{"protocolSection":{"identificationModule":{"nctId":"NCT01234675","orgStudyIdInfo":{"id":"SAV-MD-17"},"organization":{"fullName":"Cleveland Sleep Research Center","class":"OTHER"},"briefTitle":"The Effects of Milnacipran on Sleep Disturbance in Fibromyalgia","officialTitle":"The Effects of Milnacipran on Sleep Disturbance in Fibromyalgia"},"statusModule":{"statusVerifiedDate":"2019-08","overallStatus":"COMPLETED","expandedAccessInfo":{"hasExpandedAccess":false},"startDateStruct":{"date":"2010-11"},"primaryCompletionDateStruct":{"date":"2014-02","type":"ACTUAL"},"completionDateStruct":{"date":"2014-02","type":"ACTUAL"},"studyFirstSubmitDate":"2010-11-03","studyFirstSubmitQcDate":"2010-11-03","studyFirstPostDateStruct":{"date":"2010-11-04","type":"ESTIMATED"},"resultsFirstSubmitDate":"2015-02-05","resultsFirstSubmitQcDate":"2015-07-21","resultsFirstPostDateStruct":{"date":"2015-07-22","type":"ESTIMATED"},"lastUpdateSubmitDate":"2019-08-07","lastUpdatePostDateStruct":{"date":"2019-08-21","type":"ACTUAL"}},"sponsorCollaboratorsModule":{"responsibleParty":{"type":"SPONSOR_INVESTIGATOR","investigatorFullName":"Mansoor Ahmed M.D.","investigatorTitle":"Medical Director","investigatorAffiliation":"Cleveland Sleep Research Center"},"leadSponsor":{"name":"Mansoor Ahmed M.D.","class":"OTHER"},"collaborators":[{"name":"Forest Laboratories","class":"INDUSTRY"}]},"oversightModule":{"oversightHasDmc":true},"descriptionModule":{"briefSummary":"Fibromyalgia is a condition of chronic widespread pain, sleep disturbance and fatigue. Most of the patients with fibromyalgia complain of either non-restorative sleep or complaints of disturbed sleep due to pain. The study aimed at examining the effects of milnacipran on sleep disturbance in patients with fibromyalgia. The study is a randomized, double-blind, placebo controlled, two way crossover polysomnography (PSG) study to explore the effects of milnacipran on sleep disturbance. Patients received either milnacipran 50 mg twice a day (BID) or matching placebo.","detailedDescription":"The sleep disturbance in fibromyalgia is characterized as non-restorative in nature, and is defined as a feeling of light sleep, independent of duration, and as non-refreshing. As such, these patients wake up in the morning and complain of stiffness and overall aching of the body.\n\nIt is well known that reciprocal relationship exists between sleep and pain, with sleep disturbances being an important contributor to morbidity in fibromyalgia. Milnacipran, a selective serotonin norepinephrine receptor inhibitor (SNRI), was approved by the Food and Drug Administration (FDA) for the management of fibromyalgia. Although milnacipran has extensively been studied in fibromyalgia patients, but there is no objective measure, i.e., the use of overnight polysomnography, to determine its effects on sleep.\n\nThe study was undertaken to evaluate the effects of milnacipran on PSG determined measures of sleep in patients with fibromyalgia. The study also evaluated the impact of milnacipran on subjective measures of sleep and fibromyalgia symptoms."},"conditionsModule":{"conditions":["Sleep Disorders","Fibromyalgia","Sleep"],"keywords":["Fibromyalgia","Sleep disorders","Forest Laboratories","Milnacipran"]},"designModule":{"studyType":"INTERVENTIONAL","phases":["PHASE4"],"designInfo":{"allocation":"RANDOMIZED","interventionModel":"CROSSOVER","primaryPurpose":"TREATMENT","maskingInfo":{"masking":"DOUBLE","whoMasked":["PARTICIPANT","INVESTIGATOR"]}},"enrollmentInfo":{"count":19,"type":"ACTUAL"}},"armsInterventionsModule":{"armGroups":[{"label":"milnacipran","type":"EXPERIMENTAL","description":"Drug: milnacipran 7-day dose escalation, 28- day treatment with