Supplementary Appendix

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1 Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Metz LM, Li DKB, Traboulsee AL, et al. Trial of minocycline in a clinically isolated syndrome of multiple sclerosis. N Engl J Med 2017;376: DOI: /NEJMoa

2 Trial of Minocycline in Clinically Isolated Syndrome of Multiple Sclerosis Supplemental Appendix Luanne M. Metz, MD, FRCPC, 1 David K.B. Li, MD, FRCPC, 2 Anthony L. Traboulsee, MD, FRCPC, 2 Pierre Duquette, MD, FRCPC, 3 Misha Eliasziw, PhD, 4 Graziela Cerchiaro, PhD, 1 Jamie Greenfield, MPH, 1 Andrew Riddehough, BSc, 2 Michael Yeung, MD, FRCPC, 1 Marcelo Kremenchutzky, MD, FRCPC, 5 Galina Vorobeychik, MD, FRCPC, 6 Mark S. Freedman, MD, MSc, FRCPC, 7 Virender Bhan, MD, FRCPC, 8 Gregg Blevins, MD, FRCPC, 9 James J. Marriott, MD, MSc, FRCPC, 10 Francois Grand'Maison, MD, FRCPC, 11 Liesly Lee, MD, FRCPC, 12 Manon Thibault, MD, FRCPC, 13 Michael D. Hill, MD, MSc, FRCPC, 1 and V. Wee Yong, PhD, 1 for the Minocycline in MS Study Team 1 Cumming School of Medicine and the Hotchkiss Brain Institute, Calgary, AB, 2 University of British Columbia, Vancouver, BC, 3 University of Montreal, Montreal, QC, Canada, 4 Tufts University, Boston, MA, United States, 5 Western University, London, ON, 6 Fraser Health MS Clinic, Burnaby, BC, 7 University of Ottawa and the Ottawa Hospital Research Institute, Ottawa, ON, 8 Dalhousie University, Halifax, NS, 9 University of Alberta, Edmonton, AB, 10 University of Manitoba, Winnipeg, MB, 11 Clinique Neuro Rive-Sud, Greenfield Park, QC, 12 University of Toronto, Toronto, ON, 13 CHA-Hôpital Enfant-Jésus, Québec, QC, Canada 1

3 Table of Contents Table of Contents... 2 Minocycline in CIS Collaborators... 3 Supplementary Tables and Figures Figure S Table S1...5 Table S2...6 Table S3...7 Table S4...8 Table S Table S Table S Table S Table S Table S Table S Table S Table S References

4 Minocycline in MS Study Collaborators: Cumming School of Medicine (Calgary): K Alikhani, D McGowan, J Burton, F Costello, S Wiebe, J Gaythorpe; University of British Columbia: V Devonshire, L Kastrukoff, J Oger, R Tam; Dalhousie University: C Maxner, N Gormley, T Campbell; Fraser Health MS Clinic: A Kazimirchik, T Martin; University of Alberta: F Giuliani, P Smyth; P Dumont, L White; University of Manitoba: M Cossoy, R Vosoughi, B Stanger; University of Toronto: M Masellis, K Carr. 3

5 Figure S1. Adjusted Hazard Ratios for the Primary Endpoint in Subgroups 4

6 Table S1. Inclusion and Exclusion Criteria Inclusion criteria All the following criteria must be met for inclusion of a subject into the study: Age between 18 and 60 years. Individuals between ages must have CSF oligoclonal bands or spinal MRI changes typical of demyelination. First focal clinical episode suggestive of demyelinating disease within the previous 180 days (measured from onset of the first symptom to treatment start), based on the appearance of a neurological abnormality, present for at least 24 hours. Objective clinical evidence must be present or documented. At least two lesions on the T2-weighted brain MRI scan with a size of at least 3 mm, at least one of which is ovoid or periventricular or infratentorial. Sexually active women of child-bearing potential must agree to use adequate contraception. Written informed consent Exclusion criteria Subjects are to be excluded from enrolment if they display any of the following: Any disease other than MS that could better explain the patient s signs and symptoms. Any previous clinical event reasonably attributable to acute demyelination, regardless of whether medical attention was obtained. They have had two or more MRI scans at least 30 days apart to evaluate the CIS event prior to screening. Complete transverse myelitis or bilateral optic neuritis. Any patient who reaches the 2005 McDonald MS 1 endpoint by the time of the baseline assessment. Clinically significant liver, renal, or bone marrow dysfunction. Any condition that could interfere with MRI or any other evaluation in the study. Known allergy or contraindication to gadolinium-dtpa or tetracyclines including estimated GFR less than 60. Concurrent participation in any clinical therapeutic trial. Pre-treatment with the following substances prior to study enrolment: IFN-ß, glatiramer acetate (GA), total lymphoid irradiation, anti-lymphocyte monoclonal antibody treatment, mitoxantrone, cyclophosphamide, azathioprine, cyclosporine A, methotrexate, or any other immunomodulating or immunosuppressive drug including other recombinant or non-recombinant cytokines. Use, within the previous 3 months, of any treatment known to be used for experimental MS treatment including minocycline or other tetracycline. Any other condition or situation that in the opinion of the investigator would either put the patient at risk of worsening health if enrolled in the trial or would prevent completion of the trial with complete follow-up. 5

