Letter to investigators announcing suspension of 1.5mg trial arm in Arpeggio study of Laquinimod

1.
January 1, 2016
SUBJECT: DISCONTINUATION OF LAQUINIMOD 1.5 MG TREATMENT ARM
Dear ARPEGGIO Investigator,
The Data Monitoring Committee (DMC) for ARPEGGIO held an unscheduled meeting to review cardiovascular
events in the study as well is in the CONCERTO study of laquinimod in relapsing‐remitting multiple sclerosis (MS).
They found an imbalance in myocardial ischemic events in the high dose group in CONCERTO (6 cases in 1.2mg arm,
compared to none in the 0.6mg or placebo arms) along with a cerebral infarct in a 31 year old individual on the
1.2mg dose. In ARPEGGIO, one myocardial infarction was reported in the laquinimod 1.5mg dose group. As of
November 15, 2015, total exposure in CONCERTO was 3070 patient‐years in n=2199 individuals; total exposure in
ARPEGGIO was 35 patient‐years in n=191 individuals.
Due to these events, the DMC recommended stopping all laquinimod dosing arms above 0.6mg in the MS trials. In
addition, the DMC recommended re‐consenting all patients in clinical MS trials with laquinimod, informing them of
the cardiovascular concerns with higher doses of laquinimod.
TEVA is working to implement these recommendations as quickly as possible.
You will soon receive a list of study ID numbers for patients at your site who received laquinimod 1.5mg. Patients
that currently receive 1.5 mg should be contacted immediately and instructed to stop study medication. These
patients should attend an unscheduled visit to return study medication and perform drug accountability. Patients
will be encouraged to continue scheduled follow up visits after being re‐consented.
Please note that our team is working to verify that the IVRS will not dispense laquinimod 1.5mg. For those patients
who are scheduled to be randomized between Jan 3 and Jan 8, please reschedule to the week of Jan 10 to allow for
re‐configuration of the system. Subsequently, randomizations will assign treatment to laquinimod 0.6mg or placebo
daily in a 1:1 ratio.
In addition to these patient safety efforts, TEVA will forthwith inform the competent authorities and relevant ethics
committees regarding these events, the measures taken, and the plan for further action.
Kindly keep this letter and its content in confidence, except to the extent necessary to execute these safety
measures, until after notification of the competent authorities and the relevant ethics committees (anticipated
early next week).
Thank you for your prompt consideration and efforts as we work together to implement this important safety
measure. Our study team will be in close contact with you to answer any questions you may have.
Sincerely,
Volker Knappertz, MD, DMSc
Vice President, Head of Global Clinical Development, Multiple Sclerosis
Teva Pharmaceuticals Industries Ltd.