Evidence Table 12Effectiveness and adverse events in placebo-controlled trials of natalizumab

StudyDosage, PopulationWithdrawalsOutcomesAdverse eventsComments
Miller (2)
2003
US, Canada, UK

Efficacy quality: Good
AE quality: Fair
Nat
IV 3 mg/kg every 28 days, over 6 mos

N=68

Male: 21 (31%)
Female: 47 (69%)

Mean age: 43
Total WDs: 5 (7.4%)
AE WDs: 4 (5.9%)
Mean change in EDSS: −0.14

Visual-analogue scale score, mean change: 9.49 mm, P=0.04

Use of rescue medication in relapsing patients: 5/13, P<0.001

Total number of relapses (physician assessed): 3, P=0.004
Headache: 27/68 (39.7%)

Infections: 15/68 (22.1%)

UTI: 15/68 (22.1%)

Weakness/muscle weakness: 12/68 (17.6%)
On intervention: Other BL values: 3mg/kg vs 6 mg/kg vs placebo
Mean EDSS: 4.2 vs 4.3 vs 4.4
Mean relapses 2 yrs prior to study entry: 2.9 vs 3.1 vs 3.0
RRMS course: 47 (69%) vs 52 (70%) vs 45 (63%)
SPMS course: 21 (31%) vs 22 (30%) vs 26 (37%)

On outcome: Relapse rates were measured 6 mos after stopping treatment; NSD found among three treatment groups. P-values are versus placebo.
Miller (2)
2003
US, Canada, UK

Efficacy quality: Good
AE quality: Fair
Nat
IV 6 mg/kg every 28 days, over 6 mos

N=74

Male: 15 (20%)
Female: 59 (80%)

Mean age: 45
Total WDs: 8 (10.8%)
AE WDs: 3 (4.1%)
Mean change in EDSS: −0.03

Visual-analogue scale score, mean change: 6.21 mm, P=0.03

Use of rescue medication in relapsing patients: 7/14, P=0.002

Total number of relapses (physician assessed): 8, P=0.11
Headache: 20/74 (27%)

Infections: 14/74 (18.9%)

UTI: 13/74 (17.6%)

Weakness/muscle weakness: 7/74 (9.5%)
Miller (2)
2003
US, Canada, UK

Efficacy quality: Good
AE quality: Fair
Placebo
IV every 28 days, over 6 mos

N=71

Male: 25 (35%)
Female: 46 (65%)
Total WDs: 5 (7.0%)
AE WDs: 3 (4.2%)
Mean change in EDSS: 0.03

Visual-analogue scale score, mean change: − 1.38 mm

Use of rescue medication in relapsing patients: 22/27

Total number of relapses (physician assessed): 18
Headache: 27/71 (38%)

Infections: 11/71 (15.5%)

UTI: 11/71 (15.5%)

Weakness/muscle weakness: 11/71 (15.5%)
O’Connor
2004
Nat
Single dose 1 mg/kg vs Nat 3 mg/kg vs placebo, over 14 weeks

N=180
NRClinical recovery after relapse

EDSS, SNRS, patient assessment of well-being, steroid use for relapse: NSD
NSD between treatment groups
Polman
2006
AFFIRM
Havrdova
2009

Efficacy quality: Good
AE quality: Good
Nat
IV 300mg every 4 weeks, up to 116 weeks

N=627

Male: 178 (28%)
Female: 449 (72%)

Mean age (SD): 36 (8.5)
Total WDs: 52 (8.3%)
AE WDs: 15 (2.4%)
Cumulative probability of disease progression: 17%; HR 0.58 at 2 yrs, P<0.0001; 95% CI, 0.43 to 0.77

Annualized relapse rate: 0.27 at 1 yr, P<0.001; 95% CI, 0.21 to 0.33

Annualized relapse rate: 0.23 at 2 yrs, P<0.001; 95% CI, 0.19 to 0.28

Proportion of relapse-free patients: 77% at 1 yr, P<0.001

Proportion of relapse-free patients: 67% at 2 yrs, P<0.001

Nat vs placebo
Relapse free: 71% vs 43% [absolute difference 27.3% (20.6–34.0)], P<0.0001
No EDSS progression (sustained at 12 weeks): 84% vs 72% [absolute difference 12.0% (5.9–17.9)], P=0.0001
Relapse-free with stable EDSS scores (Remission), yr 2: 64% vs 39% [absolute difference 25.4% (18.7–32.1)], P<0.0001
No EDSS progression (sustained at 12 weeks): absolute difference 29.3% (24.3–34.3), P<0.0001
Highly active disease at BL: 67% vs 19% [absolute difference 48.5% (36.0–61.0)], P<0.0001
Arthralgia (joint pain): 119/627 (19%)

Depression: 119/627 (19%)

Fatigue/Tiredness: 169/627 (27%)

Headache: 238/627 (38%)

ISRs (e.g. bleeding): 19/627 (3%)

Respiratory infections: 107/627 (17.1%)

Total patients reporting any AE: 596/627 (95.1%)

UTI: 125/627 (19.9%)
On population:
Mean disease duration: 5 yrs
Mean EDSS at BL (SD): 2.3 (1.2)
Mean relapse rate/yr at BL (SD): 1.52 (0.86)

On outcome: 3 randomized patients who never received treatment were included for efficacy but not safety outcomes.

