There were 3 global amendments after start of recruitment. The following major procedural changes (not all-inclusive) were made to the protocol via this amendment: - During the Investigational New Drug (IND) process of laquinimod for HD trial, the Food and Drug Administration (FDA) commented that given that laquinimod 0.6 mg/day leads to a 5- fold reduction in the systemic concentration of caffeine, a cytochrome P450 (CYP) 1A2 probe substrate, an even larger effect on CYP1A2 may be observed when the higher doses of 1.0 mg and 1.5 mg planned in the HD trial are administered. The FDA recommended that in view of this potential increased effect of laquinimod on the pharmacokinetics of CYP1A2 substrates, use of drugs metabolized by CYP1A2 should be avoided during the trial. Based on this recommendation, Sponsor decided to modify all laquinimod protocols in which higher doses of laquinimod than 0.6 mg/day are administered and updated the guidance regarding the co-administration of laquinimod and drugs that are mainly metabolized by CYP1A2. - In addition, following the LAQ-MS-305 (CONCERTO) Data Monitoring Committee (DMC) recommendation, this amendment included a requirement to perform abdominal computed tomography (CT) as soon as possible when pancreatitis was suspected. Evaluation of pancreatitis was important in order to enable adequate or better medical treatment/care. The complete guidance for monitoring participants with elevated pancreatic amylase levels were added. - Clarifications regarding other study procedures, including (but not limited to): a) References to "postural blood pressure changes" were removed; only supine measurements were to be captured. b) Clarification regarding timing of Magnetic Resonance Imaging (MRI) scan in case of anxiolysis. c) New text to disallow benzodiazepines 3 days prior to the Positron Emission Tomography (PET) scan, as benzodiazepines could interfere with Translocator Protein (TSPO) binding.

The following major procedural changes (not all-inclusive) were made to the protocol: - Contraception language updated for consistency with other laquinimod protocols; - To reduce participant burden, the Clinical Dementia Rating - Sum of Boxes (CDR-SB), Hospital Anxiety and Depression Scale (HADS) and Problem Behaviors Assessment-Short form (PBA-s) scales will only be assessed at baseline and at Month 12/early termination (ET); - The option to perform the MRI scan at screening has been introduced to reduce participant burden; - Newly added anaemia panel assessment for consistency with other laquinimod protocols; - Clarification that both urine and pregnancy tests were to be performed at baseline, and the randomization will be based on the results of urine pregnancy test; - Washout time from previous investigational product shortened; - New text added for clarification regarding medication errors and special situations; - List of concomitant medications/therapies was updated for consistency with other laquinimod protocols and Investigator's Brochure (IB). - Newly added section to appendix to clarify monitoring of participants with haemoglobin decrease and participants with creatinine phosphokinase (CPK) increase.

The following major procedural changes (not all-inclusive) were made to the protocol: - Clarification of the study randomization following the discontinuation of the laquinimod 1.5 mg/day treatment arm; - More stringent criterion for exclusion of participants with significant cardiac events or conditions in their medical history, and for hepatic parameters. - To avoid increased exposure to laquinimod, stopping rules were introduced for renal impairment and hepatic impairment, with additional assessments of estimated creatinine clearance (CrCl) introduced for increased monitoring of renal function; - The risks and benefits sections of the protocol were updated to reflect the new findings observed in the Multiple Sclerosis (MS) trials; - Additional clarifications related to study conduct were implemented. These include (not all inclusive): a) clarifications regarding determination of eligibility of participants with exclusionary variance from historical cytosine-adenosine-guanine (CAG) repeat results, b) testing of both troponin and creatine kinase-muscle/brain (CK-MB) in case of creatine phosphokinase levels above the upper limit of normal (ULN) to provide additional cardiovascular assessment, c) and adjustment of blood volume collected to allow for unscheduled visits. - Assessment of laquinimod metabolites was added to the overall exploratory pharmacokinetic assessment for better characterization of laquinimod disposition; - As an enhanced monitoring and safety precaution, data on participant’s smoking habits were to be collected and an evaluation of cardiac risk factors was to be performed.