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| Name | Class |
|---|---|
| Forest Laboratories | INDUSTRY |
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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.
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.
It 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.
The 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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| milnacipran | Experimental | Drug: milnacipran 7-day dose escalation, 28- day treatment with milnacipran 50 mg and 7-day taper period before or after crossover to placebo |
|
| placebo | Placebo Comparator | Drug: placebo 45-day placebo treatment before or after crossover to milnacipran |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Milnacipran | Drug | 50 mg twice daily |
|
|
| Measure | Description | Time Frame |
|---|---|---|
| Number of Awakenings After Sleep Onset (NAASO) | Number of awakenings after defined sleep onset until lights on. | 4-Week maintenance treatment with milnacipran and placebo |
| Sleep Efficiency (SE) | Percentage of time spent asleep while in bed | 4-Week maintenance treatment with milnacipran and placebo |
| Wake After Sleep Onset (WASO) | Wake time after defined sleep onset until lights on. | 4-Week maintenance treatment with milnacipran and placebo |
| Measure | Description | Time Frame |
|---|---|---|
| Latency to Persistent Sleep Onset (LPS) | It is defined as time from lights out to the first consecutive 2 minutes of uninterrupted sleep. | 4-Week treatment with milnacipran and placebo |
| Total Sleep Time (TST) |
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Inclusion Criteria:
Exclusion Criteria:
Subject has any of the following medical conditions:
Liver disease, blood disorder, autoimmune disease, endocrine, cardiovascular, hypertension, renal, hepatic, gastrointestinal, or neurological disorder, active peptic ulcer or inflammatory bowel disease
Significant sleep apnea
Periodic leg movement disorder (PLMD) or restless legs syndrome (RLS)
Any form of severe psychiatric illness, moderate to severe depression, including significant risk of suicide
Patients with uncontrolled glaucoma
Inability to discontinue the prohibited medications
Female of childbearing potential not using birth control measures; or lactating.
History of alcohol, narcotic, benzodiazepines or other substance abuse within the past one year.
Patient on prohibited medication will include but not limited to:
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
History of allergy to milnacipran.
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| Name | Affiliation | Role |
|---|---|---|
| Mansoor Ahmed, MD | Cleveland Sleep Research Cneter | Principal Investigator |
| Rozina Aamir, MS, MBA | Cleveland Sleep Research Center | Study Director |
| Noel Cyrill, MD | SouthWest Cleveland Sleep Center | Study Director |
| Nosson S Goldfarb, M.D. | Cleveland Sleep Research Center | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Cleveland Sleep Research Center | Middleburg Heights | Ohio | 44130 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 26414990 | Derived | 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. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Placebo Then Milnacipran | 50 mg twice daily (BID) maintenance dose |
| FG001 | Milnacipran Then Placebo | 50 mg twice daily (BID) maintenance dose |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| First Intervention (6 Weeks) |
|
| |||||||||||||||||||||
| Second Intervention (6 Weeks) |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | All Study Participants | 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 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number of Awakenings After Sleep Onset (NAASO) | Number of awakenings after defined sleep onset until lights on. | 15 subjects completed the study | Posted | Mean | Standard Error | Awakenings | 4-Week maintenance treatment with milnacipran and placebo |
|
|
Adverse event data was collected on and after Day 1 of the first treatment period. The data collection continued till the two weeks after the second treatment period.
Additional data was collected after the end of study visit if the patient reported an adverse event.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Milnacipran | Drug: milnacipran, 50 mg twice daily for 4 weeks. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Gall Stones | Gastrointestinal disorders | Systematic Assessment | During the study the subject was diagnosed with having gall stones. After the blind was broken, the site found out that she was on placebo, and was never treated with the study drug. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| nausea | Gastrointestinal disorders | Systematic Assessment | nausea and vomiting |
A well-established adaptation and re-adaptation to laboratory effects may have compromised our results. Other study biases include biases inherent in the crossover design, and a small sample size.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Mansoor Ahmed, MD | Cleveland Sleep Research Center | 4402438044 | sleepresearchcenter@yahoo.com |
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| ID | Term |
|---|---|
| D012893 | Sleep Wake Disorders |
| D005356 | Fibromyalgia |
| ID | Term |
|---|---|
| D009422 | Nervous System Diseases |
| D009461 | Neurologic Manifestations |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D000078764 | Milnacipran |
| D000073893 | Sugars |
| ID | Term |
|---|---|
| D003521 | Cyclopropanes |
| D003516 | Cycloparaffins |
| D006840 | Hydrocarbons, Alicyclic |
| D006844 | Hydrocarbons, Cyclic |
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| Placebo | Drug | 50 mg twice daily |
|
|
Total sleep of all Rapid Eye Movement (REM) and Non- Rapid Eye Movement Sleep (NTREM) from lights out to lights on.