7 Table S2. Study Amendments Date Amendment Rationale May 2010 The age limit increased from years with additional inclusion criteria to support the CIS diagnosis. Either CSF oligoclonal bands or spinal cord lesions on MRI would be required in these older subjects. November 2011 November 2011 November 2011 November 2011 June 2012 November 2012 November 2012 Subjects would discontinue study participation after reaching the 2005 McDonald MS 1 endpoint even if they did not have a relapse. Prior to this, participants were asked to continue until they had a relapse. T2 MRI burden at 6 months was added as a secondary outcome. The period from onset of Clinically Isolated Syndrome (CIS) and the start of the study medication was increased from 90 to 180 days. The following exclusion criterion was added: They have had two or more MRI scans at least 30 days apart to evaluate the CIS event prior to screening. One lesion on spinal MRI would be allowed to substitute for one brain lesion as per the 2005 McDonald Criteria. The total number of subjects to be randomized was reduced from 200 to 154. Enrolment will cease in 2013 and subjects enrolled in 2013 will only continue until reaching the 2005 McDonald MS or for 12 months. Slow enrolment. Few subjects continued after reaching the 2005 McDonald MS endpoint so it would be futile to evaluate the impact of minocycline on this outcome and therefore unethical to continue any patients to a second relapse. To seek further evidence for a treatment effect from minocycline. To help recruitment and be more consistent with clinical practice. To reduce the risk of enrolling participants already being monitored for active disease and known to be inactive. We already require that patients with a spinal event as onset of the CIS to have a spinal MRI. These patients are known to have similar risk of reaching MS. Slow enrolment. There would still be 80% power to detect a 25% absolute treatment difference if there were 140 completers. As drop outs to date (before reaching the 6-month endpoint) were slightly below the predicted 10% rate, 154 subjects would be randomized. Slow enrolment. An end date for the trial was required and this plan would focus on the primary (6 month) outcome. 6

8 Table S3. Additional Baseline Characteristics of the Trial Subjects Characteristic All Subjects (N=142) Minocycline (N=72) Placebo (N=70) High-risk strata no. (%)* 83 (58.4) 42 (58.3) 41 (58.6) 9 or more T2 hyperintense lesions no. (%) Brain volume median (range) Location of trial site no. (%) Western Canada Eastern Canada 98 (69.0) 50 (69.4) 48 (68.6) ( ) 82 (57.7) 60 (42.2) ( ) 37 (51.4) 35 (48.6) ( ) 45 (64.3) 25 (35.7) Baseline characteristics were not significantly different between treatment groups (p>0.05). * High risk strata included subjects with > 1 enhancing lesion or evidence of dissemination in space on baseline brain MRI according to the 2005 McDonald MS criteria at baseline. Dissemination in space includes those with at least 3 of the following features on MRI: (1) an enhancing lesion or 9 T2 hyperintense lesions, (2) 1 juxtacortical lesions, (3) 1 infratentorial (or spinal cord) lesions, (4) 3 periventricular lesions. Data missing for one placebo-treated subject. For analyses, clinics were grouped into five Western Canadian sites, where treatment of a clinically isolated syndrome (CIS) was not government funded, and seven Eastern Canadian sites where treatment of CIS was funded. 7

