| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Polymyositis and dermatomyositis |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10036102 |
| E.1.2 | Term | Polymyositis |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10012503 |
| E.1.2 | Term | Dermatomyositis |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
• To assess the preliminary clinical efficacy of oral BAF312 in patients with polymyositis and dermatomyositis using the IMACS core set measures.
• To assess the safety and tolerability of oral BAF312 in polymyositis and dermatomyositis patients. |
|
| E.2.2 | Secondary objectives of the trial |
• To characterize the steady state PK of BAF312 in polymyositis and dermatomyositis patients.
• To assess the exposure-effect relationship of BAF312 on various safety and efficacy parameters.
• To assess the efficacy of BAF312 to modify health-related quality of life in polymyositis and dermatomyositis patients, as measured by SF-36.
• To assess biomarkers reflecting the efficacy of BAF312 to reduce systemic inflammatory components of the disease using serum markers such as CRP and ESR
.
• To assess the change in steroids use after BAF312 administration (Period 2 only) in polymyositis and dermatomyositis patients. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male and female patients between 18-75 years who have been defined as "definite" or “probable” based on the criteria of Bohan and Peter for PM and DM at least three mo before study entry.
2. Patients must demonstrate persisting muscle weakness defined as having a score no greater than 135/150 on the baseline manual muscle testing (maximum MMT-8 score of 150) in conjunction with at least 2 other abnormal IMACS core set measures: Patient VAS with a minimum value of 2.0cm on a 10cm scale. MD global VAS with a minimum value of 2.0cm on a 10cm scale. HAQ disability index (ranging from 0 to 3) with a minimum value of 0.25. Elevation of at least one of the muscle enzymes [includes CK, LDH, ALT and AST] at a minimum level of 1.3 x the upper limit of normal. In case of ALT or AST elevation, other criteria, at the Investigator’s discretion, should be observed to ensure this is not due to liver damage. For the efficacy EP, if more than one muscle enzyme is identified as being elevated and meeting the above guidelines then the most abnormal will be selected and this enzyme will be the target enzyme followed to evaluate disease improvement or worsening. Global extramuscular disease activity score with a minimum value of 1.0 cm on a 10cm VAS scale (this measure is the physician’s composite evaluation and is based on assessments of activity scores on the constitutional, cutaneous, skeletal, gastrointestinal, pulmonary and cardiac scales of the MDAAT.
3. Patients must have received conventional therapies as defined by corticosteroid alone or in combination with DMARDS (MTX, AZA, CyA or MMF) for at least three months before screening.
4. Patients must be on a stable dose of corticosteroid (5-20 mg prednisone or equivalent per day) for at least 2 weeks prior to screening and should not have received a medium or high dose (≥ 1 mg prednisone or equivalent per body weight kg) corticosteroid therapy in the last 8 weeks prior to study entry.
5. Those patients currently treated with DMARDs must not be responding to DMARD therapy (MTX, AZA, CyA or MMF) defined by proven toxicity or inadequate efficacy as determined by the Investigator. Withdrawal from their DMARDs therapy will occur at least 4 weeks prior to baseline.
6. Female patients of child bearing potential must be using two acceptable methods of contraception (e.g., intra-uterine device plus condom, spermicidal gel plus condom, diaphragm plus condom, etc.), from the time of screening and for the duration of the study, through Study Completion. Period abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. Postmenopausal females must have had no regular menstrual bleeding for at least one (1) year prior to initial dosing. Menopause will be confirmed by a plasma FSH level of >40 IU/L at screening. Female patients who report surgical sterilization must have had the procedure at least six months prior to initial dosing. Surgical sterilization procedures should be supported with clinical documentation made available to the sponsor and noted in the Relevant Medical History/Current Medical Conditions section of the CRF. All female patients must have negative pregnancy test results at Screening.
7. Patients must be able to communicate well with the Investigator, to understand and comply with the requirements of the study and to understand and sign the written informed consent. |
|
| E.4 | Principal exclusion criteria |
1. Other types of idiopathic inflammatory myopathies (paraneoplastic PM/DM; juv. myositis (< 18 yrs); DM with no muscle involvement; inclusion body myositis).
