Alternative Dosing Regimens in the Pharmacotherapy of Insomnia (ALPHASOM)

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

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.

Study Overview

• Status: Terminated
• Conditions: Insomnia
• Intervention / Treatment: Drug: Placebo; Drug: Amitriptyline; Drug: Amitriptyline; Drug: Zolpidem

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Phase 3

Contacts and Locations

Study Locations

• Germany
  • Hessen
    • Marburg, Hessen, Germany, 35032
      • Clinical Psychology and Psychotherapy, Department of Psychology, Philipps University Marburg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 69 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. age between 18 years to 69 years
2. fluent in German language
3. provide written informed consent
4. ability to understand the explanations and instructions given by the study physician and the investigator

Exclusion Criteria:

1. Sleep disorders caused by medical factors (e.g. sleep apnea, restless legs syndrome, narcolepsy, substance-induced insomnia)

2. 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
3. Allergies to ingredients of placebo or novel-tasting drink (CS)
4. currently pregnant (verified by urine pregnancy test) or lactating
5. patients scoring ≥12 on the Epworth Sleepiness Scale
6. patients scoring below 8 or above 21 on the Insomnia Severity Index
7. 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)
8. nicotine consumption > 10 cigarettes/day
9. unwillingness to refrain from alcohol consumption throughout the study
10. 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)
11. change in concomitant medication regime during the last 2 weeks prior to visit 1 or after randomization
12. intake of psychotropic medication during the last 3 months
13. participation in any other clinical trial 3 months prior to visit 1
14. women of childbearing age not using 2 highly effective contraceptive methods
15. employee of the Sponsor or the principal investigator

Study Plan

How is the study designed?

Design Details

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

Number of Arms

5

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Philipps University Marburg Medical Center
• Collaborators: Johannes Gutenberg University Mainz; Philipps University Marburg Coordination Centre for Clinical Trials
• Investigators: Principal Investigator: Winfried Rief, Prof. Dr., Clinical Psychology and Psychotherapy, Department of Psychology, Philipps University Marburg; Principal Investigator: Bettina K Doering, Dr., Clinical Psychology and Psychotherapy, Department of Psychology, Philipps University Marburg; Study Chair: Carmen Schade-Brittinger, Koordinierungszentrum für Klinische Studien Marburg, Philipps University Marburg

Study record dates

Study Major Dates

• Study Start: May 1, 2014
• Primary Completion (Actual): November 1, 2017
• Study Completion (Actual): November 1, 2017

Study Registration Dates

• First Submitted: April 24, 2014
• First Submitted That Met QC Criteria: May 13, 2014
• First Posted (Estimate): May 15, 2014

Study Record Updates

• Last Update Posted (Actual): March 9, 2018
• Last Update Submitted That Met QC Criteria: March 7, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Keywords: insomnia; sleep architecture; conditioning of pharmacological responses
• Additional Relevant MeSH Terms: Mental Disorders; Nervous System Diseases; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Sleep Initiation and Maintenance Disorders; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Antidepressive Agents; Hypnotics and Sedatives; GABA Agents; Antidepressive Agents, Tricyclic; Sleep Aids, Pharmaceutical; Adrenergic Uptake Inhibitors; GABA-A Receptor Agonists; GABA Agonists; Amitriptyline; Zolpidem
• Other Study ID Numbers: FOR1328-SP8; 2013-003229-27 (EudraCT Number)