9 Table S4. Blinding Assessment of Participants, Study Nurses, and Treating Physicians Guessed Assignment Minocycline (N=72) Subjects Study Nurses Treating Physicians Placebo (n=70) Minocycline (N=72) Placebo (n=70) Minocycline (N=72) Placebo (n=70) Minocycline 26 (36.1) 13 (18.6) 16 (22.2) 5 (7.1) 9 (12.5) 4 (5.7) Placebo 5 (6.9) 16 (22.9) 4 (5.6) 7 (10.0) 2 (2.8) 6 (8.6) Don t Know 19 (26.4) 20 (28.6) 33 (45.8) 39 (55.7) 41 (56.9) 41 (58.6) Missing* 22 (30.6) 21 (30.0) 19 (26.4) 19 (27.1) 20 (27.8) 19 (27.1) BI (95% CI) 0.58 (0.50 to 0.66) 0.79 (0.72 to 0.85) 0.86 (0.80 to 0.91) Data presented as number (%) of actual and guessed treatment assignments. Unblinding questionnaires were completed at the end of study visit. The Blinding Index (BI) was calculated using the James method. 2 The BI ranges from 0 to 1, where 0 is total lack of blinding (all responses are correct), 1 is complete blinding (all responses are Don t Know ), and 0.5 is random blinding (50% correct and 50% incorrect responses). There is sufficient evidence for blinding if the upper bound of the 95% CI of the BI is above * Missing responses were excluded from the BI calculation for 32 subjects who completed the study before May 2011 (n=26) when blinding questionnaires were initiated, or were lost to follow-up (n=6). 8

10 Table S5. Assessment of Characteristics that could Confound the Relationship between Treatment Assignment and the Occurrence of 2005 McDonald MS within 6 months of Randomization Model Baseline Hazard Ratio Covariate(s) (95% CI) P Value* 1 Unadjusted 0.44 (0.26 to 0.74) Risk Strata 0.42 (0.25 to 0.70) Location of Study Site 0.45 (0.27 to 0.76) Risk Strata Location of Study Site 0.43 (0.26 to 0.73) Number of Enhancing Lesions 0.55 (0.32 to 0.95) Any Enhancing Lesions 0.47 (0.28 to 0.80) Spinal Cord Onset 0.45 (0.27 to 0.76) Met 2010 McDonald MS (0.27 to 0.78) Number of Enhancing Lesions Spinal Cord Onset 0.58 (0.33 to 1.00) Any Enhancing Lesions Spinal Cord Onset 0.49 (0.29 to 0.83) Number of Enhancing Lesions Met 2010 McDonald MS 0.52 (0.30 to 0.90) Any Enhancing Lesions Met 2010 McDonald MS 0.46 (0.27 to 0.78) Spinal Cord Onset Met 2010 McDonald MS 0.47 (0.28 to 0.80) Number of Enhancing Lesions Spinal Cord Onset 0.54 (0.31 to 0.93) Met 2010 McDonald MS 15 Any Enhancing Lesions Spinal Cord Onset Met 2010 McDonald MS 0.47 (0.28 to 0.80) CI denotes confidence interval. McDonald MS denotes McDonald MS diagnostic criteria. 1,3 Hazard ratios and 95% CIs, presented for the minocycline versus placebo comparison for the primary 6 month endpoint [2005 McDonald Definite Multiple Sclerosis 1 ], were calculated from complementary log-log regression models, adjusted for the baseline covariates strata (low risk, high risk), location of study site (Western Canada, Eastern Canada), number of gadolinium-enhancing lesions (0, 1, 2), any gadolinium-enhancing lesions (yes, no), spinal cord onset (yes, no), and/or met 2010 McDonald MS criteria (yes, no). None of the adjusted hazard ratios exceeded the unadjusted hazard ratios by more than the suggested change-in-estimate threshold of 10% 4 except for number of enhancing lesions. * Wald test for treatment group effect. 9

11 Table S6. Multiple Imputation Analysis 5 Type of Analysis Minocycline Placebo Difference P Value Primary Intention to Treat (ITT) st imputation ITT nd imputation ITT rd imputation ITT th imputation ITT th imputation ITT Imputation combined ITT Six-month risks (%) of 2005 McDonald multiple sclerosis from stratified actuarial life table analyses, adjusted for enhancing lesions at baseline. 10

