3. Gold R, Giovannoni G, Selmaj K, et al. Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECT): a randomised,

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Appendix e-1. Bases for approval for drugs approved for the treatment of multiple sclerosis or its symptoms

Active substance Study name Pivotal trial design

Intervention Comparator (s)

Study duration/

Follow up

Primary outcome No. pts random- ised

ARR (95% CI)

Progression of disability

Quality of life

Alemtuzumab (Ale)

CAMMS323¹ Phase 3, randomised, rater-blinded in treatment-naive patients with RRMS

Ale 60 + 36 mg (two annual cycles IV, month 0 and 12)

Three times weekly SC IFN β-1a

2 years co-primary: rate ratio/ARR and time to SAD

581 Ale: 0.18 (0.13 to 0.23)

IFN β-1a: 0.39 (0.29 to 0.53) RR: 0.45 (0.32 to 0.63)

Ale 8.00 (5.66 to 11.24)

IFN β-1a: 11.12 (7.32 to 16.71) HR: 0∙70 (0∙40 to 1∙23) (a1)

Ale patients experienced significant improvement on the FAMS and SF-36 PCS. No data available.

CAMMS324² Phase 3 randomized, rater- and dose- blinded study in patients with RRMS who have relapsed on therapy

Ale 60 + 36 mg or 102+72 mg (two annual cycles IV, month 0 and 12)

Three times weekly IFN β- 1a

2 years co-primary: rate ratio/ARR and time to SAD

840 Ale: 0.26 (0.21 to 0.33) IFN β-1a: 0.52 (0.41 to 0.66) RR: 0.51 (0.39 to 0.65)

Ale: 12.71 (9.89 to 16.27)

IFN β-1a: 21.13 (15.95 to 27.68) HR: 0.58 (0.38 to 0.87) (a1)

Ale patients experienced significant improvement on the FAMS and SF-36 PCS. No data available.

Daclizumab (Dac) 205MS201 (SELECT)³

Phase 2 multicenter, randomized, double-blind in RRMS patients.

Dac 150 mg Dac 300 mg (SC every 4 weeks)

placebo 1 year ARR 621 Dac 150 mg: 0.21

(0.16 to 0.29) Dac 300 mg: 0∙23 (0∙17 to 0∙31) placebo: 0∙46 (0∙37 to 0∙57) Dac 150 mg:

RR 0.46 (0.32 to 0.67)

Dac 300 mg:

RR 0.50 (0.35 to 0.72)

Dac 150 mg:

HR 0.24 (0.09 to

0.63) 300 mg:

HR 0.60 (0.30 to 1.20) (a1) ____________

Dac 150 mg: HR

0.43 (0.21 to 0.88) Dac 300 mg: HR

0.57 (0.30 to 1.09) (a2)

MSIS-29 physical score (mean change from baseline ± SD) Dac 300 mg: 1.4 ± 13.5 Dac 150 mg: –1.0 ± 11.8 Placebo: 3.0 ± 13.5 Relative mean change Dac 150 Vs. placebo: -4.3 (-6.8 to – 1.8)

Dac 300 Vs. placebo: -1.9 (-4.4 to – 0.6)

(no difference in QOL) 205MS301

(DECIDE) ⁴

Phase 3 multicentre, double-blind, randomized in RRMS patients

Dac 150 mg (SC every 4 weeks)

IFN β-1a 3 years (144 weeks)

ARR 1841 Dac: 0.22 (0.19 to 0.24) IFN β-1a: 0.39 (0.35 to 0.44) RR: 0.55 (0.47 to 0.65)

IFN β-1a:- HR 0.73 (0.55 to 0.98) (a1) HR 0.84 (0.66 to

1.07) (a2) MSIS-29 physical score (% of patients with clinically meaningful worsening):

Dac 150 mg: 19%

IFN β-1a :23%

OR 0.76 (0.60 to 0.95) Dimethyl

fumarate (DMF)

109MS301⁵ Phase 3, multicenter double-blind, randomized in RRMS patients

oral DMF 240 mg BID

oral DMF 240 mg TID

placebo 2 years ARR 1237 DMF BID: 0.17

(0.14 to 0.21) DMF TID: 0.19 (0.15 to 0.23) placebo: 0.36 (0.30 to 0.44) DMF BID:

RR 0.47 (0.37 to

DMF BID:

HR 0.77 (0.52 to 1.14)

DMF TID:

HR 0.69 (0.46 to 1.04) (a1) _____________

DMF BID HR 0.62 (0.44 to

Declared as tertiary endpoints:

SF-36 -Physical Component Summary, EQ- 5D.

Data not reported.

(2)

Follow up

ARR (95% CI)

Quality of life

0.61) DMF TID:

RR 0.52 (0.40 to 0.67)

0.87) DMF TID HR 0.66 (0.48 to 0.92) (a2) 109MS302⁶ Phase 3,

multicenter double-blind, randomized controlled in RRMS patients

oral DMF 240 mg BID

oral DMF 240 mg TID

placebo, glatiramer (active reference)

2 years ARR 1430 DMF BID: 0.22

(0.18 to 0.28) DMF TID: 0.20 (0.16 to 0.25) glatiramer: 0.29 (0.23 to 0.35) placebo: 0.40 (0.33 to 0.49) DMF BID Vs.

placebo:

RR 0.56 (0.42 to 0.74)

DMF TID Vs placebo RR 0.50 (0.37 to 0.66).

glatiramer vs placebo RR 0.71 (0.55 to 0.93)

DMF BID Vs.

placebo HR 0.62 (0.37 to 1.03)

DMF TID Vs.

placebo HR 0.67 (0.40 to 1.11)

glatiramer Vs.

placebo HR 0.87 (0.55,1.38) (a1) ___________

DMF BID Vs.

placebo HR 0.79 (0.52 to 1.19)

DMF TID Vs.

placebo HR 0.76 (0.50 to 1.16) glatiramer Vs. placebo HR 0.93 (0.63 to 1.37) (a2)

SF-36 -PCS component, EQ- 5D scores were not statistically significant. Data not available.

