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Methodological quality graph: review authors' judgements on each methodological quality item presented as percentages across all included studies.
Figuras y tablas -
Figure 1

Methodological quality graph: review authors' judgements on each methodological quality item presented as percentages across all included studies.

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Methodological quality summary: review authors' judgements on each methodological quality item for each included study.
Figuras y tablas -
Figure 2

Methodological quality summary: review authors' judgements on each methodological quality item for each included study.

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Comparison 1 Primary Efficacy Outcome (Natalizumab vs Control), Outcome 1 N of pts with at least one relapse at 2 yrs.
Figuras y tablas -
Analysis 1.1

Comparison 1 Primary Efficacy Outcome (Natalizumab vs Control), Outcome 1 N of pts with at least one relapse at 2 yrs.

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Comparison 1 Primary Efficacy Outcome (Natalizumab vs Control), Outcome 2 N of pts who progressed at 2 yrs.
Figuras y tablas -
Analysis 1.2

Comparison 1 Primary Efficacy Outcome (Natalizumab vs Control), Outcome 2 N of pts who progressed at 2 yrs.

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Comparison 1 Primary Efficacy Outcome (Natalizumab vs Control), Outcome 3 PCS Change in Short Form (SF‐36) follow up 2 years.
Figuras y tablas -
Analysis 1.3

Comparison 1 Primary Efficacy Outcome (Natalizumab vs Control), Outcome 3 PCS Change in Short Form (SF‐36) follow up 2 years.

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Comparison 1 Primary Efficacy Outcome (Natalizumab vs Control), Outcome 4 MCS Change in Short Form (SF‐36) follow up 2 years.
Figuras y tablas -
Analysis 1.4

Comparison 1 Primary Efficacy Outcome (Natalizumab vs Control), Outcome 4 MCS Change in Short Form (SF‐36) follow up 2 years.

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Comparison 2 Secondary Efficacy Outcome (Natalizumab vs Control), Outcome 1 Change in Well‐being (VAS) at 2 yrs.
Figuras y tablas -
Analysis 2.1

Comparison 2 Secondary Efficacy Outcome (Natalizumab vs Control), Outcome 1 Change in Well‐being (VAS) at 2 yrs.

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Comparison 2 Secondary Efficacy Outcome (Natalizumab vs Control), Outcome 2 Gd‐enhacing lesion (at least one) at 2 yrs.
Figuras y tablas -
Analysis 2.2

Comparison 2 Secondary Efficacy Outcome (Natalizumab vs Control), Outcome 2 Gd‐enhacing lesion (at least one) at 2 yrs.

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Comparison 2 Secondary Efficacy Outcome (Natalizumab vs Control), Outcome 3 Change of MRI T2 total lesion load at 2 yrs.
Figuras y tablas -
Analysis 2.3

Comparison 2 Secondary Efficacy Outcome (Natalizumab vs Control), Outcome 3 Change of MRI T2 total lesion load at 2 yrs.

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Comparison 3 Primary Safety Outcome (Natalizumab vs Control), Outcome 1 N of pts with Severe AE over 2 yrs.
Figuras y tablas -
Analysis 3.1

Comparison 3 Primary Safety Outcome (Natalizumab vs Control), Outcome 1 N of pts with Severe AE over 2 yrs.

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Comparison 3 Primary Safety Outcome (Natalizumab vs Control), Outcome 2 N of pts with Serious AE (irrespective of treatment duration).
Figuras y tablas -
Analysis 3.2

Comparison 3 Primary Safety Outcome (Natalizumab vs Control), Outcome 2 N of pts with Serious AE (irrespective of treatment duration).

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Comparison 3 Primary Safety Outcome (Natalizumab vs Control), Outcome 3 N of pts with serious AE (irrespective of treatment duration ‐ MS relapses excluded).
Figuras y tablas -
Analysis 3.3

Comparison 3 Primary Safety Outcome (Natalizumab vs Control), Outcome 3 N of pts with serious AE (irrespective of treatment duration ‐ MS relapses excluded).