12 Table S7. Clinical Outcomes at 3, 6, 12 and 24 Months Study Month 3-Months Unadjusted Risk* no. (%) Unadjusted Risk Difference* (95% CI) P Value* Adjusted Risk % Adjusted Risk Difference (95% CI) Minocycline 19 (27.1) Placebo 33 (48.5) (5.6 to 37.2) 45.6 ( 2.4 to 26.4) 6-Months Minocycline 23 (33.4) Placebo 41 (61.0) (11.4 to 43.9) 61.5 (3.7 to 33.3) 12-Months Minocycline 27 (40.4) Placebo 44 (66.0) (9.0 to 42.1) 67.1 (2.1 to 32.2) 24-Months Minocycline 34 (55.3) Placebo 47 (72.0) ( 0.6 to 34.0) 74.2 ( 4.8 to 27.1) * Risk estimates, differences, and P values were calculated from actuarial life-table analyses. Log-rank P value = for comparing study groups over 6 months of follow-up. Risk estimates, differences, and P values were calculated from actuarial life-table analyses, stratified by baseline number of enhancing lesions. Stratified log-rank P value = and for comparing study groups over 6 months and 24 months of follow-up, respectively. P Value 11

13 Table S8. Number of Adverse Events Adverse Event All Subjects (N=394) Minocycline (N=211) Placebo (N=183) Hyperpigmentation 14 (3.6) 10 (4.7) 4 (2.2) Rash 14 (3.6) 12 (5.7) 2 (1.1) Nausea 16 (4.1) 11 (5.2) 5 (2.7) Dental discolouration* 6 (1.5) 6 (2.8) 0 (0) Upper respiratory tract infection 39 (9.9) 23 (10.9) 16 (8.7) Candida vaginitis 17 (4.3) 11 (5.2) 6 (3.3) Influenza 12 (3.0) 5 (2.4) 7 (3.8) Gastroenteritis 9 (2.3) 2 (0.9) 7 (3.8) Dizziness 11 (2.8) 10 (4.7) 1 (0.5) Headache 12 (3.0) 5 (2.4) 7 (3.8) Back pain 9 (2.3) 4 (1.9) 5 (2.7) Data presented as number (%) of adverse events. Only adverse events that involved more than 5% of subjects or were statistically significantly different between treatment groups are presented. * Only one patient with dental discolouration met the study endpoint by relapse, therefore, unblinding due to this event was unlikely to impact the study outcome. 12

14 Table S9. Relapse Outcomes at 6 and 24 Months Unadjusted Difference (95% CI) P Value* Outcome Unadjusted Findings Adjusted Findings 6 Months Relapse - no. (%) Minocycline 7 (9.7) Placebo 14 (20.0) (-1.3 to 21.9) 19.9 (-3.3 to 21.6) Adjusted Difference (95% CI) P Value ARR (95% CI) Minocycline 0.26 (0.10 to 0.53) (0.02 to 0.21) Placebo 0.60 (0.33 to 1.00) (-0.02 to 0.71) 0.23 (0.10 to 0.37) (-0.05 to 0.28) 24 Months Relapse - no. (%) Minocycline 11 (15.3) Placebo 16 (22.9) (-5.3 to 20.5) 22.6 (-6.3 to 20.1) ARR (95% CI) Minocycline 0.16 (0.08 to 0.29) (0.07 to 0.37) Placebo 0.32 (0.19 to 0.53) (-0.02 to 0.35) 0.36 (0.17 to 0.56) (-0.08 to 0.36) ARR denotes annualized relapse rate. * P values were calculated with the use of the chi-square test for proportions and the midp exact test for rates. Proportions, differences, and P values were calculated from log-binomial regression models with baseline number of enhancing lesions as the covariate. Rates, differences, and P values were calculated from Poisson regression models with baseline number of enhancing lesions as the covariate

15 Table S10. Disability Outcomes* at End of Study Outcome Unadjusted Findings Unadjusted Difference (95% CI) P Value Adjusted Findings Adjusted Difference (95% CI) P Value Change in EDSS 6 Mean ± SE Minocycline ± ± Placebo ± 0.12 (-0.26 to 0.44) ± 0.14 (-0.27 to 0.45) Improved 1 or more - No. (%) Minocycline 20 (29.0) Placebo 15 (22.1) (-0.21 to 0.08) 18.2 (-0.17 to 0.07) 1.5 or more - No. (%) Minocycline 10 (14.5) Placebo 7 (10.3) (-0.15 to 0.07) 8.5 (-0.13 to 0.06) Worsened 1 or more No. (%) Minocycline 10 (14.5) Placebo 9 (13.2) (-0.13 to 0.10) 12.7 (-0.11 to 0.11) 1.5 or more - No. (%) Minocycline 4 (5.8) Placebo 6 (8.8) (-0.06 to 0.12) 6.6 (-0.04 to 0.09) Stable 1 or less - No. (%) Minocycline 55 (79.7) Placebo 55 (80.9) (-0.12 to 0.14) 82.1 (-0.18 to 0.09) 1.5 or less No. (%) Minocycline 63 (91.3) Placebo 64 (94.1) (-0.06 to 0.12) 94.0 (-0.07 to 0.11) * 5 subjects (3 minocycline; 2 placebo) missing follow-up EDSS 4 were excluded from the analysis. P values were calculated with the use of the t-test for means and the chi-square test for proportions. Means, differences, and P values were calculated from analysis of covariance with baseline number of gadolinium-enhancing lesions as the covariate. Proportions, differences, and P values were calculated from log-binomial regression models with baseline number of gadolinium-enhancing lesions as the covariate. 14

