E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 8.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10048439 |
E.1.2 | Term | Fibromyalgia |
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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 evaluate the safety and efficacy of Xyrem (sodium oxybate) oral solution at 4.5 g/night and 6 g/night compared to placebo for the treatment of fibromyalgia in a randomized, double-blind, placebo controlled, parallel-group trial. |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Subject is able to understand the written informed consent and has signed and dated the consent prior to beginning protocol required procedures. 2. Subject is willing and able to complete the entire trial as described in the protocol. 3. Subject is male or female 18 years of age or older. 4. Subject meets the ACR criteria for fibromyalgia at screening and at baseline. 5. Subject has at least 5 out of 7 days with 100% compliance on the VAS self−rated pain scale in the week prior to Visit 4 and has an average VAS pain score of greater than or equal to 50 mm/100 mm as recorded in the subject diary on the 100% compliant days, defined as days that the morning, afternoon, and evening diaries were all completed. 6. Subject is willing to discontinue opiates, benzodiazepines, muscle relaxants (cyclobenzaprine), anticonvulsants, antidepressants, dopamine agonists and/or tramadol, or any other medications, herbal remedies, and/or devices being used to treat their fibromyalgia symptoms until trial completion. 7. Subjects who are on a consistent nutritional and/or exercise regimens and/or behavioural, massage, physical, or cognitive therapies for the last 3 months prior to baseline are willing to agree to remain on an unchanged regimen throughout the duration of the trial. 8. Subject agrees to use only paracetamol as rescue pain medication and to limit the dose to a maximum of 4 g/day throughout the course of the trial. Subjects may, for cardiac protection, take a single daily dose of 325 mg or less of aspirin. Any other use of aspirin is prohibited during this trial. 9. Subject is willing to discontinue the ingestion of alcohol for the duration of the trial. 10. Female subjects may be included if they are surgically sterile or 2 years post menopausal, but they must also have a negative pregnancy test. Female subjects of child bearing potential and peri−menopausal subjects may be included but must have a negative pregnancy test and agree to use a medically accepted method of birth control (eg, barrier method with spermicide, oral contraceptive, or abstinence) and agree to continue use of this method for the duration of the trial. 11. Subject has been screened for sleep apnoea using the Berlin Questionnaire, and a determination of the subject’s sleep apnoea status has been made. 12. Subjects with a BMI ≥35 and <40 must have AHI<15 per hour and oxygen saturation >80%, as determined by PSG at screening or must have already been on stable continuous positive airway pressure (CPAP) therapy for the last 30 days prior to baseline and agree to remain on CPAP for the duration of the study. |
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E.4 | Principal exclusion criteria |
1. Subject has any of the following medical conditions: • Rheumatic disease in addition to fibromyalgia, such as rheumatoid arthritis, inflammatory arthritis, or systemic lupus erythematosus • Symptoms of painful osteoarthritis or symptomatic osteoarthritis (e.g. osteoarthritis associated with stiffness and muscle weakness) at screening or prior to randomization • Pain from traumatic injury • Uncontrolled hypo- or hyperthyroidism of any type • Autoimmune disease (with the exception of inactive Hashimoto's thyroiditis) • Multiple sclerosis • Unstable cardiovascular (eg, cardiac insufficiency, arterial hypertension), endocrine, gastrointestinal, hematologic, hepatic, immunologic, metabolic, neurological, pulmonary, and/or renal disease • Current or recent neoplastic disease (ie, evaluable disease within the past 5 years), excluding localized basal cell carcinoma • Systemic infection • Any disease, disorder or condition that would place the subject at risk during the trial 2. Subject has a history of myocardial infarction, transient ischemic attack (TIA) or cerebrovascular accident (CVA). 3. Subject has a Major Depressive Disorder or is currently being treated for a Major Depressive Disorder or has a history of psychotic disorder and/or bipolar disorder. 4. Subject has Generalized Anxiety Disorder 5. Subject has any other problems that, in the investigator's opinion, would preclude the subject's participation and completion of this trial or compromise reliable representation of subjective symptoms. 6. Subject has a MINI suicidality module score > 0 and/or subject who answers “yes” to the suicide question (A3-g) on the Major Depressive Episode module of the MINI and/or greater than or equal to 1 on Question 9 of the BDI-II. 7. Subject has a current or past history of a substance use disorder including alcohol abuse 8. Subject has a clinically significant history of seizure disorder either past or present, a history of clinically significant head trauma, chronic persistent migraine headaches, or past invasive intracranial surgery. 9. Subject has known succinic semialdehyde dehydrogenase deficiency. 10. Subject has participated in a previous Xyrem (sodium oxybate) clinical trial (with the exception of subjects who, due to completion of enrollment for Xyrem Study 06-008, were withdrawn from the screening phase of Study 06-008 prior to being randomized). 11. Subject has received acupuncture therapy intended for the treatment of fibromyalgia within 30 days prior to baseline. 12. Subject has taken gamma-hydroxybutyrate or sodium oxybate or Xyrem at any time. 13. Subject has taken any investigational therapy within 2 months prior to signing informed consent. 14. Subject is unable to discontinue certain prohibited medications during the washout period and throughout the duration of the trial., e.g. antidepressants, mood-stabilizers, antipsychotics, NSAIDs, opiods, muscle relaxants 15. Subject is experiencing clinically significant medication withdrawal symptoms after the withdrawal/washout period. 16. Subject is experiencing fatigue and/or drowsiness/sedation in association with intake of allowed medications. 17. Subject has an allergic reaction to GHB or sodium oxybate or any of its constituents (malic acid). 18. Subject has any protocol defined exclusionary clinical laboratory tests 19. Subject is diagnosed with sleep apnea and not currently on stable continuous positive airway pressure (CPAP) therapy for the last 30 days prior to baseline. 20. Subject has a body mass index (BMI) of greater than or equal to 40. 21. Subject is on a sodium-restricted diet. 22. Subject has a visual impairment or motor disturbance which precludes capacity to make accurate notation on the electronic diary VAS scales. 23. Subject has any of the following exclusionary socio-economic factors: • Pending worker’s compensation litigation or other related monetary settlements or other pending litigation related to physical complaints • Subjects on disability or pending disability evaluation for chronic pain and/or fibromyalgia. • An occupation that requires variable shift work or routine night shifts 24. Female subject who is nursing or lactating. 25. Subject has a history of porphyria. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Pain Severity Response: The proportion of subjects in each treatment group who had at least 30% reduction in pain VAS from baseline to endpoint will be compared to assess the efficacy of Xyrem (sodium oxybate) for the treatment of fibromyalgia.
For the marketing authorization application in the EU, two co-primary efficacy parameters will be used:
• Pain Severity Response: The proportion of subjects who had at least 30% reduction in pain VAS from baseline to endpoint. • Functionality Response: The proportion of subjects who had at least 30% reduction in Fibromyalgia Impact Questionnaire (FIQ) total score from baseline to endpoint. |
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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 | Yes |
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.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 45 |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |