Study name

Clinical outcomes

Time point assessment

MRI outcomes

Time point assessment

Calabresi 2014

1.Annualised relapse rate

2. Time to disability progression confirmed at 3 months

3. Time to disability progression confirmed at 6 months

4. Safety

5. Time to first relapse

6. Proportion of relapse‐free participants

7. Change from baseline to the end of study on the MSFC score

8. Quality of life using the Euro quality of life scale (EQ‐5D)

9. Patient Reported Indices in Multiple Sclerosis

10. Fatigue using the Modified Fatigue Impact Scale

24 months

1.Percent brain‐volume change from baseline at 24 months

2.Number and volume of gadolinium‐enhancing T1 lesions

3. Number of new or newly enlarged T2 lesions

4. Proportion of participants free of gadolinium‐enhancing T1 lesions

5. Proportion of participants free of new or newly enlarged T2 lesions

6. Proportion of participants free of new inflammatory activity (no gadolinium‐enhancing T1 lesions and no new or newly enlarged T2 lesions)

7. Percentage change from baseline in volume of gadolinium‐enhanced T1 lesions

8. Percentage change from baseline in volume of new or newly enlarged T2 lesions

9. Brain volume

24 months

Cohen 2010

1. Annualised relapse rate

2. Progression of disability (confirmed at 3 months)

12 months

Number of new or enlarged lesions on T2‐weighted scans

12 months

Fox 2014

1. Treatment satisfaction

2. Fatigue

3. Depression

4. Activities of daily living

5. Health‐related Quality Of Life

6, Side effects

6 months

Not included

Kappos 2006

1. Number of participants remaining free of relapse

2. Annualised relapse rate

3, Time to the first relapse

6 months

1.Number of gadolinium‐enhanced lesions per participant recorded on T1‐weighted MRI at monthly intervals for 6 months

2.Total volume of gadolinium‐enhanced lesions per participants

3. Proportion of participants with gadolinium‐enhanced lesions

4. Total number of new lesion per participant on T‐weighted images

5. Changes in lesion volume on T2‐weighted images

6. Brain volume from baseline to month 6

6 months

Kappos 2010

1. Annualised relapse rate

2. Time to confirmed disability progression (confirmed after 3 months )

3. Time to a first relapse

4. Time to disability progression (confirmed after 6 months)

5. Changes in the EDSS score

6. Changes in the MSFC z score between baseline and 24 months

24 months

1. Number of gadolinium‐enhancing lesions

2. Proportion of participants free from gadolinium‐enhancing lesions

3. Number of new or enlarged lesions on T2‐weighted MRI scans

4. Proportion of participants free from new or enlarged lesions on T2‐weighted scan

5. Volumes of hyperintense lesions on T2‐weighted scan

6. Volumes of hypointense lesions on T1‐weighted scans

7. Change in brain volume between baseline and 24 months

8. Safety and tolerability measures

24 months

Saida 2012

Percentage of participants free from relapse

6 months

Participants free from gadolinium‐enhancing lesions

6 months

Study name

Drugs

No. participants

Female (%)

Course of disease of RR‐SP (%)

Age, years, mean (SD)

Mean EDSS score (SD)

Disease duration, mean (SD)

Pre‐1 year number of relapses, mean (SD)

Percentage of pre‐study treatment‐naive participants

Percentage of participants with MRI enhancing lesions

Mean lesion volume on T2‐weighted images (mm3 ) (SD)

Calabresi 2014

Placebo

355

81

100 ‐ 0

40·1 (8·4)

2·2 (1·5)

10·6 (7·9)

1·5 (0·9)

27

36

5553 (7841)

Fingolimod 0.5 mg

358

77

100 ‐ 0

40·6 (8·4)

2·2 (1·4)

10·4 (8·0)

1·4 (0·9)

26

39

5484 (8000)

Fingolimod 1.25 mg

370

76

100 ‐ 0

40·9 (8·9)

2·3 (2·0)

10·8 (8·2)

1·5 (1·0)

22

31

4936 (7286)

Cohen 2010

Interferon beta‐1a (Avonex)

435

67.8

100 ‐ 0

36.0 (8.3)

2.19 (1.26)

7.4 (6.3)

1.5 (0.8)

43.7

36.9

4924 (5711)

Fingolimod 0.5 mg

431

65.4

100 ‐ 0

36.7 (8.8)

2.24 (1.33)

7.5 (6.2)

1.5 (1.2)

44.8

32.6

5170 (6642)

Fingolimod 1.25 mg

426

68.8

100 ‐ 0

35.8 (8.4)

2.21 (1.31)

7.3 (6.0)

1.5 (0.9)

41.5

34.5

5085 (5962)

Fox 2014

DMD^§

263

79.1

100 ‐ 0

45.1 (9.82)

2.4 (1.32)

11.7 (8.44)

0.8 (1.32)

0

NR

NR

Fingolimod 0.5 mg

790

76.1

100 ‐ 0

46.0 (9.82)

2.4 (1.32)

12.1 (8.38)

0.8 (1.20)

0

NR

NR

Kappos 2006

Placebo

93

66

90 ‐ 10

37.1 (19‐56)*

2.6 (0.0‐6.5)*

8.4 (0.2‐28.2)*

1.2 (0‐5)*

NR

51

8805 (123‐62,218)*

Fingolimod 1.25 mg

94

75

89 ‐ 11

38.0 (19‐60)*

2.7 (0.0‐6.0)*

8.6 (0.3‐50.2)*

1.3 (0‐5)*

NR

47

10,219 (293‐104,504)*

Fingolimod 5.0 mg

94

71

87 ‐ 13

38.3 (18‐59)*

2.5 (0.0‐6.0)*

9.5 (0.5‐42.2)*

1.3 (0‐4)*

NR

57

8722 (349‐70,218)*

Kappos 2010

Placebo

418

71.3

100 ‐ 0

37.2 (8.6)