On AEs: NSDs between Nat and placebo for serious AEs and non-serious AEs. Serious AEs: cholelithiasis reported in <1% of patients in both groups (P=0.435).

On WDs: 24 additional Nat patients and 15 additional placebo patients discontinued drug due to AEs but completed FU; not counted as WDs by authors.
Polman
2002
AFFIRM

Efficacy quality: Good
AE quality: Good
Placebo
IV every 4 weeks, up to 116 weeks

N=315

Male: 104 (33%)
Female: 211 (67%)

Mean age (SD): 37 (7.8)
Total WDs: 31 (9.8%)
AE WDs: 6 (1.9%)
Annualized relapse rate: 0.73 at 2 yrs, P<0.001; 95% CI, 0.62 to 0.87

Cumulative prob. of disease progression: 29% HR 0.58 at 2 yrs, P<0.0001; 95% CI, 0.43 to 0.77

Annualized relapse rate: 0.78 at 1 yr, P<0.001; 95% CI, 0.64 to 0.94

Proportion of relapse-free patients: 56% at 1 yr, P<0.001

Proportion of relapse-free patients: 67% at 2 yrs, P<0.001
Arthralgia (joint pain): 44/312 (14.1%)

Depression: 50/312 (16%)

Fatigue/Tiredness: 66/312 (21.2%)

Headache: 103/312 (33%)

ISRs (e.g. bleeding): 6/312 (1.9%)

Respiratory infections: 50/312 (16%)

Total patients reporting any AE: 300/312 (96.2%)

UTI: 53/312 (17%)
Rudick
2006
US, Europe
SENTINEL

Efficacy quality: Good
AE quality: Fair
IFN β-1a (Avonex)
Injection 30 ug once a week, up to 116 doses

N=589

Male: 147 (25%)
Female: 442 (75%)

Mean age (SD): 39 (7.7)
Total WDs: 73 (12%)
AE WDs: 17 (3%)
Cumulative probability of disease progression: 23% at 2 yrs, P=0.02

Annualized relapse rate: 0.34 at 2 yrs, P=0.001; 95% CI, 0.29 to 0.39

Annualized relapse rate: 0.38 at 1 yr, P<0.001; 95% CI, 0.32 to 0.45

Proportion of relapse-free patients: 61% at 2 yrs, P<0.001
Depression: 124/589 (21.1%)

Flu-like illness: 118/589 (20%)

Headache: 271/589 (46%)

Other psychiatric event (anxiety, mania, etc.): 71/589 (12.1%)

Respiratory infections: 47/589 (8%)

Total patients reporting any AE: 584/589 (99.2%)
On Design: 25 post-randomization exclusions due to “data irregularities” at one study site.

On Population: Population figures exclude 25 patients from one center whose data was not counted in analysis due to data irregularities.

On Outcome: Proportion of relapse-free patients reported in text as 54% and 32% respectively; does not match values in Table 2 (61% and 37%).
Sustained disability progression over 2 yrs: HR 0.76 (95% CI, 0.61 to 0.96; P=0.02)
Risk of relapse: HR 0.50 (95% CI, 0.43 to 0.59; P<0.001)
Rudick
2006
US, Europe
SENTINEL

Efficacy quality: Good
AE quality: Fair
Nat
IV 300 mg every 4 weeks, up to 29 doses

N=589

Male: 147 (25%)
Female: 442 (75%)

Mean age (SD): 39 (7.7)
Total WDs: 73 (12%)
AE WDs: 17 (3%)
Cumulative probability of disease progression: 23% at 2 yrs, P=0.02

Annualized relapse rate: 0.34 at 2 yrs, P=0.001; 95% CI, 0.29 to 0.39

Annualized relapse rate: 0.38 at 1 yr, P<0.001; 95% CI, 0.32 to 0.45

Proportion of relapse-free patients: 61% at 2 yrs, P<0.001
Depression: 124/589 (21.1%)

Flu-like illness: 118/589 (20%)

Headache: 271/589 (46%)

Other psychiatric event (anxiety, mania, etc.): 71/589 (12.1%)

Respiratory infections: 47/589 (8%)

Total patients reporting any AE: 584/589 (99.2%)
On Design: 25 post-randomization exclusions due to “data irregularities” at one study site.

On Population: Population figures exclude 25 patients from one center whose data was not counted in analysis due to data irregularities.

