| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| DS-5565 is being developed for the treatment of pain associated with fibromyalgia (FM). |
|
| E.1.1.1 | Medical condition in easily understood language |
| Treatment of pain related to fibromyalgia |
|
| E.1.1.2 | Therapeutic area | Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Anesthesia and Analgesia [E03] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10048439 |
| E.1.2 | Term | Fibromyalgia |
| E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
|
| 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 compare change in weekly average daily pain score (ADPS) from baseline to Week 13 in subjects receiving either dose of DS-5565 versus placebo.
Weekly ADPS is based on daily pain scores reported by the subject that best describes his or her worst pain over the previous 24 hours. |
|
| E.2.2 | Secondary objectives of the trial |
The key secondary objectives are:
• To compare change in ADPS from baseline to Week 13 in subjects receiving either dose of DS-5565 versus pregabalin
• To compare the proportion of subjects with ≥ 30% reduction from baseline to Week 13 in ADPS receiving either dose of DS-5565 versus placebo
• To compare the proportion of subjects with ≥ 50% reduction from baseline to Week 13 in ADPS receiving either dose of DS-5565 versus placebo
• To assess the effects of either dose of DS-5565 versus placebo on patient global impression of change (PGIC) at Week 13
• To evaluate the change in fibromyalgia impact questionnaire (FIQ) total score from baseline to Week 13 in subjects receiving either dose of DS-5565 versus placebo |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Age ≥ 18 years
2. Able to give written informed consent
3. Able to complete subject-reported questionnaires per the investigator’s judgment
4. At screening, subjects must meet the 1990 American College of Rheumatology (ACR) criteria for FM, i.e. widespread pain present for at least 3 months and pain in at least 11 of 18 specific tender point sites. In addition, the 2010 ACR criteria must be met:
• Widespread pain index (WPI) ≥ 7 and symptom severity (SS) scale score ≥ 5, or WPI 3 to 6 and SS scale score ≥ 9
• Symptoms have been present at a similar level for at least 3 months
• The subject does not have a disorder that would otherwise explain the pain
5. ADPS of ≥ 4 on the 11-point numeric rating scale (NRS) over the past 7 days prior to randomization (based on completion of at least 4 daily pain diaries during the 7-day baseline period prior to randomization)
6. Subject must have documented evidence of a fundoscopic examination (with pupil dilation) or a scanning laser ophthalmoscopy examination within 12 months prior to screening or at screening.
7. Women of child-bearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy during the study and for 4 weeks after study completion |
|
| E.4 | Principal exclusion criteria |
1. Clinically significant unstable neurologic, psychiatric, ophthalmologic, hepatobiliary, respiratory, or hematologic illness or unstable cardiovascular disease (e.g., severe hypotension, uncontrolled cardiac arrhythmia, or myocardial infarction) or any other concurrent disease within 12 months prior to screening that in the opinion of the investigator would interfere with study participation or assessment of safety and tolerability.
2. Anticipation of initiation or significant change to normal daily exercise routines or need for ongoing use of concomitant medications or non-pharmacological pain management techniques that may confound assessments of efficacy and/or safety
3. Unable to undergo pre-study washout of prohibited concomitant medications
4. Subjects who are at risk of suicide as defined by their responses to the Columbia-Suicide Severity Rating Scale (C-SSRS) or in the opinion of the investigator. Note: Patients answering “yes” to any of the C-SSRS questions at screening must be excluded. Such patients should be referred immediately to a mental health professional for appropriate evaluation.
5. Subjects with current severe or uncontrolled major depressive disorder or anxiety disorders as assessed by the Mini-international Neuropsychiatric Interview (MINI) interview (Version 6.0) at screening, or who answer “yes” to the suicidality question (current or past) on the Major Depressive Episode Module (Module A) or who answer “yes” to any question in the Suicidality Module (Module B) are excluded. Subjects with mild to moderate major depression or anxiety disorders are permitted to enroll provided that the investigator assesses the subject as clinically stable and appropriate for entry into the study.
6. Any diagnosis of lifetime bipolar disorder or psychotic disorder
7. Subjects with pain due to other conditions (e.g., diabetic peripheral neuropathic pain or post-herpetic neuralgia) that in the opinion of the investigator, would confound assessment or self-evaluation of the pain associated with FM.
8. Subjects with pain due to any widespread inflammatory musculoskeletal disorder (e.g., rheumatoid arthritis, lupus) or widespread rheumatic disease other than FM.