Fampridine* MS-F203⁷ Phase 3,

double-blind, placebo- parallel group in MS patients

Fampridine 10 mg BID

placebo 21 weeks walking speed (T25FW test)

301 - - Not assessed

MS-F204⁸ Phase 3, multicenter, double- blind, placebo- controlled, parallel group in MS patients

Fampridine 10 mg BID

placebo 14 weeks walking speed (T25FW test)

239 - - Not assessed

Fingolimod (Fing) D2301⁹ Phase 3, double-blind, randomized, in RRMS patients

Fing 1.25 mg daily (oral) Fing 0.5 mg daily (oral)

placebo 2 years ARR 1272 Fing 1.25 mg:

0.16 (0.13 to 0.19) Fing 0.5 mg:

0.18 (0.15 to 0.22) Placebo: 0.40 (0.34 to 0.47)

Fing 1.25 mg:

HR: 0.60 (0.41 to 0.86)

Fing 0.5 mg:

HR: 0.63 (0.44 to 0.90) (b1)

Declared as additional endpoint: Impact on daily activities. Data not reported.

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Follow up

ARR (95% CI)

Quality of life

Fing 1.25 mg: RR 0.40 (CI not reported) Fing 0.5 mg: RR 0.46 (CI not reported)

____________

Fing 1.25 mg: HR:

0.68 (0.50 to 0.93).

Fing 0.5 mg:

HR: 0.70 (0.52 to 0.96) (b2) D2302

(TRASFORM)

10

Phase 3, double-blind, randomized, in RRMS patients

Fing 1.25 mg daily (oral) Fing 0.5 mg daily (oral)

IFN β-1a 1 year ARR 1292 Fing 1.25 mg 0.20

(0.16 to 0.26) Fing 0.5 mg: 0.16 (0.12 to 0.21) IFN β-1a: 0.33 (0.26 to 0.42) Fing 1.25 mg: RR 0.62 (CI not reported) Fing 0.5 mg: RR 0.48 (CI not reported)

Fing 1.25 mg: HR:

0.85 (Data not available) Fing 0.5 mg:

HR: 0.71 (0.42 to 1.21) (b2)

Not assessed

Natalizumab (Nat) C-1801 (AFFIRM) ¹¹

Nat 300 mg IV every 4 weeks

placebo 2 years 1st year: ARR 2nd year:

disability progression

942 Nat: 0.26 (0.21 to 0.32)

placebo: 0.81 (0.67 to 0.97) RR not reported

HR: 0.58 (0.43 to 0.77) (a2)

Significant improvements in visual function and mental and physical component of the SF- 36. Data not available.

C-1802 (SENTINEL) ¹²

Phase 3, double blind, randomized, in RRMS patients

Natalizumab 300 mg IV every 4 weeks + IFN β-1a

Placebo +

IFN β-1a 2 years 1st year:

ARR 2nd year:

disability progression

1196 Nat + IFN β-1a:

0.38 (0.32 to 0.45) Placebo + IFN β- 1a: 0.81 (0.72 to 0.92)

RR not reported

HR: 0.76 (0.61 to 0.96) (a2)

Declared as tertiary endpoints:

VAS assessing patient´s global impression, MSQLI or SF-36.

Data not reported.

Peg-interferon beta 1a (Peg- IFN β-1a)

105MS301 (ADVANCE) ¹³

Peg- IFN β-1a 125 µg Q2W, Peg- IFN β-1a 125 µg Q4W

placebo 1 years ARR 1516 Peg- IFN β-1a Q2W: 0.26 (0.21 to 0.32) Peg- IFN β-1a Q4W: 0.29 (0.23

Peg- IFN β-1a Q2W

HR 0.62 (0.40 to 0.97)

Not assessed

(tertiary endpoints: cognition, visual function, and various patient-reported outcomes)

(4)

Follow up

ARR (95% CI)

Quality of life

to 0.36) Placebo: 0.40 (0.33 to 0.48) RR Q2W Vs Placebo: 0.64 (0.50 to 0.83) RR Q4W Vs Placebo: 0.72 (0.56 to 0.93)

Peg- IFN β-1a Q4W

HR 0.62 (0.40 to 0.97)

(a2)

Teriflunomide (Ter)

EFC6049 (TEMSO) ¹⁴

Phase 3, double-blind, randomized, in relapsing MS patients with or without progression.

Ter 7 mg daily (oral) Ter 14 mg daily (oral)

placebo 2 years ARR 1088 Ter 7 mg: 0.37

(0.32 to 0.43) Ter 14 mg: 0.37 (0.31 to 0.44) placebo: 0.54 (0.47 to 0.62);

Ter 7 mg RR:0.69 (0.56 to 0.84) Ter 14 mg RR 0.68 (0.55- 0.85)

Ter 7 mg:

HR 0.75 (0.51 to 1.11)

Ter 14 mg:

HR 0.75 (0.50 to 1.11) (b1) Ter 7 mg HR: 0.76 (0.56 to 1.05)

Ter 14 mg HR 0.70 (0.51 to 0.97) (b2)

No difference in patient- reported outcomes, SF-36, and EQ-5D.

Data not available.

