Pramipexole ER vs. Placebo in Fibromyalgia

Study Overview
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Brief Summary
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The primary objective of this study is to assess the efficacy and safety of an extended-release (ER) formulation of pramipexole in comparison with placebo for the treatment of fibromyalgia. The objective of the open-label phase is to assess the safety profile and effect of Pramipexole (PPX) extended-release (ER) in fibromyalgia patients over a 24-week period.

Official Title
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A Randomized, Double-blind, Placebo-controlled, Dose Titration Efficacy and Safety Study of Pramipexole ER (0.75 to 4.5 mg) Administered Orally Once Daily Versus Placebo Over a 16-week Maintenance Phase in Patients Diagnosed With Fibromyalgia, as Assessed by the American College of Rheumatology (ACR) Criteria Followed by a 24-week Open-label Extension Phase

Conditions
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Fibromyalgia

Intervention / Treatment
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* Drug: pramipexole ER
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female outpatients greater than or equal to 18 years of age Meet criteria for primary fibromyalgia as defined by the American College of Rheumatology (ACR): widespread aching pain in all four quadrants of the body and axial skeleton for greater than 3 months duration and greater than or equal to 11 of 18 tender points under digital palpitation examination with an approximate force of 4 kilograms per centimeters squared (kg/cm2) Pain score of greater than or equal to 4 (scored once at screening and as a weekly mean at baseline) on the 11-point Likert pain scale with 0 = no pain and 10 = worst possible pain Score of greater than or equal to 4 (= moderately ill) on the Clinical Global Impression of Severity (CGI-S) at screening and at baseline All females of child-bearing potential must test negative for pregnancy at Visit 1. Females of child-bearing potential (not surgically sterilized and between menarche and two years postmenopausal) must agree to utilize medically acceptable and reliable means of birth control as determined by the investigator during the study and for one month following the last dose of study medication. Examples of reliable methods include: use of hormonal contraception (oral, injectable, or subcutaneous), double-barrier method, abstinence, partner with vasectomy, or hormonal intrauterine devices Educational level and degree of understanding such that the patient can communicate intelligibly with the investigator and study coordinator Judged to be reliable and agree to keep all appointments for clinic visits, tests, and procedures required by the protocol Exclusion Criteria: Employees of Boehringer Ingelheim (BI) (that is, employees, temporary contract workers, or designees responsible for the conduct of the study) Have received treatment within 30 days prior to screening with a drug that has not received regulatory approval for any indication Have previously completed or withdrawn from this study or any other study investigating pramipexole. Any current or previous diagnosis of psychosis, bipolar disorder, or schizoaffective disorder as assessed by the Mini International Neuropsychiatric Interview (MINI) Have any primary anxiety disorder within the past year as assessed by the Mini International Neuropsychiatric Interview (MINI) Have any Diagnosis of Statistical Manual of Mental Diseases, 4th Edition (DSM-IV) Axis II disorder that would interfere with protocol compliance Medium or high risk of suicidality as assessed by the Mini International Neuropsychiatric Interview (MINI) History of substance abuse/dependence within the past year, excluding nicotine and caffeine A positive urine drug screen for any substance of abuse or excluded medication Women who are pregnant or breast-feeding Have pain symptoms related to traumatic injury that will interfere with the interpretation of outcome measures Patients with regional pain syndromes, multiple surgeries or failed back surgery syndrome A confirmed or previous diagnosis of rheumatoid arthritis, inflammatory arthritis, or infectious arthritis, or an autoimmune disease Abnormal C-Reactive Protein, Anti-Nuclear Antibody (ANA), Rheumatoid factor, or Thyroid Stimulating Hormone (TSH) Any serious or unstable medical or psychiatric condition or clinically significant abnormalities in labs at screening that would lead to hospitalization during the course of the study or otherwise compromise study participation Have uncontrolled seizures Taking any prohibited medications that cannot be discontinued at screening Patients who are treatment-refractory or whose response may be compromised by disability compensation issues Patients with frequent or severe allergic reactions to multiple medications Prior or current treatment with pramipexole Clinically significant renal disease Current or previous diagnosis of malignant melanoma Clinically relevant ophthalmopathy Documented sleep apnea