milnacipran 50 mg and 7-day taper period before or after crossover to placebo","interventionNames":["Drug: Milnacipran"]},{"label":"placebo","type":"PLACEBO_COMPARATOR","description":"Drug: placebo 45-day placebo treatment before or after crossover to milnacipran","interventionNames":["Drug: Placebo"]}],"interventions":[{"type":"DRUG","name":"Milnacipran","description":"50 mg twice daily","armGroupLabels":["milnacipran"],"otherNames":["Savella"]},{"type":"DRUG","name":"Placebo","description":"50 mg twice daily","armGroupLabels":["placebo"],"otherNames":["Sugar pill"]}]},"outcomesModule":{"primaryOutcomes":[{"measure":"Number of Awakenings After Sleep Onset (NAASO)","description":"Number of awakenings after defined sleep onset until lights on.","timeFrame":"4-Week maintenance treatment with milnacipran and placebo"},{"measure":"Sleep Efficiency (SE)","description":"Percentage of time spent asleep while in bed","timeFrame":"4-Week maintenance treatment with milnacipran and placebo"},{"measure":"Wake After Sleep Onset (WASO)","description":"Wake time after defined sleep onset until lights on.","timeFrame":"4-Week maintenance treatment with milnacipran and placebo"}],"secondaryOutcomes":[{"measure":"Latency to Persistent Sleep Onset (LPS)","description":"It is defined as time from lights out to the first consecutive 2 minutes of uninterrupted sleep.","timeFrame":"4-Week treatment with milnacipran and placebo"},{"measure":"Total Sleep Time (TST)","description":"Total sleep of all Rapid Eye Movement (REM) and Non- Rapid Eye Movement Sleep (NTREM) from lights out to lights on.","timeFrame":"4-Week treatment with milnacipran and placebo"},{"measure":"Arousal Index (AI)","description":"Number of arousals per hour of sleep","timeFrame":"4-Week treatment with milnacipran and placebo"},{"measure":"Slow Wave Sleep (SWS)","description":"Time spent in stage 3 of non-rapid eye movement sleep and often referred to as deep sleep.","timeFrame":"4-Week treatment with milnacipran and placebo"},{"measure":"Sleep Problem Index 2, Medical Outcomes Study Sleep Scale (MOS-SS)","description":"This is a subjective index derived from the medical outcomes study sleep scale (MOS-SS) scored on a 0-100 possible range with higher scores indicating more severe sleep disruption. The scale is a self-report instrument consisting of 12 items that assess perceived initiation and maintenance of sleep, respiratory problems during sleep, sleep duration, perceived adequacy of sleep and daytime somnolence.","timeFrame":"4-Week treatment with milnacipran and placebo"},{"measure":"Sleep Quality Scale","description":"Sleep quality measure derived from daily sleep diary rating ranging from 0 (\"very poor\") to 10 (\"excellent\")","timeFrame":"4-Week treatment with milnacipran and placebo"},{"measure":"Fatigue Severity Scale (FSS) Total Score","description":"The scale is a 9-item self-report of fatigue in the past week and scored on a 7-point scale with 1 = strongly disagree and 7 = strongly agree. Scores range from 9 to 63 with higher scores indicating higher fatigue severity. A total score greater or equal to 36 suggests fatigue.","timeFrame":"4-Week treatment with milnacipran and placebo"},{"measure":"Fibromyalgia Impact Questionnaire (FIQ) Total Score","description":"The scale is composed of 10 items relating to fibromyalgia symptoms experienced in the past week. Score ranges from 0 to 100 with higher scores indicating a greater effect of fibromyalgia on a person's life.","timeFrame":"4-Week treatment with milnacipran and placebo"},{"measure":"Brief Pain Inventory (BPI) Mean Severity Score","description":"The score is derived from the BPI scale and measures pain intensity in the past 