| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsing-remitting multiple sclerosis |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10063399 |
| E.1.2 | Term | Relapsing-remitting multiple sclerosis |
|
| 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 |
| The primary objective of this study is to evaluate the dose response relationship among five doses of BAF312 and placebo during 3 months of treatment in patients with RRMS, as measured by the number of combined unique active [MRI] lesions (CUAL). |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the safety and tolerability (including blood pressure effects) of BAF312 during 6 months and 3 months of treatment in MS patients
• To evaluate the dose response relationship of BAF312 and placebo during 6 months of treatment in patients with RRMS, as measured by CUAL
• To explore the effect of BAF312 on the number of relapses and thereof derived measures (e.g. annualized relapse rate (ARR), proportion of relapse-free patients)
• To explore the correlation of the course of the lymphocyte count with paraclinical (MRI activity) and clinical course
|
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Pharmacogenetics/ pharmacogenomics /exploratory biomarkers: These exploratory biomarker sub-studies are optional. These assessments will only be performed on patients who agree to participate by signing the separate exploratory biomarker-blood informed consent. Laboratory manuals will be provided with detailed information on sample collection, handling, and shipment.
Further details are provided in Section 7.6.2 of the protocol. |
|
| E.3 | Principal inclusion criteria |
1. Patients must give written informed consent before any assessment is performed
2. 18 through 55 years of age inclusive
3. Male or female
4. Females of childbearing potential:
• must have a negative pregnancy test at Baseline prior to entry into the double-blind treatment phase
• must simultaneously use two forms of effective contraception (either partner) during the treatment and for one
months or one menstrual cycle, whichever is longer after discontinuation of the study drug
• if either post-menopausal for 12 months prior to randomization or surgically sterile (through hysterectomy
or bilateral oophorectomy, if documented), are not required to use birth control (refer to Section 8.3 for more
details)
5. Diagnosis of MS as defined by revised McDonald criteria (see Appendix 4)
6. A relapsing-remitting course of disease with
• at least 1 documented relapse during the previous year, or
• 2 documented relapses during the previous 2 years, or
• a positive Gd-enhanced MRI scan at screening (in case the first MRI scan obtained at screening is negative, a
second scan may be obtained 1 month later)
7. An Expanded Disability Status Scale (EDSS) score of 0-5.0 inclusive at randomization
8. Neurologically stable with no evidence of relapse or corticosteroid treatment within 30 days prior to
randomization
9. Patients who decline initiation or continuation of treatment with available disease modifying drugs for MS, for
whatever reason, after having been informed about their respective benefits and possible adverse events by the
investigator.
10. Is willing to refrain from submersion in water while wearing the MCT adherent device during dose titration |
|
| E.4 | Principal exclusion criteria |
1. Another type of MS than RRMS
2. History of chronic disease of the immune system other than MS, or a known immunodeficiency syndrome
3. Malignancy (except for successfully-treated basal or squamous cell carcinoma of skin)
4. Known, or ‘new’ diagnosis of diabetes mellitus (if screening blood glucose is suspicious for diabetes a patient should be further evaluated)
5. Macular edema during pre-randomization
6. Active systemic bacterial, viral or fungal infections, or AIDS, hepatitis B, hepatitis C infection defined as a positive HIV AB, hepatitis B surface AG or hepatitis C AB tests
7. Negative for varicella-zoster virus IgG AB at screening
8. Live or live attenuated vaccination within 2 m
9. Total lymphoid irradiation or bone marrow transplantation
10. Have been treated with:
• ACTH or oral or injected corticosteroids within 1 m
• IFN-β or glatiramer acetate within 3 m
• immunosuppressive medications such as azathioprine or methotrexate within
6 m
• immunoglobulins and/or monoclonal ABs (including natalizumab) within 6 m (this rule does not apply for alemtuzumab, rituximab)
• alemtuzumab, rituximab, cladribine, cyclophosphamide, mitoxantrone, or other immunosuppressive treatments with effects potentially lasting over 6 m, at any time
11. Any medically unstable condition, as assessed by the primary treating physician
12. Any of the following CV conditions
• history or presence of stable or unstable IHD, MI, myocarditis or cardiomyopathy
• history of Raynaud’s disease
• cardiac failure (NYHA class II - IV) at screening and/or at baseline, or any severe cardiac disease as determined by the investigator
• history of cardiac arrest
• history of symptomatic bradycardia
• resting pulse rate < 55 bpm
• history or presence of a clinically relevant impairment of cardiac conduction including sick sinus syndrome, sino-atrial block
• clinically significant AVB, bundle branch block or an increased QTc interval > 440 msec on screening ECG
• history or presence of symptomatic arrhythmia or arrhythmia requiring treatment or being otherwise of clinical significance
• arterial hypertension, uncontrolled by medication
• treatment with medication that impairs cardiac conduction
• history of syncopes of suspected cardiac origin
• history of catheter ablation
13. Any of the following pulmonary conditions:
• severe respiratory disease or pulmonary fibrosis
• tuberculosis, except for history of successfully treated TB or history of prophylactic treatment after positive PPD skin reaction
• abnormal chest High Resolution Computer Tomography (HRCT), chest X-Ray or chest MRI suggestive of active pulmonary disease
• abnormal Pulmonary Function Tests: forced expiratory volume in 1 second (FEV1) or forced vital capacity
(FVC) values lower than 70% of predicted value
• patients receiving chronic (daily) therapies for asthma
14. Any of the following hepatic conditions:
• chronic liver or biliary disease
• total bilirubin >ULN unless in context of Gilbert’s syndrome
• conjugated bilirubin >ULN
• alkaline phosphatase (AP) >1.5 x ULN
• AST or SGOT, ALT or SGPT >2 x ULN
• GGT >3 x ULN
15. Any of the following abnormal laboratory values:
• potassium >ULN
• serum creatinine > 1.7 mg/dL (150 μmol/L)
• white blood cell count < 3,500/mm3 (< 3.5 x 109/L)
• lymphocyte count < 800/mm3 (< 0.8 x 109/L)
16. Any of the following neurological/psychiatric disorders:
• history or presence of substance abuse (any illicit or prescription drugs or alcohol)
• progressive neurological disorder, other than MS
17. Unable to undergo MRI scans due to claustrophobia or metallic implants incompatible with MRI
18. Unable to receive [Gd]-based MRI contrast agents due to a history of hypersensitivity to [Gd]-based contrast agents, or severe renal insufficiency
19. Participation in any clinical research study evaluating another investigational drug or therapy within 3 m
20. History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes
21. Homozygosity for CYP2C9*3 (will be tested at Screening), and refusal to test for CYP2C9*3 haplotype
22. Patients using (or having used within 4 w or 5 half-lives, whichever is greater before initial dosing) concomitant medications that are strong or moderate inhibitors or inducers of CYP2C9
23. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin laboratory test (> 5 mIU/mL)
24. History of S1P receptor modulator therapy
25. Any other disease/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.
26. Implantable device with an active minute ventilation sensor or active magnet features
27. Allergy or hypersensitivity to adhesives or hydrogel |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Monthly number of combined unique active MRI lesions (CUAL) during 3 months of treatment. Combined unique active lesions are defined as new gadolinium [Gd]-enhancing lesions on T1-weighted MRI scans or new or enlarging lesions on T2-weighted MRI scans, without double-counting of lesions.
|
|
| 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 | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
| E.6.13 | Others | Information not present in EudraCT |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
|
| 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
| 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 | 12 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 34 |
| 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 | 7 |
| 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 | 7 |
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