EFC10531 TOWER ¹⁵

Phase 3, randomized, double-blind, in relapsing MS patients with or without progression

placebo 2∙5 years ARR 1169 Ter 7 mg:

0.39 (0.33 to 0.46) Ter 14 mg:

0.32 (0.27 to 0.38) Placebo:

0.50 (0.43 to 0.58);

Ter 7 mg:

RR 0.78 (0.63 to 0.96)

Ter 14 mg:

RR 0.64 (0.51 to 0.79)

Ter 7 mg:

HR: 1.05 (0.69 to 1.61)

Ter 14 mg:

HR: 0.84 (0.53 to 1.33) (b1) Ter 7 mg HR: 0.95 (0.68 to 1.35)

Ter 14 mg HR: 0.68 (0.47 to 1.00) (b2)

Not assessed

EFC10891 (TENERE)¹⁶

Phase 3, randomized, parallel-group, rater-blinded in relapsing MS patients

IFN β-1a 2 years Time to failure (relapse or treatment discontinuation)**

324 Ter 7 mg:

0.41 (0.27 to 0.64)

Ter 14 mg: 0.26 (0.15 to 0.44) IFN β-1a: 0.22

Not assessed Not assessed (Secondary endpoint: TSQM)

(5)

Follow up

ARR (95% CI)

Quality of life

(0.11 to 0.42)

Relative risk vs.

IFN β-1a Ter 7 mg:

1.90 (1.05 to 3.43) Ter 14 mg:

RR 1.20 (0.62 to 2.30)

*Fampridine licensed to improve walking in adults with multiple sclerosis with walking disability. ARR and disability not assessed. ** no difference

Abbreviations:

ARR: Annualized relapse rate, BID: bis in die (twice a day), CI: confidence interval, EDSS: Expanded Disability Status Scale, FAMS: Functional Assessment of Multiple Sclerosis, HR:

hazard ratio, IFN: interferon, IV: intravenous, MSIS-29: 29-item Multiple Sclerosis Impact Scale,MSQLI: Multiple Sclerosis Quality of Life Inventory , OR: odds ratio,Q2W: every 2 weeks, Q4W: every 4 weeks, RR: rate ratio, RRMS: relapsing remitting multiple sclerosis, SAD: sustained accumulation disability, SC: subcutaneous, SF3636-Item Short Form Survey, TID: tris in die (three times a day), T25FW: timed 25-food walk, TSQM: Treatment Satisfaction Questionnaire for Medication, VAS: visual analogue scale.

(a1) confirmed disability progression sustained for six months defined by at least a 1.0-point increase on the EDSS from baseline EDSS ≥1.0 or a 1.5-point increase on the EDSS from baseline EDSS =0.

(a2) confirmed disability progression sustained for three months defined by at least a 1.0-point increase on the EDSS from baseline EDSS ≥1.0 or a 1.5-point increase on the EDSS from baseline EDSS =0.

(b1) confirmed disability progression sustained for six months defined by at least a 1.0-point increase on the EDSS from baseline EDSS <5.5 or a 0.5- point increase from baseline EDSS ≥ 5.5).

(b2) confirmed disability progression sustained for three months defined by at least a 1.0-point increase on the EDSS from baseline EDSS <5.5 or a 0.5- point increase from baseline EDSS ≥ 5.5).

References

1. Cohen JA, Coles AJ, Arnold DL, et al. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet (London, England) 2012;380:1819-1828.

2. Coles AJ, Twyman CL, Arnold DL, et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet (London, England) 2012;380:1829-1839.

3. Gold R, Giovannoni G, Selmaj K, et al. Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECT): a randomised,

double-blind, placebo-controlled trial. Lancet (London, England) 2013;381:2167-2175.

(6)

4. Kappos L, Wiendl H, Selmaj K, et al. Daclizumab HYP versus Interferon Beta-1a in Relapsing Multiple Sclerosis. The New England journal of medicine 2015;373:1418-1428.

5. Gold R, Kappos L, Arnold DL, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. The New England journal of medicine 2012;367:1098-1107.

6. Fox RJ, Miller DH, Phillips JT, et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. The New England journal of medicine 2012;367:1087-1097.

7. Goodman AD, Brown TR, Krupp LB, et al. Sustained-release oral fampridine in multiple sclerosis: a randomised, double-blind, controlled trial. Lancet (London, England) 2009;373:732-738.

8. Goodman AD, Brown TR, Edwards KR, et al. A phase 3 trial of extended release oral dalfampridine in multiple sclerosis. Ann Neurol 2010;68:494-502.

9. Kappos L, Radue EW, O'Connor P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. The New England journal of medicine 2010;362:387-401.

10. Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. The New England journal of medicine 2010;362:402-415.

11. Polman CH, O'Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. The New England journal of medicine 2006;354:899-910.

12. Rudick RA, Stuart WH, Calabresi PA, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. The New England journal of medicine 2006;354:911-923.

13. Calabresi PA, Kieseier BC, Arnold DL, et al. Pegylated interferon beta-1a for relapsing-remitting multiple sclerosis (ADVANCE): a randomised, phase 3, double-blind study. The Lancet Neurology 2014;13:657-665.

14. O'Connor P, Wolinsky JS, Confavreux C, et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. The New England journal of medicine 2011;365:1293-1303.

15. Confavreux C, O'Connor P, Comi G, et al. Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet Neurology 2014;13:247-256.

16. Vermersch P, Czlonkowska A, Grimaldi LM, et al. Teriflunomide versus subcutaneous interferon beta-1a in patients with relapsing multiple

sclerosis: a randomised, controlled phase 3 trial. Multiple sclerosis (Houndmills, Basingstoke, England) 2014;20:705-716.