2.5 (1.3)

8.1 (6.4)

1.4 (0.7)

59.6

37

6162 (7085)

Fingolimod 0.5 mg

425

69.6

100 ‐ 0

36.6 (8.8)

2.3 (1.3)

8.0 (6.6)

1.5 (0.8)

57.4

38

6128 (7623)

Fingolimod 1.25 mg

429

68.8

100 ‐ 0

37.4 (8.9)

2.4 (1.4)

8.4 (6.9)

1.5 (0.8)

60.4

39.4

6829 (8491)

Saida 2012

Placebo

57

68.4

100 ‐ 0

35.0 (8.9)

2.1 (1.7)

8.2 (7.3)

1.7 (1.6)

NR

42.1

31.6 (22.6)**

Fingolimod 0.5 mg

57

70.2

94.7 ‐ 5.3

35.0 (9.0)

2.3 (1.9)

8.2 (6.8)

1.4 (1.0)

NR

42.1

30.4 (22.7)**

Fingolimod 1.25 mg

57

68.4

98.2 ‐ 1.8

36.0 (9.3)

1.8 (1.7)

7.1 (5.3)

1.5 (0.9)

NR

49.1

31.7 (23.3)**

Study name

Risk of bias

Did the researchers actively monitor for adverse events (AEs) (low risk of bias) or did they simply provide spontaneous reporting of AEs that arose (high risk of bias)?

Risk of bias

Did the authors define serious AEs (SAEs) according to an accepted international classification and report the number of SAEs?

Calabresi 2014

Low

"We did extensive safety and tolerability assessments, in part as a response to preclinical safety concerns raised by the FDA and additional safety areas of interest identified in previous phase 2 and earlier clinical studies. We also recorded adverse events, serious adverse events, serious adverse events of special interest, 24 h Holter electrocardiography (ECG) post first‐dose and at 3 months, first‐dose bradycardia events, infections, laboratory tests, vital signs, ECG, echocardiography, pulmonary function. tests, chest high‐resolution CT,chest radiographs, ophthalmic examinations, including serial optical coherence tomography, and dermatological assessments." Clinical assessments were performed at screening and at randomisation (baseline), and study visits, including safety assessments, were scheduled at 2 weeks and 1, 2, 3, 6, 9, 12, 15, 18, 21, and 24 months after randomisation"

Unclear

"We also recorded adverse events, serious adverse events, serious adverse events of special interest, 24 h Holter electrocardiography (ECG) post fist‐dose and at 3 months, first‐dose bradycardia events, infections, laboratory tests, vital signs, ECG, echocardiography, pulmonary function tests, chest high‐resolution CT,chest radiographs, ophthalmic examinations, including serial optical coherence tomography, and dermatological assessments"

Cohen 2010

Low

"An independent data and safety monitoring board evaluated overall safety in the fingolimod phase 3 program" and "Safety assessments were conducted during screening, at baseline, and at months 1, 2, 3, 6, 9, and 12" (pg 404)

Low

SAEs were predefined per standard criteria (death, life‐threatening event, persistent disability, congenital defect, unplanned hospitalisation, or otherwise medically significant) (FDA 2010 Clinical review of safety pg 151)

Fox 2014

Low

"Safety and tolerability (secondary study objectives) were assessed via reporting of
adverse events (AEs) and through physical examinations (ophthalmologist
examinations, and evaluations of vital signs, chest x‐rays, and electrocardiograms
[ECGs]), laboratory evaluations (measurement of hematology parameters, chemistry, urinalysis, serology, and lymphocyte counts)"

Unclear

Not specified

Kappos 2006

Low

"An independent external data and safety monitoring board evaluated adverse events and other safety data" and "Adverse events were assessed and reported at each visit (scheduled and unscheduled) by the treating physicians. Laboratory evaluations were undertaken at a central laboratory". "Vital signs were obtained at each visit, and laboratory and hematologic measures were obtained at baseline, day 1, and months 1,3,6,9, and 12. Electrocardiograms were obtained at baseline, on days 1 and 7, and at months 1,3,6,12, and 24 hour Holter electrocardiographic monitoring was performed at selected sites at baseline, day 1, and month 3. Pulmonary function tests... were performed at screening and months 6 and 12" (pg 1126)

Low

Categorisation of SAEs conformed to ICH guidelines (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use)

Kappos 2010

Low

"An independent data and safety monitoring board evaluated the safety" and "Study visits, including safety assessments, were scheduled at 2 weeks and 1, 2, 3, 6, 9, 12, 15, 18, 21, and 24 months after randomization" (pg 389)

Low

SAEs were predefined per standard criteria (death, life‐threatening event, persistent disability, congenital defect, unplanned hospitalisation, or otherwise medically significant) (FDA 2010 Clinical review of safety pg 151)

Saida 2012

Low

"Adverse events, serious adverse events assessments were conducted at screening, baseline, days 1 and 15, and months 1,2,3,4,5 and 6" (pg 2) and "Safety assessment included recording of AEs, SAEs, hematology values, vital signs, results of dermatological and ophthalmological examinations and results of pulmonary and liver function tests" (Supplementary data online appendix)

Low

Categorisation of SAEs conformed to ICH guidelines (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use)