| 4-Week treatment with milnacipran and placebo |
| Arousal Index (AI) | Number of arousals per hour of sleep | 4-Week treatment with milnacipran and placebo |
| Slow Wave Sleep (SWS) | Time spent in stage 3 of non-rapid eye movement sleep and often referred to as deep sleep. | 4-Week treatment with milnacipran and placebo |
| Sleep Problem Index 2, Medical Outcomes Study Sleep Scale (MOS-SS) | 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. | 4-Week treatment with milnacipran and placebo |
| Sleep Quality Scale | Sleep quality measure derived from daily sleep diary rating ranging from 0 ("very poor") to 10 ("excellent") | 4-Week treatment with milnacipran and placebo |
| Fatigue Severity Scale (FSS) Total Score | 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. | 4-Week treatment with milnacipran and placebo |
| Fibromyalgia Impact Questionnaire (FIQ) Total Score | 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. | 4-Week treatment with milnacipran and placebo |
| Brief Pain Inventory (BPI) Mean Severity Score | 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 | 4-Week treatment with milnacipran and placebo |
| Brief Pain Inventory (BPI) Mean Interference Score | 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. | 4-Week treatment with milnacipran and placebo |
| NOT COMPLETED |
|
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Baseline polysomnographic sleep parameters | Mean | Standard Deviation | minutes |
|
| Number of awakenings after sleep onset (NAASO) | Mean | Standard Deviation | awakenings |
|
| Sleep efficiency (SE) | Mean | Standard Deviation | percentage of total sleep time |
|
| Arousal index (AI) | Mean | Standard Deviation | arousals per hour |
|
| Total stage shifts | Sleep stage shifts: stage 1, stage 2, stage 3, REM sleep | Mean | Standard Deviation | Stage shifts |
|
| Rapid Eye Movement (REM) latency | Time from sleep onset to the first epoch of rapid eye movement (REM) sleep | Mean | Standard Deviation | minutes |
|
| Sleep architecture | 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) | Mean | Standard Deviation | percentage of total sleep time |
|
| Participants |
|
|
|
| Primary | Sleep Efficiency (SE) | Percentage of time spent asleep while in bed | Posted | Mean | Standard Error | percentage of total sleep time | 4-Week maintenance treatment with milnacipran and placebo |
|
|
|
|
| Primary | Wake After Sleep Onset (WASO) | Wake time after defined sleep onset until lights on. | Posted | Mean | Standard Error | minutes | 4-Week maintenance treatment with milnacipran and placebo |
|
|
|
|
| Secondary | Latency to Persistent Sleep Onset (LPS) | It is defined as time from lights out to the first consecutive 2 minutes of uninterrupted sleep. | Posted | Mean | Standard Error | minutes | 4-Week treatment with milnacipran and placebo |
|
|
|
|
| Secondary | Total Sleep Time (TST) | Total sleep of all Rapid Eye Movement (REM) and Non- Rapid Eye Movement Sleep (NTREM) from lights out to lights on. | Posted | Mean | Standard Error | minutes | 4-Week treatment with milnacipran and placebo |
|
|
|
|
| Secondary | Arousal Index (AI) | Number of arousals per hour of sleep | Posted | Mean | Standard Error | arousals per hour | 4-Week treatment with milnacipran and placebo |
|
|
|
|
| Secondary | Slow Wave Sleep (SWS) | Time spent in stage 3 of non-rapid eye movement sleep and often referred to as deep sleep. | Posted | Mean | Standard Error | percentage of total sleep time | 4-Week treatment with milnacipran and placebo |
|
|
|
|
| Secondary | Sleep Problem Index 2, Medical Outcomes Study Sleep Scale (MOS-SS) | 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. | Posted | Mean | Standard Error | score on a scale | 4-Week treatment with milnacipran and placebo |
|
|
|
|
| Secondary | Sleep Quality Scale | Sleep quality measure derived from daily sleep diary rating ranging from 0 ("very poor") to 10 ("excellent") | Posted | Mean | Standard Error | score on a scale | 4-Week treatment with milnacipran and placebo |
|
|
|
|
| Secondary | Fatigue Severity Scale (FSS) Total Score | 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. | Posted | Mean | Standard Error | score on a scale | 4-Week treatment with milnacipran and placebo |
|
|
|
|
| Secondary | Fibromyalgia Impact Questionnaire (FIQ) Total Score | 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. | Posted | Mean | Standard Error | score on a scale | 4-Week treatment with milnacipran and placebo |
|
|
|
|
| Secondary | Brief Pain Inventory (BPI) Mean Severity Score | 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 | Posted | Mean | Standard Error | score on a scale | 4-Week treatment with milnacipran and placebo |
|
|
|
|
| Secondary | Brief Pain Inventory (BPI) Mean Interference Score | 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. | Posted | Mean | Standard Error | score on a scale | 4-Week treatment with milnacipran and placebo |
|
|
|
|
| 0 |
| 19 |
| 12 |
| 19 |
| EG001 | Placebo | Drug: Placebo 50 mg, twice daily for 4 weeks. | 1 | 19 | 10 | 19 |
|
| Headache | Nervous system disorders | Systematic Assessment |
|
| Dry Mouth | General disorders | Systematic Assessment |
|
| Flushing | Nervous system disorders | Systematic Assessment |
|
| Constipation | Gastrointestinal disorders | Systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | Systematic Assessment |
|
| Sinusitis | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Worsening of pain | Nervous system disorders | Systematic Assessment |
|
| Increased Perspirations | General disorders | Systematic Assessment |
|
| cold/flu | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Increased Heartrate | Cardiac disorders | Systematic Assessment |
|
| diarrhea | Gastrointestinal disorders | Systematic Assessment |
|
| Excessive menstrual bleeding | Reproductive system and breast disorders | Systematic Assessment |
|
| Streptococcal infection (throat) | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Excessive urination | Renal and urinary disorders | Systematic Assessment |
|
| Periodontal disease | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Elevated Blood Pressure | Cardiac disorders | Systematic Assessment |
|
| Cold sweats | General disorders | Systematic Assessment |
|
| Abnormal ejaculation | Reproductive system and breast disorders | Systematic Assessment |
|
| Foot sprain | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Pruritis | Immune system disorders | Systematic Assessment |
|
| Petechial rash | Immune system disorders | Systematic Assessment |
|
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| D001523 | Mental Disorders |
| D009135 | Muscular Diseases |
| D009140 | Musculoskeletal Diseases |
| D012216 | Rheumatic Diseases |
| D009468 | Neuromuscular Diseases |
| D006838 |
| Hydrocarbons |
| D009930 | Organic Chemicals |
| D002241 | Carbohydrates |