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Comparison 4 Secondary Safety Outcome (Natalizumab vs Control), Outcome 1 N of pts with at least one AE (irrespective of treatment duration).
Figuras y tablas -
Analysis 4.1

Comparison 4 Secondary Safety Outcome (Natalizumab vs Control), Outcome 1 N of pts with at least one AE (irrespective of treatment duration).

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Comparison 4 Secondary Safety Outcome (Natalizumab vs Control), Outcome 2 Treatment Discontinuation caused by AE (irrespective of treatment duration).
Figuras y tablas -
Analysis 4.2

Comparison 4 Secondary Safety Outcome (Natalizumab vs Control), Outcome 2 Treatment Discontinuation caused by AE (irrespective of treatment duration).

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Comparison 5 Adverse Event Analysis, Outcome 1 Headache.
Figuras y tablas -
Analysis 5.1

Comparison 5 Adverse Event Analysis, Outcome 1 Headache.

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Comparison 5 Adverse Event Analysis, Outcome 2 Pain in arms or legs ‐ Arthralgia.
Figuras y tablas -
Analysis 5.2

Comparison 5 Adverse Event Analysis, Outcome 2 Pain in arms or legs ‐ Arthralgia.

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Comparison 5 Adverse Event Analysis, Outcome 3 Depression.
Figuras y tablas -
Analysis 5.3

Comparison 5 Adverse Event Analysis, Outcome 3 Depression.

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Comparison 5 Adverse Event Analysis, Outcome 4 Anxiety.
Figuras y tablas -
Analysis 5.4

Comparison 5 Adverse Event Analysis, Outcome 4 Anxiety.

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Comparison 5 Adverse Event Analysis, Outcome 5 Insomnia.
Figuras y tablas -
Analysis 5.5

Comparison 5 Adverse Event Analysis, Outcome 5 Insomnia.

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Comparison 5 Adverse Event Analysis, Outcome 6 Influenza Like Illness.
Figuras y tablas -
Analysis 5.6

Comparison 5 Adverse Event Analysis, Outcome 6 Influenza Like Illness.

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Comparison 5 Adverse Event Analysis, Outcome 7 Nasopharyngitis.
Figuras y tablas -
Analysis 5.7

Comparison 5 Adverse Event Analysis, Outcome 7 Nasopharyngitis.

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Comparison 5 Adverse Event Analysis, Outcome 8 Pharyngitis.
Figuras y tablas -
Analysis 5.8

Comparison 5 Adverse Event Analysis, Outcome 8 Pharyngitis.

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Comparison 5 Adverse Event Analysis, Outcome 9 Sinusitis.
Figuras y tablas -
Analysis 5.9

Comparison 5 Adverse Event Analysis, Outcome 9 Sinusitis.

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Comparison 5 Adverse Event Analysis, Outcome 10 Sinus Congestion.
Figuras y tablas -
Analysis 5.10

Comparison 5 Adverse Event Analysis, Outcome 10 Sinus Congestion.

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Comparison 5 Adverse Event Analysis, Outcome 11 Sinus Headache.
Figuras y tablas -
Analysis 5.11

Comparison 5 Adverse Event Analysis, Outcome 11 Sinus Headache.

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Comparison 5 Adverse Event Analysis, Outcome 12 Upper Respiratory Infection.
Figuras y tablas -
Analysis 5.12

Comparison 5 Adverse Event Analysis, Outcome 12 Upper Respiratory Infection.

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Comparison 5 Adverse Event Analysis, Outcome 13 Influenza.
Figuras y tablas -
Analysis 5.13

Comparison 5 Adverse Event Analysis, Outcome 13 Influenza.

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Comparison 5 Adverse Event Analysis, Outcome 14 Cough.
Figuras y tablas -
Analysis 5.14

Comparison 5 Adverse Event Analysis, Outcome 14 Cough.

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Comparison 5 Adverse Event Analysis, Outcome 15 Diarrhea.
Figuras y tablas -
Analysis 5.15

Comparison 5 Adverse Event Analysis, Outcome 15 Diarrhea.

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Comparison 5 Adverse Event Analysis, Outcome 16 Nausea.
Figuras y tablas -
Analysis 5.16

Comparison 5 Adverse Event Analysis, Outcome 16 Nausea.