Ages Eligible for Study
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Minimum Age: 18 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: Pramipexole ER<br>0.75 mg to 4.5 mg tablets of Pramipexole ER, once daily in the evening | Drug: pramipexole ER<br> <br> |
| Placebo Comparator: Placebo<br>Placebo tablets, once daily in the evening | Drug: placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Change in the Weekly Mean of the 24-hour Average Pain Score From a Daily Diary as Measured by the 11-point Likert Pain Scale | The 11-point Likert Pain Scale is a numerical rating scale completed by the patient that measures the intensity of pain. The intensity scores range from 0 (no pain) to 10 (worst possible pain) | Baseline and Week 29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Proportion of Patients Very Much Improved or Much Improved on the Patient's Global Impression of Improvement (PGI-I) 7-point Scale | PGI-I is a self-reported scale completed by the patient that measures the degree of improvement at the time of assessment. The score ranges from 1 = very much improved to 7 = very much worse | Week 29 (at the end of the maintenance phase) | 
| The Short Form 36 (SF-36) Health Survey, Physical Functioning Subscale (Change From Baseline). | The SF-36 Health Survey is a self-administered 36-item instrument completed by the patient . SF 36 has subscales as follows: i) physical functioning (PF), ii) role limitations due to physical problems (RP), iii) bodily pain (BP), iv) general health perceptions (GH), v) vitality (VT), vi) social function (SF), vii) role limitations due to emotional problems (RE), viii) mental health (MH),ix)physical component summary (PCS)and x)mental component summary(MCS). Among the subscales, Physical functioning was key secondary endpoint while other were additional secondary endpoints. Each domain is scored by summing the individual items and transforming the scores into a 0 to 100 scale, with higher scores indicating better health status or functioning. The number of items per domain varies from 2 to 1 | Baseline and Week 29 | 
| The Proportion of Patients With at Least a 30% or at Least a 50% Improvement Relative to Baseline in Pain (Assessed on the 11-point Likert Pain Scale | 11-Point Likert Pain Scale is a numerical rating scale completed by the patient that measures the intensity of pain. The intensity scores range from: 0 = no pain to 10 = worst possible pain . | Baseline and Week 29 | 
| Fibromyalgia Impact Questionnaire (FIQ) Total Score (Change From Baseline) | FIQ is a self-reported scale completed by the patient that measures patient status, progress, and outcomes over the past week. The FIQ is composed of a total of 20 items; the first 11 items measure physical functioning, and each item is rated on a four-point Likert scale. Items 12 and 13 measure the number of days the patient felt well and the number of days the patient felt unable to work due to their fibromyalgia symptoms. Items 14 through 20 are numerical, 11-point Likert scales (marked in 10-point increments) on which the patient rates work difficulty, pain, fatigue, morning tiredness, stiffness, anxiety, and depression. The total score ranges from 0 to 80. A higher score indicates a more negative impact | Baseline and Week 29 | 
| Hospital Anxiety and Depression Scale (HADS) (Change From Baseline). | The Hospital Anxiety and Depression Scale (HADS) measures the severity of anxiety and depression. The severity score ranges from: 0 = least severe to 3 = most severe. The total score ranges from 0 to 21; the higher the score, the more severe the anxious/depressive symptoms | Baseline and Week 29 | 
| The Short Form 36 (SF-36) Health Survey (Change From Baseline) (Excluding the Physical Functioning Subscale(PF)). | The SF-36 Health Survey is a self-administered 36-item instrument completed by the patient . SF 36 has subscales as follows: i) physical functioning (PF), ii) role limitations due to physical problems (RP), iii) bodily pain (BP), iv) general health perceptions (GH), v) vitality (VT), vi) social function (SF), vii) role limitations due to emotional problems (RE), viii) mental health (MH),ix)physical component summary (PCS)and x)mental component summary(MCS). Among the subscales, Physical functioning was key secondary endpoint while other were additional secondary endpoints. Each domain is scored by summing the individual items and transforming the scores into a 0 to 100 scale, with higher scores indicating better health status or functioning. The number of items per domain varies from 2 to 1 | Baseline and Week 29 | 
| Euroqol- 5 Dimensions (EQ-5D) Survey (Change From Baseline) | The Euroqol- 5 Dimension (EQ-5D) Health Survey is a generic, multidimensional, health related, quality-of-life instrument that contains two parts-a health status profile and a visual analog scale (VAS) to rate global health-related quality of life. The profile contains five items corresponding to five health domains- mobility, self-care, usual activities, pain/discomfort, and mood. A single score is generated for each health state. Data from the EQ-5D can be converted into 243 unique health states. For each health state, there exists a corresponding valuation that allows the patient's health to be represented as an index, which is a value between -0.594 and 1; the higher the score, the better the quality of life. | Baseline and Week 29 | 
| Multidimensional Assessment of Fatigue (MAF) Index (Change From Baseline) | The Multidimensional Assessment of Fatigue (MAF) Index is a 16-item, self-reporting instrument designed to collect data on four dimensions of fatigue- severity, distress, degree of interference in activities of daily living, and timing . | Baseline and Week 29 | 
| Medical Outcomes Study (MOS) Sleep Scale (Change From Baseline) | The Medical Outcomes Study (MOS) sleep scale is a 12-item (MOS1 to MOS12) self reporting sleep measure. | Baseline and Week 29 | 
| Clinical Global Impression of Severity (CGI-S Scores) | Clinical Global Impression of Severity (CGI-S) Scale is a clinician's assessment of patient's severity of illness. The score ranges from 1 = normal, not at all ill to 7 = among the most extremely ill patients | Baseline and Week 29 | 
| Frequency of Rescue Medication for Pain | Acetaminophen/paracetamol (maximum of 4 g/day) to be allowed as rescue medication for pain. | Week 29 | 
| Change From Baseline in Mean Tender Point Threshold | The Tender Point Pain Threshold will be assessed for all 18 tender points by a study clinician. A dolorimeter will be used to exert the pressure at each point and to measure the threshold reading; when the patient first indicates pain, the threshold will be recorded in kg/sq.cm ;If the patient reports pain before 1.0 kg/sq.cm is reached (>0 kg/sq.cm), 1.0 kg/sq.cm will be entered. If the patient does not report pain when the maximum pressure is applied (10.0 kg/sq.cm),0 (no pain) will be entered. | Baseline and Week 29 |