On Outcome: Proportion of relapse-free patients reported in text as 54% and 32% respectively; does not match values in Table 2 (61% and 37%).
Sustained disability progression over 2 yrs: HR 0.76 (95% CI, 0.61 to 0.96; P=0.02)
Risk of relapse: HR 0.50 (95% CI, 0.43 to 0.59; P<0.001)
Rudick
2006
US, Europe
SENTINEL

Efficacy quality: Good
AE quality: Fair
IFN β-1a (Avonex)
Injection 30 ug once a week, up to 116 weeks

N=582

Male: 162 (28%)
Female: 420 (72%)

Mean age (SD): 39 (7.6)
Total WDs: 95 (16%)
AE WDs: 14 (2%)
Cumulative probability of disease progression: 29% at 2 yrs, P=0.02

Annualized relapse rate: 0.75 at 2 yrs, P=0.001; 95% CI, 0.67 to 0.84

Annualized relapse rate: 0.81 at 1 yr, P<0.001; 95% CI, 0.72 to 0.92

Proportion of relapse-free patients: 37% at 2 yrs, P<0.001
Depression: 105/582 (18%)

Flu-like illness: 111/582 (19.1%)

Headache: 256/582 (44%)

Other psychiatric event (anxiety, mania, etc.): 47/582 (8.1%)

Respiratory infections: 41/582 (7%)

Total patients reporting any AE: 578/582 (99.3%)
Rudick
2006
US, Europe
SENTINEL

Efficacy quality: Good
AE quality: Fair
Placebo
IV every 4 weeks, up to 29 weeks

N=582

Male: 162 (28%)
Female: 420 (72%)

Mean age (SD): 39 (7.6)
Total WDs: 95 (16%)
AE WDs: 14 (2%)
Cumulative probability of disease progression: 29% at 2 yrs, P=0.02

Annualized relapse rate: 0.75 at 2 yrs, P=0.001; 95% CI, 0.67 to 0.84

Annualized relapse rate: 0.81 at 1 yr, P<0.001; 95% CI, 0.72 to 0.92

Proportion of relapse-free patients: 37% at 2 yrs, P<0.001
Depression: 105/582 (18%)

Flu-like illness: 111/582 (19.1%)

Headache: 256/582 (44%)

Other psychiatric event (anxiety, mania, etc.): 47/582 (8.1%)

Respiratory infections: 41/582 (7%)

Total patients reporting any AE: 578/582 (99.3%)
Sheremata
1999
US

Efficacy quality: Fair
AE quality: Poor
Nat
IV 0.03–3.0 mg/kg 1x, single dose

N=21
Total WDs: 0 (0%)
AE WDs: 0 (0%)
NRTotal patients reporting any AE: 17/21 (81%)On population: Other BL values:
RRMS: 20/28 (71%)
SPMS: 8/20 (29%)
Relapse rate 2 yrs prior to study entry: 0.7–2.3 (mean NR)
Sheremata
1999
US

Efficacy quality: Fair
AE quality: Poor
Placebo
IV single dose

N=7
Total WDs: 0 (0%)
AE WDs: 0 (0%)
NRTotal patients reporting any AE: 6/7 (85.7%)
Tubridy
1999
UK

Efficacy quality: Fair
AE quality: Poor/Fair
Nat
IV 3 mg/kg of body weight every 4 weeks, 2 doses

N=37

Male: 12 (32%)
Female: 25 (68%)

Mean age: 40
Total WDs: 0 (0%)
AE WDs: 0 (0%)
Mean change in EDSS: −0.02 at 24 weeks

Mean change in EDSS: −0.06 at 12 weeks

Exacerbation requiring hospitalization: 4 at 24 weeks

Exacerbation requiring hospitalization: 2 at 12 weeks

Total number of patients experiencing an exacerbation: 14 at 24 weeks, P=0.005

Total number of patients experiencing an exacerbation: 9 at 12 weeks, P=0.57
Fatigue/Tiredness: 12/37 (32.4%)

Total patients reporting any AE: 19/37 (51.4%)
On intervention: Nat was diluted to 100 ml with saline

On Population: BL values, Nat vs placebo:
Mean EDSS: 4.9 vs 4.7
RRMS: 25 (68%) vs 28 (80%)
SPMS: 12 (32%) vs 7 (20%)
Tubridy
1999
UK

Efficacy quality: Fair
AE quality: Poor/Fair
Placebo
IV 100 ml saline every 4 weeks, two doses

N=35

Male: 14 (40%)
Female: 21 (60%)

Mean age: 41
Total WDs: 2 (6%)
AE WDs: 0 (0%)
Mean change in EDSS: 0.02 at 24 weeks

Mean change in EDSS: 0.18 at 12 weeks

Exacerbation requiring hospitalization: 3 at 12 weeks

Exacerbation requiring hospitalization: 0 at 24 weeks

Total number of patients experiencing an exacerbation: 11 at 12 weeks, P=0.57

Total number of patients experiencing an exacerbation: 4 at 24 weeks, P=0.005
Fatigue/Tiredness: 4/35 (11.4%)

Total patients reporting any AE: 24/35 (68.6%)

From: Evidence Tables

Cover of Drug Class Review: Disease-modifying Drugs for Multiple Sclerosis
Drug Class Review: Disease-modifying Drugs for Multiple Sclerosis: Final Update 1 Report [Internet].
Smith B, Carson S, Fu R, et al.
Portland (OR): Oregon Health & Science University; 2010 Aug.
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