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Comparison 5 Adverse Event Analysis, Outcome 17 Vomiting.
Figuras y tablas -
Analysis 5.17

Comparison 5 Adverse Event Analysis, Outcome 17 Vomiting.

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Comparison 5 Adverse Event Analysis, Outcome 18 Abdominal Pain or Discomfort.
Figuras y tablas -
Analysis 5.18

Comparison 5 Adverse Event Analysis, Outcome 18 Abdominal Pain or Discomfort.

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Comparison 5 Adverse Event Analysis, Outcome 19 Muscle Cramp.
Figuras y tablas -
Analysis 5.19

Comparison 5 Adverse Event Analysis, Outcome 19 Muscle Cramp.

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Comparison 5 Adverse Event Analysis, Outcome 20 Myalgia.
Figuras y tablas -
Analysis 5.20

Comparison 5 Adverse Event Analysis, Outcome 20 Myalgia.

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Comparison 5 Adverse Event Analysis, Outcome 21 Seasonal Allergy.
Figuras y tablas -
Analysis 5.21

Comparison 5 Adverse Event Analysis, Outcome 21 Seasonal Allergy.

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Comparison 5 Adverse Event Analysis, Outcome 22 Peripheral Edema.
Figuras y tablas -
Analysis 5.22

Comparison 5 Adverse Event Analysis, Outcome 22 Peripheral Edema.

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Comparison 5 Adverse Event Analysis, Outcome 23 Tremor.
Figuras y tablas -
Analysis 5.23

Comparison 5 Adverse Event Analysis, Outcome 23 Tremor.

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Comparison 5 Adverse Event Analysis, Outcome 24 Flushing.
Figuras y tablas -
Analysis 5.24

Comparison 5 Adverse Event Analysis, Outcome 24 Flushing.

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Comparison 5 Adverse Event Analysis, Outcome 25 Fatigue ‐ Myasthenia.
Figuras y tablas -
Analysis 5.25

Comparison 5 Adverse Event Analysis, Outcome 25 Fatigue ‐ Myasthenia.

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Comparison 5 Adverse Event Analysis, Outcome 26 Urinary Urgency / Frequency.
Figuras y tablas -
Analysis 5.26

Comparison 5 Adverse Event Analysis, Outcome 26 Urinary Urgency / Frequency.

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Comparison 5 Adverse Event Analysis, Outcome 27 Hypersensitivity reactions.
Figuras y tablas -
Analysis 5.27

Comparison 5 Adverse Event Analysis, Outcome 27 Hypersensitivity reactions.

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Comparison 5 Adverse Event Analysis, Outcome 28 Chest Discomfort.
Figuras y tablas -
Analysis 5.28

Comparison 5 Adverse Event Analysis, Outcome 28 Chest Discomfort.

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Comparison 5 Adverse Event Analysis, Outcome 29 Local Bleeding.
Figuras y tablas -
Analysis 5.29

Comparison 5 Adverse Event Analysis, Outcome 29 Local Bleeding.

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Comparison 5 Adverse Event Analysis, Outcome 30 Rigors.
Figuras y tablas -
Analysis 5.30

Comparison 5 Adverse Event Analysis, Outcome 30 Rigors.

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Comparison 5 Adverse Event Analysis, Outcome 31 Syncope.
Figuras y tablas -
Analysis 5.31

Comparison 5 Adverse Event Analysis, Outcome 31 Syncope.

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Comparison 5 Adverse Event Analysis, Outcome 32 Urinary Infection.
Figuras y tablas -
Analysis 5.32

Comparison 5 Adverse Event Analysis, Outcome 32 Urinary Infection.

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Comparison 5 Adverse Event Analysis, Outcome 33 Lower Respiratory Infection.
Figuras y tablas -
Analysis 5.33

Comparison 5 Adverse Event Analysis, Outcome 33 Lower Respiratory Infection.

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Comparison 5 Adverse Event Analysis, Outcome 34 Tonsillitis.
Figuras y tablas -
Analysis 5.34

Comparison 5 Adverse Event Analysis, Outcome 34 Tonsillitis.

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Comparison 5 Adverse Event Analysis, Outcome 35 Gastroenteritis.
Figuras y tablas -
Analysis 5.35

Comparison 5 Adverse Event Analysis, Outcome 35 Gastroenteritis.