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Appendix e-2. Post-marketing evidence (randomized controlled trials) for drugs approved for the treatment of multiple sclerosis or its symptoms

Active substance

Study name/

registration

Main objective

& population

Intervention Com- parator(s)

Sample size

Primary outcome Results What this study

adds to the evidence at the

time of MA

Alemtuzumab No studies

Daclizumab (Dac)

Selection NCT00870740

1,2

(SELECT study extension)

Safety and immunogenicity of extended treatment with Dac in adult pts with RRMS

Pts in the placebo group of SELECT randomized to:

1. Dac 150 or 300 mg Pts in the active groups of SELECT randomized to:

2. the same dose of Dac as in SELECT 3. placebo for 20 wks then same dose of Dac as in SELECT

- 517 Safety and

immunogenicity

Any AE

1: 118/170=69%

2: 119 /173=69%

3: 131/174= 75%

SAE

1: 26 /170=15%

2: 26/173=15%

3: 33 /174=19 % Antidrug antibodies 1: 7/162 (4%) 2: 1/128 (1%) 3: 19/129 (15%)

Neutralising antidrug antibodies 1: 4/162 (2%)

2: 1/128 (1%) 3: 2/129 (2%)

Safety profile appears similar after 1 or 2 years of treatment with Dac.

Descriptive information on durability of effect (ARR and the proportion of patients who relapsed) but the study was not powered to show this.

Dimethyl fumarate (DMF)

ENDORSE NCT00835770

3, 4

6-year efficacy and safety of DMF in adults with RRMS (DEFINE and CONFIRM studies extension)

Pts in the placebo or glatiramer groups of DEFINE and CONFIRM randomized to:

DMF 240 mg BID DMF 240 mg TID Pts in the active groups of DEFINE and CONFIRM

229 Long-term safety and efficacy profile of DMF in patients with RRMS.

Interim results (6 out of 8 years) Any AE:

DMF/DMF: 132/144 (92%) Placebo/DMF:80/85 (94%) cumulative ARRs

DMF/DMF: 0.14 (0.10 to 0.19) placebo/DMF: 0.17 (0.11 to 0.25 RR: 0.81 (0.51 to 1.31)

Disability progression

No significant difference between two groups

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Gerardi, 2 Active

substance

Study name/

registration

Main objective

& population

Sample size

time of MA continue on the same

dose (DMF 240 mg BID or TID)

HR: 0.51 (0.27 to 0.97)

Fampridine (Fam)

MOBILE NCT01597297

5, 6

Effect of Fam on self-assessed walking disability, dynamic/static balance and safety in pts with MS (all forms)

Fam 10 mg BID placebo 132 No pre-specified primary/secondary outcomes

Walking ability, mobility and dynamic balance, QoL, safety.

Post hoc analyses:

Mean changes from baseline in the 29-item MSIS-29 PHYS and PSYCH subscales.

Greater median improvements from baseline in TUG speed, BBS total score and MSWS-12 score compared with placebo Data in figures, only p-value reported

EQ-5D-5L VAS 0.00 (–4.17 to 4.67)

Utility index: 0.00 (–0.04 to 0.04) Any AE

Fam: 51/68 (75%) placebo: 49/64 (77%) SAE

Fam: 2/68 (3%) placebo: 5/64 (8%)

Mean change from baseline MSIS-29 PHYS 89%

Mean change from baseline MSIS-29 PSYCH: 148

Further information on questionable measure of walking ability.

No benefit in terms of QOL

ENHANCE NCT02219932

Evaluate a meaningful effect on patient- reported walking ability in pts with MS (all forms)

Fam 10 mg BID placebo 646 Proportion of pts achieving an

improvement on MSWS- 12 of ≥8-points

Fam: 43.2%

Placebo: 33.6%

Risk difference 10.4%

(95%CI 3 to 17.8%) OR: 1.61 (1.15 to 2.26)

Further information on questionable measure of walking ability Study supporting the conversion from CA to regular approval

(9)

Study name/

registration

Main objective

& population

Sample size

time of MA NCT01444300 Effect of Fam on

imbalance in pts with PPMS or SPMS and imbalance

Fam 10 mg BID placebo 24 Change in APR Latency Fam: 5.71 (16.2) Placebo: 4.58 (23.0) Difference: not significant

Nothing

NCT01328379 Safety and efficacy of lower dose of Fam in improving walking in pts with MS (all forms)

Fam 5 mg BID Fam 10 mg BID

placebo 430 Change from baseline in walking speed measured with T25FW

Fam5 mg BID: 0.42 (0.05) Fam10 mg BID: 0.48 (0.06) Placebo: 0.36 (0.05) Fam 5 mg vs. placebo:

Mean difference: 0.05 (95%CI -0.09 to 0.20)

Fam 10 mg vs. placebo:

Mean difference: 0.12 (95%CI -0.03 to 0.26)

Nothing

NCT01356940 Effect of Fam on walking ability in pts with MS (all forms)

Fam 10 mg BID/

placebo

placebo/

Fam 10 mg BID

43 Peak Activity Index Mean (SD):

Fam 10 mg BID/placebo: 0.6 (0.54) Placebo/Fam 10 mg BID : 0.3 (0.55) Difference: 0.59 (not significant)

Nothing

Fingolimod (Fing)

EPOC

NCT01216072

7-10,11,12, 13

Assess physician- and patient- reported outcomes in pts with RRMS candidate for therapy change from injectable IFN or GA

Fing 0.5 mg (oral) iDMT:

glatiramer acetate, IM or SC IFN beta-1a, or IFN beta- 1b

1053 TSQM Global Satisfaction score Secondary: fatigue, depression, activities of daily living, and health- related QOL.

TSQM Fing: 20.4 iDMT: 2.9

Mean difference (standard error):

-17.5 (1.68)

Patients also reported significant improvements in health-related quality of life, less depression, and less severe fatigue after switching to Fing

Information on convenience of use of oral therapy vs. injectable therapy.

