E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10036102 |
E.1.2 | Term | Polymyositis |
E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
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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 clinical effect of 2 mg BAF312 once daily in patients with PM over 12 weeks using both manual muscle testing (MMT-8) and serum creatine kinase (CK) as a combined endpoint |
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E.2.2 | Secondary objectives of the trial |
- To assess the safety and tolerability of BAF312 in patients with PM
- To characterize the steady state pharmacokinetics of BAF312 in patients with PM
Further objectives see protocol |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subjects eligible for inclusion in this study have to fulfill all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed
2. Male and female patients between 18 - 75 (inclusive) years of age who have been defined as "definite" or “probable” based on the criteria of Bohan and Peter (Bohan and Peter 1975) for polymyositis at least three months before Baseline. Patients must have a history of muscle inflammation documented through objective evidence in at least one of EMG, MRI or biopsy
3. At screening, and baseline, vital signs (systolic and diastolic blood pressure and pulse rate) will be assessed in the sitting position after the subject has rested for at least three minutes. Sitting vital signs should be within the following ranges:
- oral body temperature between 35.0-37.5 °C
- systolic blood pressure, 90-140 mm Hg
- diastolic blood pressure, 50-90 mm Hg
- pulse rate, 50 - 90 bpm
4. Able to communicate well with the investigator, to understand and comply with the requirements of the study
5. Patients must have active disease as defined by CK levels elevated to at least 1.3-fold of the ULN. Such elevated CK levels must be demonstrated at least twice between Screening and Baseline (inclusive)
6. 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)
7. Patients must have received (but inadequately responding to) standard therapies as defined by corticosteroid alone or in combination with second line immunosuppressive agents
such as methotrexate, azathioprine, cyclosporine A or mycophenolate for at least three months before Baseline
8. Patients must be on a stable dose of corticosteroid (5-20 mg prednisone or equivalent per day) for at least 2 weeks prior to Baseline and should not have received a medium or high dose (≥ 100 mg prednisone or equivalent per day) corticosteroid therapy in the last 8 weeks prior to study entry
9. Patients currently treated with oral or subcutaneous methotrexate must have been on a stable dose of no more than 25 mg per week for at least 6 weeks prior to Baseline. Concomitant methotrexate therapy is permitted but not mandatory for patients to enter the study |
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E.4 | Principal exclusion criteria |
Subjects fulfilling any of the following criteria are not eligible for inclusion in this study:
1. Use of other investigational drugs (other than BAF312)- see protocol
2. History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes
3. Polymyositis patients having
a. overlap polymyositis (see protocol)
b. preexisting severe cardiac or pulmonary involvement or any major internal organ damage which deemed by the Investigator to be clinically significant
c. late-stage polymyositis whose muscle weakness, according to the Investigator, could be attributable to muscle damage rather than to myositis disease activity
4. Patients with other types of myositis or myopathies including:
a. dermatomyositis. PM patients with sign of overlapping PM and DM (e.g. based on histology) but with no typical DM skin lesions may be eligible at the investigator`s discretion
b. paraneoplastic polymyositis
c. inclusion body myositis
d. necrotizing myopathy
e. any myopathy due to conditions other than PM
5. Patients who have been treated with other therapies as defined in the protocol
6. Patients with concurrent or history of macular edema or any significant eye disease that increases the risk of macular edema
7. Any of the following cardiovascular conditions:
a. History of or current significant cardiac disease including cardiac failure (NYHA functional class II-IV), myocarditis, cardiomyopathy, angina pectoris or myocardial infarction (within 12 months), or uncontrolled arterial hypertension.
b. Cardiac conduction or rhythm disorders including complete left bundle branch block, sinus arrest or sino-atrial block, symptomatic bradycardia, sick sinus syndrome,Mobitz Type II second degree AV-block or high grade AV-block (either history or observed at screening),
c. Cardiac arrhythmias requiring treatment or ablation (either history or observed at screening), or a history of cardiac syncope.
d. Patients receiving current treatment with Class Ia or III antiarrhythmic drugs
e. Conditions requiring treatment with medication that may cause AV block and suppress AV conduction (e.g. beta-blockers, carbamazepine, lamotrigine, nondihydropyridine
calcium-channel blockers, or cardiac glycosides)PR interval >230 msec. Long QT syndrome or QTcF prolongation >450 msec in males or >470 msec in females, on screening electrocardiogram (ECG)
f. Severe autonomic nervous system dysfunction
g. Catheter ablation
8. Certain pulmonary conditions (see protocol)
9. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases.
10. Uncontrolled diabetes mellitus or diabetes complicated with organ involvement such as diabetic nephropathy or retinopathy.
11. Active systemic bacterial, viral or fungal infections, or diagnosis of AIDS, Hepatitis B, Hepatitis C infection.
12. Evidence of any other acute or chronic infectious diseases.
13. Negative for varicella-zoster virus IgG antibodies at Screening.
14. Have received any live or live attenuated vaccines (including for varicella-zoster virus or measles) within 2 months prior to randomization.
15. Homozygosity for CYP2C9*3 (will be tested at Screening), and/or refusal to test for CYP2C9*3 haplotype.
16. Patients using (or having recently used) concomitant medications that are strong or moderate inducers of CYP2C9.
17. Evidence of drug or alcohol abuse as indicated by the laboratory assays conducted during the screening or baseline evaluations
18. Patients with any condition (e.g. allergy to hydrogel) or an implantable device that is incompatible with the mobile cardiac telemetry monitoring
19. Pregnant or nursing (lactating) women
20. Women of child-bearing potential unless they are using highly effective methods of contraception during dosing and for 7 days after the last dose of BAF312.
21. Certain hepatic conditions (see protocol)
22. Patients with certain abnormal laboratory values prior to randomization (see protocol)
23. Any other disease of condition which could interfere with the participation in the study according to the study protocol, or with the ability with the patients to cooperate and comply with the study procedures
24. Score 4 or 5 on the Screening and/or Baseline Suicidal Ideation item or any “yes” on the Suicidal Behavior item of the C-SSRS that is related to suicidal behavior occurring during the last 2 years
No additional exclusions may be applied by the Investigator, in order to ensure that the study population will be representative of all eligible patients.
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E.5 End points |
E.5.1 | Primary end point(s) |
manual muscle testing (MMT) and serum CK levels |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
IMACS, 6 minutes walking distance (6MWD) test, Timed “up and go” (TUG) test
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
E.6.7 | Pharmacodynamic | No |
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 | 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.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 8 |
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 |
Canada |
Czech Republic |
Hungary |
Poland |
United States |
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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
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | |
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 | 8 |