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Comparison 5 Adverse Event Analysis, Outcome 36 Vaginitis.
Figuras y tablas -
Analysis 5.36

Comparison 5 Adverse Event Analysis, Outcome 36 Vaginitis.

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Comparison 5 Adverse Event Analysis, Outcome 37 Menstrual disorders.
Figuras y tablas -
Analysis 5.37

Comparison 5 Adverse Event Analysis, Outcome 37 Menstrual disorders.

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Comparison 5 Adverse Event Analysis, Outcome 38 Skin Rash.
Figuras y tablas -
Analysis 5.38

Comparison 5 Adverse Event Analysis, Outcome 38 Skin Rash.

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Comparison 5 Adverse Event Analysis, Outcome 39 Dermatitis.
Figuras y tablas -
Analysis 5.39

Comparison 5 Adverse Event Analysis, Outcome 39 Dermatitis.

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Comparison 5 Adverse Event Analysis, Outcome 40 Pruritus.
Figuras y tablas -
Analysis 5.40

Comparison 5 Adverse Event Analysis, Outcome 40 Pruritus.

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Comparison 5 Adverse Event Analysis, Outcome 41 Vertigo.
Figuras y tablas -
Analysis 5.41

Comparison 5 Adverse Event Analysis, Outcome 41 Vertigo.

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Comparison 5 Adverse Event Analysis, Outcome 42 Infection.
Figuras y tablas -
Analysis 5.42

Comparison 5 Adverse Event Analysis, Outcome 42 Infection.

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Comparison 5 Adverse Event Analysis, Outcome 43 Infusion reactions.
Figuras y tablas -
Analysis 5.43

Comparison 5 Adverse Event Analysis, Outcome 43 Infusion reactions.

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Comparison 5 Adverse Event Analysis, Outcome 44 Back Pain.
Figuras y tablas -
Analysis 5.44

Comparison 5 Adverse Event Analysis, Outcome 44 Back Pain.

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Comparison 5 Adverse Event Analysis, Outcome 45 Fall.
Figuras y tablas -
Analysis 5.45

Comparison 5 Adverse Event Analysis, Outcome 45 Fall.

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Comparison 5 Adverse Event Analysis, Outcome 46 Neoplasms.
Figuras y tablas -
Analysis 5.46

Comparison 5 Adverse Event Analysis, Outcome 46 Neoplasms.

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Comparison 5 Adverse Event Analysis, Outcome 47 Abnormal liver function tests.
Figuras y tablas -
Analysis 5.47

Comparison 5 Adverse Event Analysis, Outcome 47 Abnormal liver function tests.

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Comparison 5 Adverse Event Analysis, Outcome 48 Death.
Figuras y tablas -
Analysis 5.48

Comparison 5 Adverse Event Analysis, Outcome 48 Death.

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Comparison 5 Adverse Event Analysis, Outcome 49 MS relapse as a serious AE.
Figuras y tablas -
Analysis 5.49

Comparison 5 Adverse Event Analysis, Outcome 49 MS relapse as a serious AE.

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Table 1. ABBREVIATIONS

ABBREVIATION

TERM

AIFA

Agenzia Italiana Farmaco

CD

Crohn Disease

CDER

Center for drug evaluation and research (FDA)

CI

Confidence Interval

CNS

Central Nervous System

CIS

Clinically Isolated Syndrome

DMDs

Disease‐Modifying Drugs

EDSS

Expanded Disability Status Scale

EMA

European Medicines Agency

FDA

Food and Drug Administration

GA

Glatiramer Acetate (Copaxone®)

Gd+

Gadolinium enhancing lesion in MRI

HRQoL

Health Related Quality of Life

HSRs

hypersensitivity reactions

IFNß

Interferon beta

IFNß‐1a

Interferon beta‐1a

IgG

Immunoglobulin G

IRIS

Immune reconstitution inflammatory syndrome

ITT

intention‐to‐treat

IV

intravenous

MCS

Mental Component Summary (composite scores of SF‐36)