No information on comparative effectiveness and patients relevant outcome NCT00340834

14

To compare patients receiving

Pts in the IFN group of TRASFORM

1027 ARR ARR

1. 0.22 (0.15 to 0.31) Information on

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substance

Study name/

registration

Main objective

& population

Sample size

time of MA Fing for up to 2

years and those switched from INF to Fing RRMS Ext

TRANSFORM

randomized to:

1. Fing 0.5 mg 2. Fing 1.25 mg

Pts in the Fing groups of TRASFORM continued same dose of

3.Fing 0.5 mg 4. Fing 1.25 mg

2. 0.18 (0.12 to 0.27) 3 . 0.11 (0.08 to 0.16) 4 . 0.11 (0.08 to 0.16)

No benefit in terms of disability progression

treatment duration

ACROSS ¹⁵¹⁶

11

NCT02307838

Efficacy, safety, and tolerability of Fing at five years follow up RRMS Ext

FTY720D2201

Pts in the placebo group of FTY720D2201 randomized to:

1. Fing 1.25 mg 2. Fing 5.0 mg*

Pts in the fing groups of FTY720D2201 continued same dose of

3. Fing 1.25 mg 4. Fing 5.0 mg*

*switched to 1.25 because of

unfavorable benefit- risk of higher dose

281 ARR ARR (5 years)

1,2: 0.23 3: 0.17 4: 0.19 HR

3 vs.1,2: 0.64 (0.40 to 1.02) 4 vs. 1,2: 0.55 (0.33 to 0.90)

Information on treatment duration

INFORMS ¹⁷ NCT00731692

Efficacy of Fing on disability progression in PPMS

Fing 1.25 mg daily (then cut to 0.5 mg)

placebo 970 Time to CDP defined as change from baseline in:

EDSS, 25TWT, 9-HPT

3-month CDP composite

HR: 0.95 (95% CI 0.80 to 1.12)

Fing did not slow disease

progression in PPMS FREEDOMS

II ¹⁸¹⁹

Efficacy and safety of Fing

Fing 0.5 mg daily Fing 1.25mg daily

placebo 1083 ARR Fing 1.25 mg: 0.20 (0.17 to 0.25) Fing 0.5 mg: 0.21 (0.17 to 0.25)

Confirmation of efficacy of Fing

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Study name/

registration

Main objective

& population

Sample size

time of MA NCT00355134

0.5mg daily in pts with RRMS

*(then stopped) Placebo: 0.40 (0.34 to 0.48)

Fing 1.25 mg: 0.50 (0.39 to 0.65) Fing 0.5 mg: 0.52 (0.40 to 0.66)

in reducing relapses in RRMS.

Study conducted to comply with FDA requirements PREFERMS

NCT01623596

2021

To evaluate efficacy of Fing vs. DMT by assessing patients retention on treatment.

RRMS

Fing 0.5 mg daily DMT (IFN or

glatiramer)

875 Retention on treatment over a 12 month period

Patients who completed randomised treatment:

Fing 0.5 mg: 352 (81.3%) DMT: 125 (29.2%) p<0.001

Information on treatment duration

NCT01333501 COGNITION

22

Effects of Fing and IFN beta on cognitive dysfunction progression in people with RRMS and aassessment of possible

relationship with brain atrophy

Fing IFN β-1b 151 • Change in selective reminding test raw score

• Change in spatial recall test raw score

• Change in symbol digit modalities test raw score

• Change in paced auditory serial addition test raw score

• Change in selective reminding test-delayed recall test raw score

Change in selective reminding test raw score on 108 patients analysed Mean (SD)

Fing: 6.32 (1.33) IFN β-1b: 4.46 (2.28)

Information on cognitive dysfunction

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substance

Study name/

registration

Main objective

& population

Sample size

time of MA Natalizumab

(Nat)

RESTORE ²³

2425

NCT01071083

PK, PD, immune and radiological parameters in patients stopping Nat compared to patients

remaining on Nat RRMS

1. continue Nat therapy 300 mg iv

2. placebo 3. other immuno- therapy (IFN, glatiramer, methylprednisone )

175 clinical and radiological outcomes

MRI disease activity recurrence:

1 new Gd1 lesion of 0.8 cm3 or 2 or more Gd1 lesions of any size as determined by the central reader

MRI disease activity recurrence:

1: 0/45 (0%) (95% CI 0 to 7.9) 2: 19/41 (46%) (95% CI 30.7 to 62.8)

3. 30/81 (37%) (95% CI not reported)

Relapses 1: 2/45 2,3: 23/122 AE

1: 5/38 (84%) 2: 5/35 (83%) 3: 72/88 (82%)

Exploratory study Information on treatment duration

REFINE ²⁶ Multiple regimens of Nat RRMS

1: Nat 300 mg sc every 4 Weeks, 2: Nat 300 mg iv every 12 Weeks, 3: Nat 300 mg sc every 12 Weeks, 4: Nat 150 mg iv every 12 Weeks, 5: Nat 150 mg sc every 12 Weeks

6: Nat 300 mg iv every 4 weeks

290 Cumulative Number of Combined Unique Active Lesions Serious adverse events

Mean (SD) 1: 0.02 (0.15) 2: 3.84 (8.05) 3: 3.08 (8.21) 4: 6.09 (15.4) 5: 6.44 (11.2) 6: 0.23 (1.26) SAE

1: 4/45 (8.9%) 2: 4/52 (7.7%) 3: 3/53 (5.7%) 4: 4/47 (8.5%) 5: 1/38 (2.6%) 6: 7/54 (13.0% )

Exploratory study, no new

information.