24 hour. The pain severity score is derived as the average score of 4 pain items assessing pain at its \"worst\", \"least\", \"average\" and \"now\" and ranges from 0-10 with higher scores reflecting greater pain","timeFrame":"4-Week treatment with milnacipran and placebo"},{"measure":"Brief Pain Inventory (BPI) Mean Interference Score","description":"The score is derived from the BPI scale and measures the effect of pain on functioning in the past 24 hour. It is the average score of 7 items interfering with general activity, mood, walking ability, normal work, relations with other people, sleep and enjoyment of life. Score ranges from 0-10 with higher scores reflecting greater interference.","timeFrame":"4-Week treatment with milnacipran and placebo"}]},"eligibilityModule":{"eligibilityCriteria":"Inclusion Criteria:\n\n1. Men or women at least 18 years or older\n2. Diagnosis of fibromyalgia\n3. Clinically significant sleep disturbance, defined as difficulty in maintaining sleep (wake after sleep onset and arousal index) at least three times per week for at least one month\n4. Understand and willing to cooperate with the study procedures\n5. Maintain a normal sleep schedule, with daytime-awake and nighttime-sleep schedule, with customary bedtime between 9 PM and midnight, and rise time 5 AM and 9 AM\n6. Patients who are able to speak, read, and understand English language and able to follow the study protocol, and are able to sign the informed consent\n\nExclusion Criteria:\n\n1. Subject has any of the following medical conditions:\n\n   Liver disease, blood disorder, autoimmune disease, endocrine, cardiovascular, hypertension, renal, hepatic, gastrointestinal, or neurological disorder, active peptic ulcer or inflammatory bowel disease\n2. Significant sleep apnea\n3. Periodic leg movement disorder (PLMD) or restless legs syndrome (RLS)\n4. Any form of severe psychiatric illness, moderate to severe depression, including significant risk of suicide\n5. Patients with uncontrolled glaucoma\n6. Inability to discontinue the prohibited medications\n7. Female of childbearing potential not using birth control measures; or lactating.\n8. History of alcohol, narcotic, benzodiazepines or other substance abuse within the past one year.\n9. Patient on prohibited medication will include but not limited to:\n\n   * Anxiolytics, anti-convulsants, antipsychotics, lithium, barbiturates, anti-histamines, monoamine oxidase inhibitors, or medications that affect sleep\n   * Any prescription or over the counter stimulants\n   * Medications that are contraindicated with the use of milnacipran\n10. Excessive caffeine use, defined as a consumption of more than 500 mg of caffeine or other xanthines, smoking \\>1/2 a pack/day or alcohol use \\>14 units/week\n11. History of allergy to milnacipran.","healthyVolunteers":false,"sex":"ALL","minimumAge":"18 Years","stdAges":["ADULT","OLDER_ADULT"]},"contactsLocationsModule":{"overallOfficials":[{"name":"Mansoor Ahmed, MD","affiliation":"Cleveland Sleep Research Cneter","role":"PRINCIPAL_INVESTIGATOR"},{"name":"Rozina Aamir, MS, MBA","affiliation":"Cleveland Sleep Research Center","role":"STUDY_DIRECTOR"},{"name":"Noel Cyrill, MD","affiliation":"SouthWest Cleveland Sleep Center","role":"STUDY_DIRECTOR"},{"name":"Nosson S Goldfarb, M.D.","affiliation":"Cleveland Sleep Research Center","role":"STUDY_DIRECTOR"}],"locations":[{"facility":"Cleveland Sleep Research Center","city":"Middleburg Heights","state":"Ohio","zip":"44130","country":"United States","geoPoint":{"lat":41.36144,"lon":-81.81291}}]},"referencesModule":{"references":[{"pmid":"26414990","type":"DERIVED","citation":"Ahmed M, Aamir R, Jishi Z, Scharf MB. The Effects of Milnacipran on Sleep Disturbance in Fibromyalgia: A Randomized, Double-Blind, Placebo-Controlled, Two-Way Crossover Study. J Clin Sleep Med. 2016 Jan;12(1):79-86. doi: 10.5664/jcsm.5400."