| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Fibromyalgia, also known as FMS, is a common systemic rheumatologic disorder estimated to affect 2 to 4% of the population
Fibromyalgia is associated with a reduced threshold for pain, generally identified by an increased sensitivity to pressure at particular points on the body, and is often accompanied by fatigue, sleep disturbance, and morning stiffness.
Other common symptoms include headache, migraine, variable bowel habits, diffuse abdominal pain, and urinary frequency. |
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| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To demonstrate the efficacy of milnacipran 200 mg/day as compared to placebo in the treatment of the fibromyalgia syndrome in outpatients after a 12-week period of fixed dose exposure through a primary composite criterion incorporating two domains: pain and patient global status, and key secondary criteria measuring physical and emotional functioning. |
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| E.2.2 | Secondary objectives of the trial |
| To compare the efficacy of 200 mg/day of milnacipran to placebo on a number of additional secondary criteria To establish the safety profile of 200 mg/day of milnacipran in patients with FMS |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Female or male patient aged 18 - 70 years with a diagnosis of fibromyalgia according to the 1990 ACR criteria.
(for women) Either postmenopausal (no menses for at least 1 year) or -has a post-hysterectomy, -oophorectomy (bilateral), -tubal ligation status or, if of childbearing potential, has a negative urine pregnancy test at BL1 Visit/V2/D-14, and has been using a medically acceptable form of contraception for about two months before the inclusion in this study (i.e., hormonal birth control, IUD, double barrier [male condom, female condom, diaphragm] or a barrier method plus a spermicidal agent [contraceptive foam, jelly, or cream]). The patient should be advised to continue the contraception one month after the intake of the last dose of study treatment.
Is able to give an informed consent.
Is willing to withdraw from CNS-active therapies commonly used for FMS, including anti-depressants, anti-convulsants, mood stabilizers, opioids and central anaesthetics (ketamine) whatever the route of administration.
Is willing to discontinue treatment with transcutaneous electrical nerve stimulation, trigger point, tender point or joint injections, acupuncture, and local anaesthetics (patches).
Is able to read and understand the text in local language on the Patient Electronic Diary (PED) screen.
Is able to hear and respond to the PED audible prompts.
Is willing and able to use a PED device daily for a minimum of 21 weeks.
Has at least 10 PED morning reports over the 14 relevant days of the baseline period (i.e., the 14 days immediately prior to randomisation). The baseline period must be a minimum of 14 days.
With an average VAS intensity pain scale recording (based on the electronic diary daily pain recall) between 40 and 90 units (both limits included) on a 0-100 units scale at the end of the baseline period (over 14 days).
With a BDI <or = to25 at the end of the wash-out period and at randomisation.
With a FIQ-PF >or= to 3 at randomisation. |
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| E.4 | Principal exclusion criteria |
With a severe psychiatric illness and significant risk of suicide at screening (V1) or randomisation (V3) according to the MINI performed by a trained staff.
With a current major depressive episode (MDE-current), or a generalised anxiety disorder (GAD) at screening (V1) or randomisation (V3) as defined by the MINI performed by a trained staff.
Abusing of alcohol, benzodiazepines or other drugs, substances (cannabis) as defined by the MINI performed by trained staff at screening (V1). Patients with a positive urine drug screen for benzodiazepines and opiates at BL1 Visit (V2/D-14) will not be included.
With a history or behaviour that would, in the Investigator’s estimation, prohibit compliance for the duration of the study.
With myocardial infarction within the past 24 months, active cardiac disease (American Heart Association Functional Class 2, 3 or 4), congestive heart failure, haemodynamically significant valvular heart disease (including patients with a prosthetic heart valve), and/or clinically significant cardiac rhythm or conduction abnormalities and/or unstable or uncontrolled hypertension.
With pulmonary dysfunction or severe chronic obstructive pulmonary disease that, in the Investigator’s judgment, could interfere with the study participation and completion.
With evidence of active liver disease (levels of AST, ALT and/or alkaline phosphatase >1.5x the upper limit of the normal range for the laboratory performing the test).
With renal impairment (Cockroft creatinine clearance < 60 ml/min: adjustment for patient gender, age and lean body mass).
With documented systemic autoimmune disease.
With chronic inflammatory rheumatoid disease.
With current systemic infection.
Epileptic.
With active cancer, (except basal cell carcinoma), or patients currently undergoing therapy for cancer.
With a current life expectancy less than one year.
With sleep apnea severe enough that, in the Investigator‘s opinion, it would interfere with interpretation of changes in sleep habits.
With active peptic ulcer, inflammatory bowel disease.
With unstable endocrine disease, including unstable diabetes or thyroid disease. Disorders that have been stable under treatment for the preceding 3 months before screening will be acceptable.
(for men) With prostatic enlargement or other genito-urinary disorders, that might be at significant risk of dysuria and/or urinary retention when taking agents with noradrenaline re-uptake inhibition properties.
(for women) Pregnant or breastfeeding.
With a known hypersensitivity to milnacipran
Has received treatment with an experimental agent within the last 30 days before screening.
Is receiving concomitant therapy with MAO-A or -B inhibitors, tricyclics, tetracyclics, SSRIs agents, NARIs agents, SNRIs agents or alpha-agonists, anticonvulsants (phenytoin), dopamine agonists, or muscle relaxants.
Is receiving concomitant therapy with metabolic enzyme inhibitors (i.e., cimetidine) and enzyme inducers (including phenytoin and phenobarbital), oral anticoagulants (warfarin), type 1C antiarrhythmics (propafenone, flecainide, encainide).
Is receiving concomitant therapy with epinephrine, norepinephrine (alpha and beta sympathomimetics) especially when given by parenteral route.
Has been receiving statines, except if stable, for 4 weeks prior to randomisation.
With concurrent usage of hypericum, SAMe, melatonine, or DHEA.
With concurrent usage of digitalis (digoxin) preparations.
With concurrent usage of centrally acting analgesics, including tramadol, codeine, dextropropoxyphene and other opioids or opiates.
With concurrent usage of long term systemic corticoids except if stable and at low doses (equivalent to 10 mg of cortisone). |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Efficacy:
Primary parameter: responder status based on two patient self-reported assessments (on the PED): Morning 24h Recall Pain Score and Patient Global Impression of Change (PGIC).
Secondary parameters:
Fibromyalgia Impact Questionnaire (FIQ total and FIQ-PF), Brief Pain Inventory-Short Form (BPI-SF), 24h recall and weekly recall pain VAS (paper), Multiple Ability Self-report Questionnaire (MASQ, cognitive function), the Multi-dimensional Fatigue Inventory (MFI), SF-36 Physical Component Summary (SF-36 PCS), Beck Depression Inventory BDI, State Trait Anxiety Inventory (STAI), sleep quality scale (MOS).
Electronic diary assessments include morning report pain (current and 24-hour recall,), evening report pain (current pain), overall pain last week (weekly report Friday evening), study medications taken (morning and evening report), concomitant treatment (evening report for the last 24 hours), overall fatigue VAS and sleep VAS in the last week (weekly report on Friday evening), PGIC and FIQ during on site visits.
Safety:
Adverse events, vital signs, ECG and clinical laboratory data.
Diagnosis:Psychological assessments: M.I.N.I. validated tool to exclude major depressive episode (MDE) and Generalized Anxiety Disorder (GAD) |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| The date of the last visit of the last patient undergoing the trial |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
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