Nat vs. placebo or IFN, GA,

methylprednisone in the long term

TOFIINGO Effect of different 1: 8-week WO from - 142 Number of active T2 Mean (SD) Information on

(13)

Study name/

registration

Main objective

& population

Sample size

time of MA NCT01499667

27

Nat washout (WO) periods in pts with RRMS switching from Nat to Fing

Nat + 24 weeks Fing 2: 12-week WO from Nat (8 weeks no treatment and 4 weeks placebo) + 20 weeks Fing

3: 16-week WO from Nat (8 weeks no treatment and 8 weeks placebo) + 16 weeks Fing

lesions 1: 2.1 (7.24) 2: 1.7 (3.78) 3: 8.2 (16.81)

Significantly higher in the 16-week WO than the 12-week WO group

optimal length of treatment suspension

GLANCE

28

To evaluate the safety and tolerability of combination Nat and GA. RRMS

Nat + GA placebo+

GA

110 Radiological outcomes Primary: active lesions defined as new Gd lesions and

nonenhancing new or newly enlarging T2 lesions

New active lesions Nat+GA: 0.03 Placebo+GA: 0.11

Mean numbers of new gadolinium-enhancing lesions Nat+GA: 0.6

Placebo+GA: 2.3

New/newly enlarging T2- hyperintense lesions Nat+GA: 0.5 Placebo+GA: 1.3

CI not reported, reported as significant

Defined as safety and tolerability Combination therapy efficacy only in terms of radiological outcomes

NCT01144052

293031

The effect of escalating dose of Nat and switch to INF-beta 1b RRMS

Continue monthly Nat 300 mg IV

IFN-beta 1b 250 µg every other

19 Median time to first on study relapse

Median time to first on study relapse IFN beta: 103 days

Nat: 0 days Number of relapses

Time to first on- study relapse

(14)

substance

Study name/

registration

Main objective

& population

Sample size

time of MA

day IFN beta: 3

Nat: 0 NCT01416181

(ASCEND)

Effects of Nat in reducing accumulation of disability not related to relapses in people with SPMS

Nat Placebo 889 Percentage of

participants with

confirmed progression of disability in one or More of the following scale:

EDSS, T25FW, 9HPT

Confirmed on ≥1 of EDSS, T25FW, or 9HPT at 2 years

Nat: 44 (39.8 to 49.1) placebo: 48 (43.1 to 52.4) OR: 0.86

95 % CI (0.66 to 1.13)

Efficacy of Nat in SPMS

Peg-interferon beta 1a (Peg IFN β-1a)

ADVANCE NCT00906399

32, 33

to characterize the incidence and impact of immunogenicity to Peg IFN β-1a over 2 years RRMS

Peg- IFN β-1a 125 μg every 2 or 4 weeks

placebo 1512 Incidence of treatment- emergent antibodies

6%, less than 1%, and 7% of patients developed anti-IFN BAbs,

NAbs, and anti-PEG antibodies

Incidence and impact of

immunogenicity to Peg IFN β-1

Teriflunomide (Ter)

TOPIC NCT00622700

34,35

To assess the efficacy and safety of Ter in pts with clinically isolated

syndrome (first clinical episode suggestive of MS)

Ter 14 mg Ter 7 mg

placebo 618 Time to relapse (defined as a new neurological abnormality separated by

≥30 days from a preceding clinical event, present for ≥24 h in the absence of fever or known infection)

% patients with relapse Ter 14 mg: 38 (18%) Ter 7 mg: 39 (19%) Placebo: 55 (28%) HR (versus placebo)

Ter 14 mg: 0.57 (0.40 to 0.87) Ter 7 mg: 0.63 (0.42 to 0.95)

Information on effects of Ter in the early stages of MS

NCT00475865

36

Safety and tolerability of combination Ter + GA in patients with RRMS who relapsed while on a stable dose of GA

Ter 14 mg + GA Ter 7 mg + GA

Placebo + GA

148 Overview of AE Overview of AE with potential risk of occurrence (hepatic and immune disorders;

pancreatic disorders;

malignancy; skin disorders, pulmonary disorders; hypertension;

peripheral neuropathy;

Any AE*

Ter 14 mg + GA: 35/40 Ter 7 mg + GA: 35/42 Placebo + GA: 32/41 SAE

Ter 14 mg + GA: 1/40 Ter 7 mg + GA: 3/42 Placebo + GA: 3/41

Any AE with potential risk of

Exploratory study Preliminary information on combination Ter + GA

(15)

Study name/

registration

Main objective

& population

Sample size

time of MA psychiatric disorders;

hypersensitivity) Liver function

occurrence

Ter 14 mg + GA: 28/40 Ter 7 mg + GA: 28/42 Placebo + GA: 24/41 NCT00489489

37, 38

Safety and tolerability of combination Ter + IFN β (1a/1b) in patients with RRMS who relapsed while on a stable dose of IFN-β

Ter 14 mg + IFN-β

Ter 7 mg + IFN-β Placebo +

IFN-β 118 Overview of AE Overview of AE with potential risk of occurrence (hepatic and immune disorders;

psychiatric disorders;

hypersensitivity) Liver function

Any AE*

Ter 14 mg + IFN-β: 32/38 Ter 7 mg + IFN-β: 33/37 Placebo + IFN-β: 35/41 SAE Ter 14 mg + IFN-β: 0/38 Ter 7 mg + IFN-β: 2/37 Placebo + IFN-β: 1/41

Any AE with potential risk of occurrence

Ter 14 mg + IFN-β: 26/38 Ter 7 mg + IFN-β: 25/37 Placebo + IFN-β: 24/41

Exploratory study Preliminary information on combination Ter + IFN-β

NCT00811395

39

Long-term safety and tolerability of combination Ter + GA or Ter + IFN-β in patients with RRMS who relapsed while on a stable dose of GA or IFN-β extension of NCT00489489 and

NCT00475865

Ter 14 mg + IFN-β Ter 7 mg + IFN-β Ter 14 mg + GA Ter 7 mg + GA

Placebo + IFN-β;

Placebo + GA

239 Overview of adverse events

Overview of AE with potential risk of occurrence (hepatic and immune disorders;

psychiatric disorders;

hypersensitivity)