}]}},"resultsSection":{"participantFlowModule":{"groups":[{"id":"FG000","title":"Placebo Then Milnacipran","description":"50 mg twice daily (BID) maintenance dose"},{"id":"FG001","title":"Milnacipran Then Placebo","description":"50 mg twice daily (BID) maintenance dose"}],"periods":[{"title":"First Intervention (6 Weeks)","milestones":[{"type":"STARTED","achievements":[{"groupId":"FG000","numSubjects":"10"},{"groupId":"FG001","numSubjects":"9"}]},{"type":"COMPLETED","achievements":[{"groupId":"FG000","numSubjects":"9"},{"groupId":"FG001","numSubjects":"8"}]},{"type":"NOT COMPLETED","achievements":[{"groupId":"FG000","numSubjects":"1"},{"groupId":"FG001","numSubjects":"1"}]}],"dropWithdraws":[{"type":"Adverse Event","reasons":[{"groupId":"FG000","numSubjects":"0"},{"groupId":"FG001","numSubjects":"1"}]},{"type":"Withdrawal by Subject","reasons":[{"groupId":"FG000","numSubjects":"1"},{"groupId":"FG001","numSubjects":"0"}]}]},{"title":"Second Intervention (6 Weeks)","milestones":[{"type":"STARTED","achievements":[{"groupId":"FG000","numSubjects":"9"},{"groupId":"FG001","numSubjects":"8"}]},{"type":"COMPLETED","achievements":[{"groupId":"FG000","numSubjects":"7"},{"groupId":"FG001","numSubjects":"8"}]},{"type":"NOT COMPLETED","achievements":[{"groupId":"FG000","numSubjects":"2"},{"groupId":"FG001","numSubjects":"0"}]}]}]},"baselineCharacteristicsModule":{"groups":[{"id":"BG000","title":"All Study Participants","description":"2 treatment period, with each period 6 weeks and 7 day washout period Milnacipran in treatment period 1, Placebo in treatment period 2 Placebo treatment in Period 1, and Milnacipran in Period 2"}],"denoms":[{"units":"Participants","counts":[{"groupId":"BG000","value":"19"}]}],"measures":[{"title":"Age, Continuous","paramType":"MEAN","dispersionType":"FULL_RANGE","unitOfMeasure":"years","classes":[{"categories":[{"measurements":[{"groupId":"BG000","value":"49.2","lowerLimit":"28","upperLimit":"72"}]}]}]},{"title":"Sex: Female, Male","paramType":"COUNT_OF_PARTICIPANTS","unitOfMeasure":"Participants","classes":[{"categories":[{"title":"Female","measurements":[{"groupId":"BG000","value":"17"}]},{"title":"Male","measurements":[{"groupId":"BG000","value":"2"}]}]}]},{"title":"Baseline polysomnographic sleep parameters","paramType":"MEAN","dispersionType":"STANDARD_DEVIATION","unitOfMeasure":"minutes","classes":[{"title":"Latency to persistent sleep (LPS)","categories":[{"measurements":[{"groupId":"BG000","value":"49.4","spread":"43.4"}]}]},{"title":"Total sleep time (TST)","categories":[{"measurements":[{"groupId":"BG000","value":"340.7","spread":"78.9"}]}]},{"title":"Wake after sleep onset (WASO)","categories":[{"measurements":[{"groupId":"BG000","value":"97.2","spread":"70.6"}]}]}]},{"title":"Number of awakenings after sleep onset (NAASO)","paramType":"MEAN","dispersionType":"STANDARD_DEVIATION","unitOfMeasure":"awakenings","classes":[{"categories":[{"measurements":[{"groupId":"BG000","value":"31.9","spread":"12.9"}]}]}]},{"title":"Sleep efficiency (SE)","paramType":"MEAN","dispersionType":"STANDARD_DEVIATION","unitOfMeasure":"percentage of total sleep time","classes":[{"categories":[{"measurements":[{"groupId":"BG000","value":"72.3","spread":"15.8"}]}]}]},{"title":"Arousal index (AI)","paramType":"MEAN","dispersionType":"STANDARD_DEVIATION","unitOfMeasure":"arousals per hour","classes":[{"categories":[{"measurements":[{"groupId":"BG000","value":"24.8","spread":"9.8"}]}]}]},{"title":"Total stage shifts","description":"Sleep stage shifts: stage 