2. Overlap PM/DM if muscle symptoms due to other causes (e.g. arthritis scleroderma, steroid induce myopathy +/or signif. organ damage (e.g lupus nephritis, CNS vasculitis). Overlap patients who satisfy Bohan+Peter criteria +signs of autoimmune disease may be eligible
3. Myopathy due to conditions other than PM/DM
4. Severe pharyngeal, cardiac, pulmonary involvement; any major internal organ damage which deemed clin. significant
5. Late-stage PM/DM whose muscle weakness could be attributable to muscle damage rather than myositis disease activity
6. Treatment with IGs and/or mAbs within 6 m prior to randomization: rituximab, cyclophosphamide, other immunosuppressive treatments with effects potentially lasting over 6m, within 12m prior randomization
7. Pregnant, planning to get pregnant, and/or lactating females.
8. Participation in any CT within 4 w prior to screening or longer if required locally
9. Hist. of macular edema, diabetic retinopathy, uveitis, central serous retinophathy, retinal vein occlusion, any other eye disease that inc. the risk of macular edema
10. Hist. or presence of stable or unstable IHD, MI, myocarditis, cardiomyopathy, history of angina pectoris due to coronary spasm, history of Reynaud's disease with cardiac sympt. +/or severe peripheral sympt., cardiac failure at screening (NYHA II-IV) or any severe cardiac disease, hist. of cardiac arrest or symptomatic bradycardia, resting pulse rate <55 bpm prior randomization, history or presence of a clin. relevant impairment of cardiac conduction incl. sick sinus syndrome or sino-atrial block, clin. sig. AV block, bundle branch block or an increased QTc > 450 msec for males and > 470 msec for females at screening or baseline ECG and/or the Screening Holter, symptomatic arrhythmia or arrhythmia requiring treatment or being otherwise of clin. significance, uncontrolled art. hypertension. Treatment with medication impairing cardiac conduction (e.g., beta blockers, verapamil-type and diltiazem-type calcium channel blockers, or cardiac glycosides), hist. of syncopes of suspected cardiac origin or catheter ablation
11. Severe respiratory disease or pulm. fibrosis, TB, except for history of successfully treated TB or history of prophylactic treatment after positive PPD skin reaction, abnormal chest x-ray or HRCT suggestive of active pulm. disease, abnormal Pulm. Function Tests: FEV1, FVC < 70% of predicted value, DLCO < 60% of predicted value, pats receiving chronic (daily) therapies for asthma
12. Significant drug allergy/history of atopic allergy. Hypersensitivity to study drug or similar
13. Hist./presence of malignancy (except successfully treated basal or squamous cell carcinoma)
14. Uncontrolled diabetes or diabetes complicated with organ involvement such as nephro- or retinopathy
15. Systemic bacterial, viral or fungal infections, or diagnosis of AIDS, HepB, HepC
16. Other acute or chronic infectious diseases
17. Neg. for varicella-zoster IgG antibodies at screening
18. Have received any live or live attenuated vaccines within 2 m prior to randomization
19. Have received total lymphoid irradiation or bone marrow transplantation
20. Any medically unstable condition
21. Surgical or med. condition significantly altering ADME of drugs or which may jeopardize patient in case of participation in the study. Investigator to be guided by evidence of any of the following: history of IBD, gastritis, ulcers, GI/rectal bleeding, history of major GI tract surgery, history/clin. evidence of pancreatic injury or pancreatitis
22. Liver disease/injury/any of the following: hist. of alcohol abuse, chronic liver or biliary disease, total bilirubin > ULN unless in context of Gilbert's syndrome, conjugated bilirubin > ULN, AP > 1.5 x ULN range, AST, ALT > 2 x ULN range if the elevation of AST or ALT, according to the Inv., is attributable to liver disease. Pats with elevated AST and/or ALT due to myositis disease activity are eligible, GGT > 2 x ULN range
23. Following abnormal lab values: potassium > ULN, serum CREA > 1.7 mg/dL (150 µmol/L), total WBC outside the range of 3,500-12,000/µl. Pats with mild leukocytosis (WBC not higher than 15,000 /µl) may be eligible, if the elevated WBC, according to the Investigator, is attributable to corticosteroid therapy and other causes such as hematological or infectious diseases can be excluded, platelets <100,000/µl at inclusion, lymphocyte count <800/mm3
24. Impaired renal function (clin. significantly abnormal CREA or urea or abnormal urinary constituents)
25. Homozygosity for CYP2C9*3 allele
26. Use of concomitant medications that inhibit/induce CYP2C9
27. drug abuse
28/29. Has an implantable device +an active minute ventillation sensor +active magnet features
30. Has known allergy or hypersensitivity to adhesive or hydrogel |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Binary (responder/non-responder) outcome using the IMACS Definition of Improvement core set measures; patients who are known to have worsened (and consequently may drop out of the study) are treated as non-responders. |
|
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| In period 2 all patients will receive BAF312 |
|
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 5 |
| 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 |
|
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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