Any AE*

Ter 14 mg + IFN-β: 33/38 Ter 7 mg + IFN-β: 35/37 Ter 14 mg + GA: 38/41 Ter 7 mg + GA: 5/42 Placebo + IFN-β: 35/41 Placebo + GA: 39/40

SAE Ter 14 mg + IFN-β: 1/38 Ter 7 mg + IFN-β: 4/37 Ter 14 mg + GA: 2/41 Ter 7 mg + GA: 5/42

Information on combination Ter + IFN-β and Ter + GA

(16)

substance

Study name/

registration

Main objective

& population

Sample size

time of MA Liver function

Placebo + IFN-β: 2/41 Placebo + GA: 6/40

Any AE with potential risk of occurrence

Ter 14 mg + IFN-β: 30/38 Ter 7 mg + IFN-β: 39/37 Ter 14 mg + GA: 32/41 Ter 7 mg + GA: 33/42 Placebo + IFN-β: 28/41 Placebo + GA: 34/40 TERACLES

NCT01252355

40

Efficacy of combination Ter + IFN-β in patients with RRMS treated with IFN-β

Ter 14 mg + IFN-β

Ter 7 mg + IFN-β Placebo +

IFN-β 534 ARR ARR (95% CI)

Ter 14 mg + IFN β: 0.24 (0.16 to 0.35) Ter 7 mg + IFN-β:

0.24 (0.15 to 0.39)

placebo + IFN-β: 0.30 (0.21 to 0.43)

Information on combination Ter + IFN-β

FUP TEMSO NCT00803049

41, 42

To assess long- term safety of ter in patients with RRMS up to 9 years

Ext TEMSO

Pts in the placebo group of TEMSO randomized to:

1.Ter 14 mg 2.Ter 7 mg Pts in the ter groups of TEMSO continued same dose of 3.Ter 14 mg 4.Ter 7 mg

- 742 TEAE % TEAE

1. 94.4%

2. 93.8 % 3. 91.2%

4. 91.3%

Any AE (n, %) 1. 97 (91.5) 2. 122 (93.8) 3. 224 (89.6) 4. 230 (90.6)

Serious AE (n, %) 1. 19 (17.9) 2. 30 (23.1)

Long term safety of Ter

(17)

Study name/

registration

Main objective

& population

Sample size

time of MA 3. 55 (22.0)

4. 62 (24.4)

*when primary endpoints were AE, SAE and other specific adverse events we report only AE and SAE since the other specific AE were already included in the first group

Abbreviations:

APR: Automatic Postural Response, ARR Annualized relapse rate, BBS: Berg Balance Scale, BID: bis in die (twice a day), CDP: confirmed disability progression, CI: confidence interval DMT:

disease-modifying therapy HR: hazard ratio, EDSS: Expanded Disability Status Scale, EQ-5D-5L: EuroQoL-5 Dimension 5-level, GA: glatiramer acetate, iDMT: injectable disease modifying therapy, IFN: interferon, MS: multiple sclerosis, MSIS-29: 29-item Multiple Sclerosis Impact Scale, MSWS-12: 12-item Multiple Sclerosis Walking Scale, ND: not determined, PHYS: physical subscale, PPMS: primary-progressive multiple sclerosis, PR: prolonged-release, RMS relapsing forms of MS, RR rate ratio, RRMS: relapsing remitting multiple sclerosis, SAD: sustained accumulation disability, SD: standard deviation, SF36: 36-Item Short Form Survey, SPMS: secondary-progressive multiple sclerosis, TEAE: Treatment-Emergent Adverse Events, TID: tris in die (three times a day), 25TWT: Timed 25 Foot Walk, TSQM: treatment satisfaction questionnaire for medication, TUG: Timed Up and Go, VAS: visual analogue scale.

9-HPT: Nine-Hole Peg Test.

(a1) confirmed disability progression sustained for six months defined by at least a 1.0-point increase on the EDSS from baseline EDSS ≥1.0 or a 1.5-point increase on the EDSS from baseline EDSS =0.

(a2) confirmed disability progression sustained for three months defined by at least a 1.0-point increase on the EDSS from baseline EDSS ≥1.0 or a 1.5-point increase on the EDSS from baseline EDSS =0.

(b1) confirmed disability progression sustained for six months defined by at least a 1.0-point increase on the EDSS from baseline EDSS <5.5 or a 0.5- point increase from baseline EDSS ≥ 5.5).

(b2) confirmed disability progression sustained for three months defined by at least a 1.0-point increase on the EDSS from baseline EDSS <5.5 or a 0.5- point increase from baseline EDSS ≥ 5.5).

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Appendix e-3. Post-marketing randomized controlled trials (ongoing, terminated or completed without results) for drugs approved for the treatment of multiple sclerosis or its symptoms .

Registration number Study name,

Main objective & population Intervention Comparator(s) Sample Primary outcome Status

Alemtuzumab No studies

Daclizumab No studies

Dimethyl fumarate (DMF)

NCT02428231 TITRATION

To assess whether slower titration is effective in reducing the incidence of DMF-related gastrointestinal AEs in people with MS

6-week titration:

120 mg DMF once daily and placebo once daily for 2 weeks, then 120 mg DMF twice daily for 2 weeks, then 240 mg DMF in the morning and 120 mg in the evening for 2 weeks, then 240 mg DMF twice daily for 6 weeks

1-week titration:

120 mg DMF twice daily for 1 week, then 240 mg twice daily for 11 weeks

62 Proportion of participants with worsening severity of gastrointestinal AEs

Terminated (sponsor decision)

NCT02430532 INSPIRE

To investigate whether treatment with DMF slows the

accumulation of disability not related to relapses in people with SPMS

DMF 120 mg oral BID for 1 week, followed by DMF 240 mg oral BID

Placebo 58 Time to onset of confirmed progression of disability (EDSS, T25FW or 9HPT)

Terminated (sponsor decision)