1, stage 2, stage 3, REM sleep","paramType":"MEAN","dispersionType":"STANDARD_DEVIATION","unitOfMeasure":"Stage shifts","classes":[{"categories":[{"measurements":[{"groupId":"BG000","value":"147.4","spread":"42.2"}]}]}]},{"title":"Rapid Eye Movement (REM) latency","description":"Time from sleep onset to the first epoch of rapid eye movement (REM) sleep","paramType":"MEAN","dispersionType":"STANDARD_DEVIATION","unitOfMeasure":"minutes","classes":[{"categories":[{"measurements":[{"groupId":"BG000","value":"126.5","spread":"91.3"}]}]}]},{"title":"Sleep architecture","description":"Pattern of sleep as it shifts between the different sleep stages. Sleep stages 1-3 are collectively referred to as non--rapid eye movement sleep (NREM)","paramType":"MEAN","dispersionType":"STANDARD_DEVIATION","unitOfMeasure":"percentage of total sleep time","classes":[{"title":"Stage N1","categories":[{"measurements":[{"groupId":"BG000","value":"18.9","spread":"6.6"}]}]},{"title":"Stage N2","categories":[{"measurements":[{"groupId":"BG000","value":"59.0","spread":"13"}]}]},{"title":"Stage N3","categories":[{"measurements":[{"groupId":"BG000","value":"4.2","spread":"8.4"}]}]},{"title":"REM Sleep","categories":[{"measurements":[{"groupId":"BG000","value":"18.0","spread":"7.3"}]}]}]}]},"outcomeMeasuresModule":{"outcomeMeasures":[{"type":"PRIMARY","title":"Number of Awakenings After Sleep Onset (NAASO)","description":"Number of awakenings after defined sleep onset until lights on.","populationDescription":"15 subjects completed the study","reportingStatus":"POSTED","paramType":"MEAN","dispersionType":"Standard 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the first consecutive 2 minutes of uninterrupted sleep.","reportingStatus":"POSTED","paramType":"MEAN","dispersionType":"Standard Error","unitOfMeasure":"minutes","timeFrame":"4-Week treatment with milnacipran and placebo","groups":[{"id":"OG000","title":"Milnacipran","description":"Treatment with 50 mg BiD"},{"id":"OG001","title":"Placebo","description":"50 mg placebo BiD"}],"denoms":[{"units":"Participants","counts":[{"groupId":"OG000","value":"15"},{"groupId":"OG001","value":"15"}]}],"classes":[{"categories":[{"measurements":[{"groupId":"OG000","value":"41.6","spread":"6.2"},{"groupId":"OG001","value":"38.6","spread":"5.8"}]}]}],"analyses":[{"groupIds":["OG000","OG001"],"nonInferiorityType":"SUPERIORITY","pValue":"0.683","statisticalMethod":"Paired T test","paramType":"Paired difference","paramValue":"-6.1","ciPctValue":"95","ciNumSides":"TWO_SIDED","ciLowerLimit":"-12.5","ciUpperLimit":"18.5"}]},{"type":"SECONDARY","title":"Total Sleep Time (TST)","description":"Total sleep of all Rapid Eye Movement (REM) and Non- Rapid Eye Movement Sleep (NTREM) from lights out to lights on.","reportingStatus":"POSTED","paramType":"MEAN","dispersionType":"Standard Error","unitOfMeasure":"minutes","timeFrame":"4-Week treatment with milnacipran and placebo","groups":[{"id":"OG000","title":"Milnacipran","description":"Treatment with 50 mg BiD"},{"id":"OG001","title":"Placebo","description":"50 mg placebo BiD"}],"denoms":[{"units":"Participants","counts":[{"groupId":"OG000","value":"15"},{"groupId":"OG001","value":"15"}]}],"classes":[{"categories":[{"measurements":[{"groupId":"OG000","value":"361.7","spread":"19.6"},{"groupId":"OG001","value":"386.1","spread":"12.5"}]}]}],"analyses":[{"groupIds":["OG000","OG001"],"nonInferiorityType":"SUPERIORITY","pValue":"0.155","statisticalMethod":"Paired T test","paramType":"Paired difference","paramValue":"-1.502","ciPctValue":"95","ciNumSides":"TWO_SIDED","ciLowerLimit":"-59.1","ciUpperLimit":"10.4"}]},{"type":"SECONDARY","title":"Arousal 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