Alternative Dosing Regimens in the Pharmacotherapy of Insomnia

Study Overview
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Brief Summary
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The purpose of this study is to evaluate whether drug efficiency of zolpidem and amitriptyline can be conditioned according to learning theory in patients with primary insomnia.

Detailed Description
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Previous research has shown that repeated drug treatments can be regarded as conditioning processes. Sleep disorders are especially of interest to be investigated under the perspective of conditioning with drugs, since sleep quality can be defined both in terms of subjective ratings (self-rated sleep quality parameters) and objective measures (via polysomnographic assessment PSG; e.g., total sleep time, sleep onset, sleep architecture). By using two different drugs (zolpidem, amitriptyline) that modulate sleep differentially, the investigators intend to implement a conditioning paradigm in sleep disorders dissociating conditioning effects on subjective and objective sleep parameters. Both drugs should affect objective and subjective sleep parameters positively, while only amitriptyline should modulate the objectively assessed sleep architecture by REM-suppression (latency of REM-sleep onset, percentage of REM-sleep).Patients with mild to moderate insomnia will undergo a classical conditioning paradigm with one of two study medications: amitriptyline or zolpidem. After an acquisition period and a wash-out period, conditioned sleep changes are assessed in an evocation trial. During a second treatment phase of 7 days, patients receive different doses of amitriptyline (between 0mg and 50mg per night) or zolpidem (between 0mg and 5mg per night) to evaluate alternative dosing regimens in the pharmacotherapy of mild to moderate Insomnia.

Official Title
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Phase III Study on Alternative Dosing Regimens in the Pharmacotherapy of Mild to Moderate Insomnia

Conditions
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Insomnia

Intervention / Treatment
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* Drug: Amitriptyline
* Drug: Zolpidem
* Drug: Amitriptyline
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age between 18 years to 69 years fluent in German language provide written informed consent ability to understand the explanations and instructions given by the study physician and the investigator Exclusion Criteria: Sleep disorders caused by medical factors (e.g. sleep apnea, restless legs syndrome, narcolepsy, substance-induced insomnia) Contraindications to study medication intake according to the information sheet for health professionals (Summary of medicinal Product Characteristics, SmPC; Fachinformation in Germany) assessed by physical examination (including ECG) and medical history allergies to amitriptyline hydrochloride or any of its ingredients allergies to zolpidem or any of its ingredients acute intoxication with alcohol, analgetics, hypnotics or any other psychotropic drug urinary retention delirium untreated closed-angle glaucoma prostatic hyperplasia pyloric stenosis paralytic ilius suicidal thoughts liver/ kidney/ pulmonary insufficiency myasthenia gravis hypokalemia bradycardia coronary heart disease, cardiac arrhythmias, long QT syndrome or other clinically relevant cardiac disorders increased risk of seizures/ history of seizures substance dependence syndrome/ history of substance dependence syndrome Allergies to ingredients of placebo or novel-tasting drink (CS) currently pregnant (verified by urine pregnancy test) or lactating patients scoring ≥12 on the Epworth Sleepiness Scale patients scoring below 8 or above 21 on the Insomnia Severity Index patients suffering from a mental disorder as verified by the SCID (major depression; psychosis; brain injury; substance abuse or dependency syndrome during the last 6 months before V1) nicotine consumption > 10 cigarettes/day unwillingness to refrain from alcohol consumption throughout the study Concomitant medication interfering with study medication intake due to potential interactions (all psychotropic medication including analgetics and muscle relaxants, hypericum derivatives; antihypertensives; anti-arrhythmic agents; antibiotics; cisaprid; anti-malaria drugs; diuretics; imidazole antifungals; cumarin derivatives; antihistaminics; calcium channel blockers; medications that enlarge the QT interval or may lead to hypokalemia) change in concomitant medication regime during the last 2 weeks prior to visit 1 or after randomization intake of psychotropic medication during the last 3 months participation in any other clinical trial 3 months prior to visit 1 women of childbearing age not using 2 highly effective contraceptive methods employee of the Sponsor or the principal investigator

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 69 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Amitriptyline flexible dosing<br>50 mg capsule amitriptyline before going to bed on 8 out of 17 nights/placebo | Drug: Amitriptyline<br>* 50 mg capsule amitriptyline before going to bed on 8 out of 17 nights<br>Drug: Placebo<br>* Placebo<br>|
| Experimental: Zolpidem flexible dosing<br>5 mg capsule zolpidem before going to bed on 8 out of 17 nights/placebo | Drug: Zolpidem<br>* 5 mg capsule zolpidem before going to bed on 8 out of 17 nights<br>Drug: Placebo<br>* Placebo<br>|
| Active Comparator: Amitriptyline fixed dosing<br>50 mg capsule amitriptyline before going to bed on 8 out of 17 nights | Drug: Amitriptyline<br>* 50 mg capsule amitriptyline before going to bed on 8 out of 17 nights<br>|
| Active Comparator: Zolpidem fixed dosing<br>5 mg capsule zolpidem before going to bed on 8 out of 17 nights | Drug: Zolpidem<br>* 5 mg capsule zolpidem before going to bed on 8 out of 17 nights<br>|
| Active Comparator: Amitriptyline continuous dosing<br>50 mg capsule amitriptyline before going to bed on 13 out of 17 nights | Drug: Amitriptyline<br>* 50 mg capsule amitriptyline before going to bed on 13 out of 17 nights<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Total Sleep Time | assessed by polysomnography | Change from baseline to day 10 after first medication intake | 
| Objective Sleep Onset Latency | assessed by polysomnography | Change from baseline to day 10 after first medication intake | 
| Self-reported Total Sleep Time | assessed by sleep diary | Change from baseline to day 10 after first medication intake | 
| Self-Reported Sleep Onset Latency | assessed by sleep diary | Change from baseline to day 10 after first medication intake | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of REM sleep | assessed by polysomnography | Change from baseline to day 10 after first medication intake | 
| REM onset latency | assessed by polysomnography | Change from baseline to day 10 after first medication intake | 
| Objective Sleep Efficiency | assessed by actigraphy | Change from baseline to day 17 after first medication intake | 
| Objective Total Sleep Time | assessed by actigraphy | Change from baseline to day 17 after first medication intake | 
| Self-Reported Total Sleep Time | assessed by sleep diary | Change from baseline to day 18 after first medication intake | 
| Self-reported Sleep Onset Latency (min) | assessed by sleep diary | Change from baseline to day 18 after first medication intake | 
| Self-reported Sleep Onset Latency (evaluation) | assessed by sleep diary | Change from baseline to day 18 after first medication intake | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sleep architecture, conditioning of pharmacological responses, insomnia