnia Therapy: Sleep hygiene, stimulus control, and sleep restriction presented in four sessions.	Zolpidem: 5mg or 10mg	Total of all reporting groups
Overall Participants	104	107	211
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	45.9 (14.4)	45.4 (15.5)	45.6 (14.9)
Sex: Female, Male (Count of Participants)
Female	64 61.5%	68 63.6%	132 62.6%
Male	40 38.5%	39 36.4%	79 37.4%
Race/Ethnicity, Customized (Count of Participants)
White	94 90.4%	93 86.9%	187 88.6%
Black	6 5.8%	8 7.5%	14 6.6%
Other	3 2.9%	3 2.8%	6 2.8%
Hispanic	4 3.8%	8 7.5%	12 5.7%

Outcome Measures

1. Primary Outcome

Title	Percent of Participants Who Met Remission as Measured by the Insomnia Severity Index
Description	The Insomnia Severity Index (ISI) is a self-report questionnaire assessing the nature, severity, and impact of insomnia. Remission is determined to be a score less-than 8.
Time Frame	6 weeks, 12 weeks, 3 months, 6 months, 9 months & 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Non-drug Sleep Therapy 1	Sleep Medication 1	Sleep Medication 1 Plus Non-drug Sleep Therapy 1	Sleep Medication 1 Plus Sleep Medication 2	Non-drug Sleep Therapy 1 Plus Non-drug Sleep Therapy 1	Non-drug Sleep Therapy 1 Plus Sleep Medication 1
Arm/Group Description	Behavioral Insomnia Therapy: Sleep hygiene, stimulus control, and sleep restriction presented in four sessions.	Zolpidem: 5mg or 10mg	Zolpidem Plus Behavioral Therapy	Zolpidem Plus Trazodone	Behavioral Therapy Plus Cognitive Therapy	Behavioral Therapy Plus Zolpidem
Measure Participants	90	83	27	27	27	27
Number [percent remitted]	40.00	34.94	37.04	48.15	44.44	55.56

Adverse Events

Time Frame	Adverse event data were collected during the period from March 1, 2012 to July 1, 2017. Adverse Events were monitored in participants during the entirety of their participation, up to approximately 17 months for each participant.
Arm/Group Title	Non-drug Sleep Therapy 1		Sleep Medication 1		Non-drug Sleep Therapy 2		Sleep Medication 2
Arm/Group Description	Behavioral Insomnia Therapy: Sleep hygiene, stimulus control, and sleep restriction presented in four sessions.		Zolpidem: 5mg or 10mg		Cognitive Therapy: Cognitive restructuring, constructive worry, behavioral experiments presented in four sessions.		Trazodone: 50mg to 150mg
All Cause Mortality
	Non-drug Sleep Therapy 1		Sleep Medication 1		Non-drug Sleep Therapy 2		Sleep Medication 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/131 (0%)		0/134 (0%)		0/27 (0%)		0/27 (0%)
Serious Adverse Events
	Non-drug Sleep Therapy 1		Sleep Medication 1		Non-drug Sleep Therapy 2		Sleep Medication 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/131 (0%)		0/134 (0%)		0/27 (0%)		0/27 (0%)
Other (Not Including Serious) Adverse Events
	Non-drug Sleep Therapy 1		Sleep Medication 1		Non-drug Sleep Therapy 2		Sleep Medication 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/131 (0%)		0/134 (0%)		0/27 (0%)		0/27 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.