Added safety measures imposed by health authorities in the Phase III program studying BAF312 in secondary progressive multiple sclerosis. The safety measures also included new exclusion criteria that reflected updates to the label for Gilenya®, which belongs to the same pharmacological class

The planned expansion of the study to more countries, in some of which the MCT system was not available. The cardiac monitoring was performed with a Holter ECG instead of the MCT used in the other participating countries. New clinical information had become available (study CBAF312A2116) that justified the concomitant use of beta blockers with study drug; corresponding changes were made to the eligibility criteria to allow the use of beta blockers. Azathioprine was added as permitted background medication (methotrexate or azathioprine) since it was a frequently used steroid-sparing agent in this patient population. The ivIg therapy washout window was decreased to 3 months to allow more patients in to the study. Changes were made to update safety and tolerability information on BAF312, and to align and make consistent eligibility criteria with another similar study of BAF312 in dermatomyositis patients.

The addition of recent findings in a mouse carcinogenicity study. A section of efficacy data in PM/DM was updated with final data of a completed proof-of-concept that had become available. The study stopping rules were modified to allow for a full safety review prior to discontinuation of all subjects in case of 2 patients experiencing a study drug related AE, as specified in the stopping rules

The requirement for vital signs to be within defined ranges at screening and baseline was deleted (systolic blood pressure 90 - 140 mm Hg; diastolic blood pressure 50 -90 mm Hg; pulse rate, 50- 90 bpm). The requirement for elevated levels of blood creatine kinase at baseline (≥1.3 × ULN) was changed to allow for alternative indicators of active muscle inflammation, i.e. other muscle enzymes, MRI imaging, or recent biopsy. The inclusion requirement for muscle weakness based on an MMT8 score of no more than 135/150 was changed to be based on the MMT24 scoring system, i.e. patients had an MMT24 score of no more than 245/260. The assessment of 6-minutes-walking distance (6MWD) was moved from exploratory to secondary objective. The requirement for previous treatment failure or toxicities to previous treatment was removed. The washout times for immunosuppressive regimens were adapted based on current knowledge about the duration of physiological effects of individual drugs and clinical practice for switching therapeutic regimens. If a patient had interrupted the intake of study drug, the permitted duration of treatment pause was changed from “48 hours” to less than four missed doses. In patients with specific genetic variants of CYP2C9 (CYP2C9*1*3 and *2*3), new restrictions applied for the use of CYP3A4 inhibitors. Potent CYP2C9 inhibitors as well as potent CYP2C9 and/or CYP3A4 inducers were not permitted during the study. The screening and baseline windows were expanded for logistical reasons. An additional dose arm of 10 mg BAF312 was added. The titration period was increased for all dosing arms. A new set of randomization numbers were generated to modify the ratio of subjects assigned to the placebo, 2 mg and 10 mg. The total number of subjects to be enrolled was increased from 30 to up to 45.

To ensure that the maximum exposure reported at maximum tolerated dose (MTD) (20 mg q.d.) in the multiple ascending dose (MAD) study 2105 won’t be exceeded, especially in the 10 mg dose group, specific exclusions criteria in terms of 2C9/3A4 inhibitors were defined for CYP2C9 *1/*3, *2/*2 and *2/*3 carriers. Further to the CYP2C9*3 genotyping at screening, this amendment additionally described the need for CYP2C9*2 genotyping