16 Negative values indicate improvement in EDSS scores and positive values indicate worsening in EDSS scores. 15

17 Table S11. Comparison of Study Design from CIS Trials Reporting 2005 McDonald MS Outcomes Treatment Groups Outcome: 2005 McDonald MS Criteria Time of Primary Analysis Minocycline Interferon -beta 1b Interferon beta-1a Teriflunomide Oral Cladribine MinoCIS BENEFIT 7 REFLEX 8 TOPIC 9 ORACLE MS 10 N=142 N=468 N=517 N=618 N=616 Interferon-beta 1a Interferon-beta 1b 44 mcg sc three 250 mcg sc every Teriflunomide 14 mg times weekly vs other day vs vs 7 mg vs placebo once weekly vs placebo placebo Minocycline 100 mg twice daily vs placebo Cladribine 5.25 mg/kg vs 3.5 mg/kg vs placebo Primary Co-Primary Primary Secondary Secondary 6 months (secondary outcome at 24 months) 24 months 24 months 24 months or early study termination 24 months Inclusion Criteria: Age years Time from onset to treatment days Mechanism of balancing risks across groups at randomization * Stratification (> 1 enhancing lesion or dissemination in space vs neither) Minimization (steroid use, monofocal onset, number of enhancing lesions, presence of CSF oligoclonal bands) Minimization (age, steroid use, monofocal onset, any enhancing lesions) Stratification (monofocal vs multifocal onset) Stratification (geographic region) 16

18 Unique features of relapse definitions Subject Participation: Point when subject data was censored Recruitment and Sites: Recruitment period (duration - months) 48 hr duration; EDSS increase of 0.5, or FS increase of 2, or increase of 1 in 2 FS scores; Confirmation by steering committee member Clinical and MRI data censored at 2005 McDonald MS endpoint, dropout, or 24 months (six subjects enrolled in 2013 censored at month 12 per protocol) Dec June 2013 (55) 24 hr duration; Relevant neurologic abnormality; Confirmation by central committee Clinical data censored at dropout or 24 months. MRI data censored at CDMS. Feb Jun 2003 (17) 24 hr duration; Relevant neurologic abnormality; Confirmation by central committee Clinical and MRI data censored at drop-out or 24 months (participants started active drug after reaching CDMS) Nov Aug 2008 (21) 24 hr duration; Minimum EDSS or FS increase of 1.0 in the relevant FS Clinical and MRI data censored at drop out, CDMS or 24 months (unknown number of subjects censored early due to study termination) Feb Aug 2012 (55) Not defined Clinical and MRI data censored at drop-out, CDMS or 24 months (unknown number of subjects censored early due to study termination) Oct Oct 2010 (49) Locations Canada only 20 countries 28 countries 20 countries 34 countries Number of sites Number of subjects randomized per site per month Source of Funding MS Society of Canada Pharmaceutical Industry Pharmaceutical Industry Pharmaceutical Industry Pharmaceutical Industry 17

19 Only variables that differed in a way that may impact interpretation are included. CIS denotes clinically isolated syndrome, McDonald MS denotes McDonald MS diagnostic criteria, sc denotes subcutaneous, CDMS denotes clinically definite MS. * Represents maximum of 75 days to screening and maximum 28 days for screening. All studies required new neurologic symptoms, clinical stability for the previous 30 days in the absence of fever or infection, and objective evidence of at least one new neurological abnormality detected by a blinded evaluating neurologist. Assumed based on reported last 24 month visit date of August