NCT02739542 ARISE

Efficacy of DMF in

radiologically isolated syndrome (white matter anomalies within the brain following MRI performed for a reason other than MS)

DMF 120 mg oral BID for 1 week, followed by DMF 240 mg oral BID

Placebo 210 Time to first demyelinating event (acute or development of an initial symptom resulting in a progressive clinical course)

Recruiting Estimated primary

completion date:

December 2019 NCT02746744

RIFUND-MS

To compare rituximab and DMF in people with early RRMS and CIS

DMF

(sodium chloride solution as sham comparator)

Rituximab infusion every six months

200 Relapse risk Recruiting

Estimated primary

completion date:

May 2021 NCT02959658 To evaluate safety and efficacy DMF Placebo 90 Change in neuro-filament light-chain Recruiting

(21)

FUMAPMS of DMF treatment in people with PPMS

load in liquor Estimated

primary

completion date:

May 2018 Fampridine

(Fam)

NCT00342381 To investigate the effect of Fam on fatigue and the correlation between symptoms and cerebral changes in people with MS

FAM/placebo Placebo/FAM 120 • Subjective fatigue

• Maximal voluntary isometric contraction

• Digit Symbol-Coding scores

• Changes in normal appearing white matter and normal appearing gray matter

• Cortical atrophy

• Intracortical inhibition

Completed No results posted or published

NCT01337986 To evaluate prolonged-release FAM in people with incomplete visual recovery after optic neuritis from MS

Prolonged-release FAM/placebo

Placebo/

prolonged- release FAM

53 Visual function (contrast sensitivity) Completed No results posted or published NCT01576354

FAMPKIN

Effects of prolonged-release FAM on walking function of people with MS

Placebo/

70 Change in walking pattern Ongoing, but not recruiting participants NCT01656148 Effects of prolonged-release

FAM on walking function measured with a different walking test (SSST) in people with MS

Prolonged-release FAM Placebo 125 Mean change in SST Completed

No results posted or published NCT01667497 Effects of prolonged-release

FAM on cognitive fatigue in people with MS

Placebo/

60 Change in Paced Auditory Serial Addition Test (PASAT) Cognitive Fatigue scores

Completed No results posted or published NCT02006160 Effects of prolonged-release

FAM on motor- mediated and/or cognitive outcomes in people with MS

Prolonged-release FAM Placebo 74 Symbol digit modalities test Completed No results posted or published NCT02143167 Effects of prolonged-release Prolonged-release Placebo/ 50 Muscle power in the lower limbs Unknown

(22)

RETRAP FAM in people with MS FAM/placebo Prolonged-

release FAM

No results posted or published (the available publications do not report trial findings) NCT02146534 Effects of prolonged-release

FAM on active motor training

Prolonged-release FAM 10 mg BID

Placebo 44 Change in mobility (T8MW, 6MW, FTSST)

Completed No results posted or published NCT02208050 Effects of FAM on upper limb

function in people with SPSM, PPMS

FAM/placebo Placebo/

FAM

66 Upper limb responders:

number of participants improved of 20% on 9-HPT

Ongoing, but not recruiting participants NCT02259361 Effects of prolonged-release

FAM on upper limb function in people with MS

Placebo 30 9-HPT Unknown

No results posted or published NCT02280096 Effects of FAM on cognitive

performance and motor function in people with MS

FAM Placebo 24 • Neuropsychological tests to assess:

verbal learning, visuo-spatial perception, working memory, verbal fluency, attention

• neuropsychological tests: attention, working and verbal memory, constructive praxis

• visual implicit memory

• divided attention and interference

Ongoing, but not recruiting participants

NCT02391961 Effects of prolonged-release FAM on visual dysfunction and motor fatigue in people with MS

Placebo 30 Eye movement Recruiting.

Estimated primary

completion date:

January 2018 EudraCT

Number:

2015-000182-

Effects of FAM on eye movements and nerve

conduction in patients with MS

Prolonged-release FAM 10 mg /placebo

Placebo/

Prolonged- release FAM 10

24 • Eye movements at each day and time point. Variables will include:

Ongoing

(23)

31 and unilateral or bilateral internuclear ophthalmoplegia

mg - Eye position and velocity and the

abducting/adducting eye

- Peak velocity ratio for each saccade - Saccadic pulse in the 2 eyes

- VDI (versional disconjugacy index) - FPA (first-pass amplitude)

EudraCT Number:

2012-000287- 17

Effects of FAM on upper limb function and rehabilitation (rehab)-related clinical benefits in MS and to qualify imaging markers associated with performance improvements

Prolonged-release FAM 10 mg

Placebo 100 • Rehab clinical benefits assessed using 9-HPT

• Identification of imaging markers of clinical improvements

• additional clinical benefit of the association of rehab with drug

Ongoing

EudraCT Number:

2012-005076- 34

Effect of FAM on quantified gait analysis parameters (kinematics, dynamics, mechanical work).

Prolonged-release FAM 10 mg BID/placebo

Placebo/

Prolonged- release FAM 10 mg BID

110 • Change from baseline in quantified gait analysis kinematics, dynamics and mechanical work parameters

Ongoing

EudraCT Number:

2013-002558- 64

Effect of FAM on cerebral circuits involved in cognitive and motor function of patients with multiple sclerosis.

Prolonged-release FAM 10 mg

Placebo 123 • Analyze the effects of the drug on cerebral circuits involved in cognitive function in MS patients.

• detect changes in activation patterns during a cognitive and a motor task

• analyze changes in rest networks

Ongoing

Fingolimod (Fing)

NCT01633112 Effects of two doses of Fing in people with RRMS

Fing 0.5 mg oral once daily Fing 0.25 mg oral once daily

Glatiramer acetate 20 mg SC once daily

1064 ARR Ongoing, but not

recruiting participants