| 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 | 19.0 |
| 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 assess the long-term safety of DS-5565 in subjects with FM |
|
| E.2.2 | Secondary objectives of the trial |
• To observe the effects of DS-5565 on average daily pain score (ADPS) and pain-associated average daily sleep interference score (ADSIS) (both recorded in a diary). 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.
• To observe the effects of DS-5565 on Patient Global Impression of Change (PGIC)
• To observe the effects of DS-5565 on depression and anxiety as assessed by the Hospital Anxiety and Depression Scale (HADS)
• To observe the effects of DS-5565 on subject quality of life as assessed by the EuroQoL Instrument 5 Domains (EQ-5D) and the Short Form 36 (SF-36). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects who completed one of the preceding Phase 3 DS-5565 study (DS5565-A-E309, DS5565-A-E310, or DS5565-A-E311):
1. Able to give written informed consent
2. Completed participation (i.e. completed the End-of-Tapering visit) in a preceding study of DS-5565 in FM (DS5565-A-E309, DS5565-A-E310, or DS5565-A-E311)
3. 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
4. The subject must not have experienced any significant safety issues during the preceding study that, in the investigator’s judgment, would adversely impact the subject’s well-being in the long-term extension
De Novo Subjects:
5. Age ≥ 18 years
6. Able to give written informed consent
7. Able to complete subject-reported questionnaires per the investigator’s judgment
8. 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
9. ADPS of ≥ 4 on the 11-point numeric rating scale (NRS) over the past 7 days prior to first dose (based on completion of at least 4 daily pain diaries during the 7-day baseline period)
10. 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
11. 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 |
All Subjects:
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 during the preceding study (for rollover subjects) or within 12 months prior to screening (for de novo subjects) that in the opinion of the investigator would interfere with study participation or assessment of safety and tolerability
2. 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: Subjects answering “yes” to any of the questions about active suicidal ideation/intent/behaviors occurring within the past 12 months must be excluded (C-SSRS Suicide Ideation section – Questions 3, 4, or 5; C-SSRS Suicidal Behavior section, any of the suicide behaviors questions). Such subjects should be referred immediately to a mental health professional for appropriate evaluation.
3. 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
4. Subjects with severe or uncontrolled depression that, in the judgment of the investigator, makes the subject inappropriate for entry into the study
5. 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
6. Subjects with pain due to any widespread inflammatory musculoskeletal disorder (e.g. rheumatoid arthritis, lupus) or widespread rheumatic disease other than FM.
7. Abuse or dependence of prescription medications, street drugs, or alcohol within the last 1 year
8. Any history of a malignancy other than basal cell carcinoma within the past 5 years
9. A diagnosis of untreated sleep apnea or initiation of treatment for sleep apnea within the past 3 months
10. Known hypersensitivity to α2δ ligands or other components of the study medications
11. Pregnancy or breast-feeding, or intent to become pregnant during the study period
12. Abnormal investigative tests (i.e. ECGs) and laboratory values judged by the investigator to be clinically significant at the End-of-Treatment visit (Visit 11, Week 13) in the preceding study (for rollover subjects) or at screening (for de novo subjects), with particular focus on:
• Abnormal renal function defined as calculated CrCl < 60 mL/min determined by the central laboratory using the Cockcroft-Gault equation(4); blood urea nitrogen> 1.5 × ULN; serum creatinine > 1.6 mg/dL (> 141.4 μmol/L); or
• Abnormal liver function defined as AST (SGOT) > 2.0 × ULN, ALT (SGPT) > 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
• Creatine kinase> 3.0 × ULN;
For De Novo Subjects Only:
13. Unable to undergo pre-study washout of prohibited concomitant medications
14. 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 are excluded, but mild to moderate major depression or anxiety disorders are permitted provided that the investigator assesses the patient as clinically stable and appropriate for entry into the study
15. Any diagnosis of lifetime bipolar disorder or psychotic disorder
16. 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
17. 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) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Long-term safety based on assessment of treatment-emergent adverse events (TEAEs), clinical laboratory evaluations, physical examinations, electrocardiograms (ECGs), the Columbia-Suicide Severity Rating Scale (C-SSRS), and the Physician Withdrawal Checklist (PWC) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
from the screening/baseline visit to
the end of treatment visit (ECGs) / end of the follow-up visit (TEAEs, C-SSRS, PWC) / early termination visit |
|
| E.5.2 | Secondary end point(s) |
• Changes from baseline to scheduled timepoint in ADPS and ADSIS
• Proportion of subjects with improvement in overall status at Week 52 as assessed by PGIC
• Changes from baseline to Week 52 in HADS depression and anxiety scores
• Changes in EQ-5D and SF-36 parameters from baseline to Week 52 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Changes from baseline to scheduled timepoint in ADPS and ADSIS:
from baseline visit to end of treatment (Week 52)/early termination visit
• Proportion of subjects with improvement in overall status at Week 52 as assessed by PGIC:
at end of treatment (Week 52)/early termination visit
• Changes from baseline to Week 52 in HADS depression and anxiety scores:
from baseline visit to end of treatment (Week 52)/early termination visit
• Changes in EQ-5D or SF-36 parameters from baseline to Week 52:
from baseline visit to end of treatment (Week 52)/early termination visit |
|
| 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| 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 | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 268 |
| 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 |
| Australia |
| Austria |
| Belarus |
| Belgium |
| Brazil |
| Bulgaria |
| Canada |
| Chile |
| Colombia |
| Croatia |
| Czech Republic |
| Denmark |
| Estonia |
| Finland |
| France |
| Georgia |
| Germany |
| Hungary |
| India |
| Israel |
| Italy |
| Latvia |
| Lithuania |
| Mexico |
| Netherlands |
| New Zealand |
| Norway |
| Poland |
| Portugal |
| Puerto Rico |
| Romania |
| Russian Federation |
| Serbia |
| Slovakia |
| Slovenia |
| South Africa |
| Spain |
| Sweden |
| Switzerland |
| Turkey |
| Ukraine |
| United Kingdom |
| 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
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