| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsing multiple sclerosis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Multiple Sclerosis with relapses |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10028245 |
| E.1.2 | Term | Multiple sclerosis |
| E.1.2 | System Organ Class | 10029205 - Nervous system 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 evaluate long-term safety and tolerability.
Specific emphasis will be on
•effects on cardiac conduction during the titration of the study drug
• long term blood pressure effects
• viral infections
• macular edema
• dermatologic alterations |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate long-term efficacy on clinical grounds
• relapse rate
• disability progression
To evaluate long-term efficacy on paraclinical grounds
• neuroradiological measures of neurodegeneration |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Patients completed the core study CBAF312A2201
2.Written informed consent provided before any assessment of the extension study
3.Female patients at risk of becoming pregnant must have a negative pregnancy test and use simultaneously two forms of effective contraception during dosing and for 30 days after the
last dose of BAF312.
|
|
| E.4 | Principal exclusion criteria |
1.Premature discontinuation of the study drug during the core study due to occurrence of discontinuation withdrawal criteria or due to non-compliance.
2.Newly diagnosed systemic disease other than MS which may require immunosuppressive treatment
3.Presence of malignancy (except for successfully-treated basal or squamous cell carcinoma of skin)
4.Diagnosis of macular edema. Patients with ME history are allowed to enter into the extension phase if ME did not occur during the core study or at the Screening visit for the extension
5.Newly diagnosed diabetes mellitus or a blood glucose obtained suspicious for diabetes
6.Active systemic bacterial, viral or fungal infections, or known to have AIDS, defined as a positive HIV antibody test, Hepatitis B, Hepatitis C infection, defined as Hepatitis B surface antigen or Hepatitis antibody tests, respectively, or having a positive referring laboratory test
7.Any medically unstable condition, as assessed by the treating physician
8.Any of the following CV conditions:
•history or presence of stable or unstable IHD, MI, myocarditis or cardiomyopathy;
•cardiac failure (NYHA Class II-IV) or any severe cardiac disease
•history or presence of symptomatic arrhythmia requiring current treatment or being otherwise of clinical significance
•history or presence of a clinically relevant impairment of cardiay conduction including sick sinus syndrome, sino-atrial heart block
•clinically significant AV block, bundle branch block or an increased QTc interval > 440 msec on screening electrocardiogram (ECG) prior to enrollment
•arterial hypertension, uncontrolled by medication
•newly diagnosed Raynaud’s syndrome
•history of symptomatic bradycardia
•required treatment with medication that impairs cardiac conduction with the exception of beta-blockers (Section 5.5.7) (e.g., beta blockers, verapamil-type and diltiazem-type calcium-channel blockers, or cardiac glycosides)
•history of syncope of suspected cardiac origin
•history of catheter ablation
9.Any of the following pulmonary conditions:
•Severe respiratory disease or pulmonary fibrosis diagnosed during the core study
•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 pulmonary disease in the core study or at screening (if appropriate) in the extension
•Abnormal pulmonary function tests: FEV1 or FVC values lowed than 70% of predicted value
•chronic (daily) treatment for asthma
10.History or presence, i.e any use of illicit or prescription drugs or alcohol constituting an abuse pattern
11.Use of other investigational drugs during the study participation
12.Patients using (or having used within 4 weeks or 5 half-lives, whichever is greater before initial dosing) concomitant medications that are potent inducers of CYP2C9 (see Appendix 3 )
13.Pregnant or nursing (lactating) women
14.Have received any vaccination with live or live attenuated vaccines (including for varicella-zoster virus or measles) within 2 months prior to dosing in the extension
15.Have received total lymphoid irradiation or bone marry transplantation
16.Any of the following abnormal laboratory values at entering the extension assessment:
• Total bilirubin greater than the ULN unless in context of Gilbert’s syndrome
• Conjugated bilirubin greater than the ULN
• AP greater than 1.5 x ULN
• AST or SGOT, ALT or SGPT greater than 2 x ULN
• GGT greater than 3 x ULN
• Serum creatinine > 1.7 mg/dL (150 µmol/L)
• WBC count < 3500/mm3 (< 3.5 x 109/L)
• Lymphocyte count < 800/mm3 (< 0.8 x 109/L)
• Potassium > ULN
17. Have been treated with:
•ACTH or oral or injected corticosteroids within 1 week prior to first dose of the extension
•Immunosuppressive medications such as azathioprine or methotrexate as well as immunoglobulins and/or monoclonal antibodies (including natalizumab) within 6 months prior to first dose of the extension (this role does not apply for alemtuzumab, rituximab, see below)
•Alemtuzumab, rituximab, cladribine, caclophosphamide, mitoxantrone or other immunosuppressive treatments with effects potentially lasting over 6 months, at any time
18.Unable to undergo MRI scans (e.g development of claustrophobia since completion of the core study or due to metallic implant incompatible)
19. Unable to receive gadolinium-based MRI contrast agents due to hypersensitivity to gadolinium-based contrast agents or severe renal insufficiency
20. For patients who will use the MCT device:
• Have an implantable device with an active minute ventilation sensor or active magnet features
• Have a known allergy or hypersensitivity to adhesives or hydrogel
• Patient is willing to refrain from subversion in water (i.e. bathing or swimming) while wearing the Mobile Cardiac Telemetry (MCT) adherent device during dose titration
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Evaluate long term safety and tolerability |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Periodically throughout the study and at Month 60/End of study |
|
| E.5.2 | Secondary end point(s) |
To evaluate long-term efficacy on clinical gorunds
To evaluate long-term efficacy on paraclinical grounds |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Periodically throughout the study and at Month 60/End of Study |
|
| 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) | 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 | 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 42 |
| 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 |
| Russian Federation |
| Turkey |
| 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 | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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