9. Abuse or dependence of prescription medications, street drugs, or alcohol within the last 1 year
10. Any history of a malignancy other than basal cell carcinoma within the past 5 years
11. A diagnosis of untreated sleep apnea or initiation of treatment for sleep apnea within the past 3 months
12. Known hypersensitivity to alpha2-delta (α2δ) ligands or other components of the study medications. Note: Prior exposure to DS-5565 is allowed, as long as hypersensitivity to DS-5565 was not observed.
13. Pregnancy or breast-feeding, or intent to become pregnant during the study period
14. Subject is currently enrolled in or has not yet completed at least 30 days since ending another investigational device or drug study or is receiving other investigational agents.
15. Subject is an employee of the study center, an immediate family member* of an employee of the study center or an employee of Daiichi Sankyo, INC Research or any of the study vendors supporting this study. *(spouse, parent, child, or sibling, whether biological or legally adopted)
16. Subjects who are unlikely to comply with the protocol (e.g., uncooperative attitude, inability to return for subsequent visits) and/or otherwise considered by the investigator to be unlikely to complete the study.
17. Abnormal investigative tests (i.e. ECGs) and laboratory values judged by the investigator to be clinically significant at screening, with particular focus on:
• Abnormal renal function defined as calculated CrCl < 60 mL/min determined by the central laboratory using the Cockcroft-Gault equation(11); blood urea nitrogen > 1.5 × ULN; creatine kinase> 3.0 × ULN; serum creatinine > 1.6 mg/dL (> 141.4 μmol/L); or
• Abnormal liver function defined as AST > 2.0 × ULN, ALT > 2.0 × ULN; alkaline phosphatase > 1.5 × ULN; total bilirubin > 1.2 × ULN. If a subject has total bilirubin > 1.2 ULN, unconjugated and conjugated bilirubin fractions should be analyzed and only subjects documented to have Gilbert’s syndrome may be enrolled; or
• creatinine kinase > 3.0 x ULN. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change in weekly ADPS from baseline to Week 13 (Visit 11) for either dose of DS-5565 versus placebo |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Weekly ADPS is based on daily pain scores reported by the subject (from baseline to Week 13) that best describes his or her worst pain over the previous 24 hours.
The final evaluation of the primary endpoint will be done at Week 13. |
|
| E.5.2 | Secondary end point(s) |
The key secondary endpoints are:
• Proportion of subjects who answered "much improved or better" in PGIC at Week 13 receiving either dose of DS-5565 versus placebo
• Change in ADPS from baseline to Week 13 (Visit 11) in subjects receiving either dose of DS-5565 versus pregabalin
• Proportion of subjects with ≥ 30% reduction from baseline to Week 13 (Visit 11) in ADPS receiving either dose of DS-5565 versus placebo
• Proportion of subjects with ≥ 50% reduction from baseline to Week 13 (Visit 11) in ADPS receiving either dose of DS-5565 versus placebo
• Change in FIQ total score from baseline to Week 13 (Visit 11) in subjects receiving either dose of DS-5565 versus placebo
The remaining secondary endpoints are:
• Changes in multidimensional fatigue inventory (MFI-20) parameters from baseline to Week 13 (Visit 11) for DS-5565 versus placebo
• Changes from baseline to Week 13 (Visit 11) in hospital anxiety and depression scale (HADS) depression and anxiety scores for DS-5565 versus placebo
• Changes in short form 36 (SF-36) parameters from baseline to Week 13 (Visit 11) for DS-5565 versus placebo
• Changes in EuroQoL instrument 5 domains (EQ-5D) parameters from baseline to Week 13 (Visit 11) for DS-5565 versus placebo
• Changes in medical outcomes study (MOS) and average daily sleep interference score (ADSIS) from baseline to Week 13 (Visit 11) for DS-5565 versus placebo
• Changes in brief pain inventory short form (BPI-SF9) parameters from baseline to Week 13 (Visit 11) for DS-5565 versus placebo
• Proportion of days rescue medication was used (number of days rescue medication used divided by total number of study days) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The final evaluation of all the secondary endpoints mentioned above will be done at Week 13. |
|
| 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 | Yes |
| 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 | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 64 |
| 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 | No |
| 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 |
| Argentina |
| Austria |
| Belarus |
| Belgium |
| Brazil |
| Chile |
| Colombia |
| Israel |
| Mexico |
| Poland |
| Portugal |
| Slovenia |
| Spain |
| Switzerland |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
|
| 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 | 7 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
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