20 Table S12. Comparison of Baseline Characteristics from CIS Trials Reporting 2005 McDonald MS Outcomes Treatment Groups Minocycline Interferon -beta 1b Interferon beta-1a Teriflunomide Oral Cladribine MinoCIS BENEFIT 7 REFLEX 8 TOPIC 9 ORACLE MS 10 N=142 N=468 N=517 N=618 N=616 Minocycline 100 mg twice daily vs placebo Interferon-beta 1b 250 mcg sc EOD (n=292) vs placebo (n=176) Interferon-beta 1a 44 mcg sc three times weekly vs once weekly vs placebo Teriflunomide 14 mg (n=216) vs 7 mg (n=205) vs placebo (n=197) Cladribine 5.25 mg/kg vs 3.5 mg/kg vs placebo Age at CIS onset years Mean ± SD 35.8 ± ± 8.2 Median (IQR) 34.5 ( ) 30 ( )/ 30 (25-36) 32.8 ± 8.1/ 31.6 ± 9.0/ 32.0 ± ± 8.7 Female sex % / / 63/ White race % 84.5* 97.9/ 98.9 NR 96/ 97/ EDSS Mean ± SD 1.6 ± ± 0.97/ 1.5 ± 1.02/ 1.71 ± 1.00 Median (IQR) 1.5 ( ) 1.5 (0-4.0) 1.5 (0-4.0) 1.5 ( ) 19

21 Anatomical site of onset % Spinal cord / 26.9 Brainstem/Cerebellum 34.5/ / 23.7 Optic nerve / 37.6 Other (Cerebral) / 11.8 Multifocal symptom onset % CIS duration days / or 46 (investigator or adjudication committee) Mean ± SD 84.5 ± ± / 40/ ± 17.0/ 57.5 ± 17.0/ 57.2 ± or 49 (investigator or adjudication committee) 79.1 ± 17.2 Median (IQR) 83.5 ( ) 80.0 ( ) Steroid treatment of CIS - % / Met 2010 McDonald MS criteria at baseline % 29.6 NR 37.7 NR 37 Nine or more T2 enhancing lesions % / NR 75 20

22 T2 burden of disease mm 3 Mean ± SD ± ± Median (IQR) ( ) ( )/ ( ) 8780 ± 9360/ 8070 ± 9980/ 9150 ± ( ) Number of enhancing lesions % None / / 59/ 60 NR One 16.9 NR NR NR NR Two or more 17.6 NR NR NR NR Mean ± SD 1.2 ± ± 2.9 Median (IQR) 0 (0-1.0) 0 (0-1.0)/ 0 (0-1.0) 0 (0-1.0) CIS denotes clinically isolated syndrome, McDonald MS denotes McDonald diagnostic criteria, EOD denotes every other day, sc denotes subcutaneous, CDMS denotes clinically definite MS, EDSS denotes extended disability status scale score, NR denotes not reported, SD denotes standard deviation, IQR denotes interquartile range. * Non-white included South Asian (n=9), Asian (n=5), Black (n=3), Aboriginal (n=2), other (n=2), and unknown (n=1), where multiple ethnic groups could be selected. Non-white included Black (n=5, <1%), Asian (n=28, 5%), other (n=1, <1%). Months were converted to days where 1 month = 30 days. Converted from ml to mm 3. 21

23 Table S13. Comparison of Hazard Ratios from CIS Trials Reporting 2005 McDonald MS Outcomes Treatment Groups Minocycline Interferon -beta 1b Interferon beta-1a Teriflunomide Oral Cladribine MinoCIS BENEFIT 7 REFLEX 8 TOPIC 9 ORACLE MS 10 N=142 N=468 N=517 N=618 N=616 Interferon-beta 1a Interferon-beta 1b 44 mcg sc three 250 mcg sc every Teriflunomide 14 mg times weekly vs other day vs vs 7 mg vs placebo once weekly vs placebo placebo Minocycline 100 mg twice daily vs placebo Cladribine 5.25 mg/kg vs 3.5 mg/kg vs placebo Time to 2005 McDonald MS Hazard Ratio (95% CI) Unadjusted* Adjusted High dose Over 6 months Over 24 months Over 24 months Over 24 months Over 24 months *0.44 ( ) 0.55 ( ) Low dose sc denotes subcutaneous, CI denotes confidence interval. Adjusted for number of enhancing lesions at baseline. *0.54 ( ) 0.49 ( ) 0.69 ( ) 0.65 ( ) 0.69 ( ) 0.43 ( ) 0.50 ( ) 22

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