| 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. Male patients must be using two acceptable methods of contraception, (e.g., spermicidal gel plus condom) for the entire duration of the study, up to Study Completion visit, and refrain from fathering a child in the three (3) months following last study drug administration. Periodic abstinence and withdrawal are not acceptable methods of contraception.
8. 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; juvenile myositis (< 18 yrs); DM with no muscle involvement; inclusion body myositis; overlap PM or DM. Pats with serological ANA, anti-dsDNA, anti-topo or clinical signs of other autoimmune diseases but not fulfilling diagnostic criteria for such connective tissue diseases are allowed to enter the study at the Investigator`s discretion. PM/DM pats with secondary Sjögren`s syndrome are eligible.
2. Myopathy due to conditions other than PM/DM.
3. Severe pharyngeal, cardiac, pulmonary involvement; any major internal organ damage which deemed clinically significant.
4. Late-stage PM/DM whose muscle weakness could be attributable to muscle damage rather than to myositis disease activity.
5. Treatment with IGs and/or mAbs within 6 mos prior to randomization: rituximab, cyclophosphamide, other immunosuppressive treatments with effects potentially lasting over 6 months, within 12 mos prior randomization.
6. Pregnant, planning to get pregnant, and/or lactating females, males planning to father a child.
7. Participation in any CT within 4 wks prior to screening or longer if required locally, for any other limitation of participation if required locally.
8. History of macular edema, diabetic retinopathy, uveitis, central serous retinophathy, retinal vein occlusion, any other eye disease that increases the risk of macular edema.
9. MI within the past 6 mos prior enrollment or current unstable ischemic heart disease, history of angina pectoris due to coronary spasm, cardiac failure at time of screening (NYHA III) or any severe cardiac disease, history of cardiac arrest or symptomatic bradycardia, resting pulse rate <55 bpm prior randomization, history of sick sinus syndrome or sino-atrial block, history or presence of any second degree AV block, or a third degree AV block or Long QT syndrome or QTc > 450 msec for males and > 470 msec for females at screening or baseline, arrhythmia requiring current treatment with class III antiarrhythmics, history of a positive tilt test during workup for vasovagal syncope, uncontrolled hypertension.
10. Severe respiratory disease, TB, except for history of successfully treated TB or history of prophylactic treatment after positive PPD skin reaction, abnormal Pulmonary Function Tests: FEV1, FVC < 70% of predicted value, DLCO < 60% of predicted value, pats receiving chronic (daily) therapies for asthma.
11. Significant drug allergy/history of atopic allergy. Hypersensitivity to study drug or similar drugs.
12. History/presence of malignancy (except successfully treated basal or squamous cell carcinoma).
13. Uncontrolled diabetes or diabetes complicated with organ involvement such as nephro- or retinopathy.
14. Systemic bacterial, viral or fungal infections, or diagnosis of AIDS, HepB, HepC.
15. Other acute or chronic infectious diseases.
16. Negative for varicella-zoster IgG antibodies at screening.
17. Have received any live or live attenuated vaccines within 2 mos prior to randomization.
18. Have received total lymphoid irradiation or bone marrow transplantation.
19. Any medically unstable condition, as assessed by the primary treating physician.
20. Surgical or medical 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/clinical evidence of pancreatic injury or pancreatitis.
21. Liver disease/injury/any of the following: history of alcohol abuse, chronic liver or biliary disease, total bilirubin greater than ULN range, AP greater than 1.5 x ULN range, AST, ALT greater than 2 x ULN range if the elevation of AST or ALT, according to the Investigator, is attributable to liver disease. Pats with elevated AST and/or ALT due to myositis disease activity are eligible, GGT > 2 x ULN range
22. Following abnormal laboratory values: 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.
23. History/presence of impaired renal function (clinically significantly abnormal CREA or urea or abnormal urinary constituents).
24. Urinary obstruction/difficulty in voiding at screening.
25. Homozygous genotype of the CYP2C9*3 allele.
26. Using/having used within 4 wks or 5 half- lives, whichever is greater before initial dosing concomitant medications that are potent inhibitors or inducers of CYP2C9.
27. Drug/alcohol abuse indicated by lab assays conducted during screening/baseline evaluations. |
|
| 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 | 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
|
|
| 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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