MD

mean difference

MFIS

Modified Fatigue Impact Scale

MSFC

Multiple Sclerosis Functional Composite

MRI

Magnetic resonance imaging

MS

Multiple Sclerosis

N

number

n.a.

not available

NICE

National Institute for Clinical Excellence

NNB

Number Needed to Benefit

NNH

Number Needed to Harm

NNT

Number Needed to Treat

NTZ

natalizumab

PASAT

Paced Auditory Serial Addition Task (one of the components of MSFC)

PCS

Physical Component Summary (composite scores of SF‐36)

PML

Progressive Multifocal Leukoencephalopathy

QoL

Quality of Life

SF‐36

Short Form 36

VAS

Visual Analog Scale
Figuras y tablas -
Table 1. ABBREVIATIONS
Ir a la tabla de la revisión
Table 2. Baseline patient characteristics in studies which contributed to primary efficacy outcomes (AFFIRM and SENTINEL)

Characteristic

Patients randomised to NTZ (with or without IFNß‐1a)

(n=1216)

Patients randomised to placebo or IFNß‐1a alone

(n=897)

Total

(n= 2113)

Age range

18–55

19–55

18–55

Sex

N of male: N of female

325:891

266:631

591:1522

Disease duration* ‐ years (range)

1‐41

1‐34

N of patients with 1 relapse in previous 1 yr (% of total)

758

537

1295 (61)

N of patients with ≥ 2 relapse in previous 1 yr (% of total)

450

353

803 (38)

N of patients with EDSS ≤ 3.5 (% of total)

1056

769

1825

N of patients with EDSS > 3.5 (% of total)

160

128

288

N of patients with 0 Gd+ (% of total)

699

544

1243

N of patients with ≥ 1 Gd+ (% of total)

511

348

859 (41)

Duration ≥ 10 months of previous IFNß‐1a therapy

(% of total)

589

582

1171 (55)

*Definition of disease duration (from the onset? form the diagnosis?) was not available for AFFIRM and SENTINEL trials. We used time since first MS symptoms for participants in GLANCE trial.

Figuras y tablas -
Table 2. Baseline patient characteristics in studies which contributed to primary efficacy outcomes (AFFIRM and SENTINEL)
Ir a la tabla de la revisión
Table 3. Protocol violations in AFFIRM trial

Type of protocol violation

N of violations in NTZ group

N of patients with at least one protocol violation in NTZ group

N of violations in control group

N of patients with at least one protocol violation in control group

Total N of violations in all randomised patients

Total N of patients with at least one protocol violation in all randomised patients

Details

Reference

Inclusion criteria:

diagnosis of relapsing multiple sclerosis according to McDonald criteria

9

9

4

4

13

13 (1.4%)

These patients only satisfied CIS criteria

Polman 2006 AFFIRM 2006

Inclusion criteria: at least one medically documented relapse within 12 months before randomisation

6

6 (1%)

6

6 (2%)

12

12 (1.3%)

No relapse in previous year

Polman 2006 AFFIRM 2006

Prohibited concomitant medication

29

22 (3.5%)

17

11 (3.5%)

46

33 (3.5%)

Only data from the first year of study is reported. Data for all the duration of the trial is not available.

Medications prohibited: cyclophosphamide, mitoxantrone IFNß,
GA, cyclosporine, azathioprine,
methotrexate, intravenous immune globulin, experimental drugs.

Center for drug evaluation and research. Medical Review. November 23, 2004‐ Drug Approval Package ‐ http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/125104s000_Natalizumab.cfm

Other eligibility criteria

58

46 (7.3%)

27

21 (6.7%)

85

67 (7.1%)

Only data from the first year of study is reported. Data for all the duration of the trial is not available.

No other detail is available.

Center for drug evaluation and research. Medical Review November 23, 2004 ‐ Drug Approval Package ‐ http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/125104s000_Natalizumab.cfm

Missed, partial or incorrect dosing

323

144 (23.0%)

145

77 (24.4%)

468

221 (23.4%)

Only data from the first year of study is reported. Data for all the duration of the trial is not available.

No other detail is available.

Center for drug evaluation and research. Medical Review. November 23, 2004 ‐ Drug Approval Package ‐ http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/125104s000_Natalizumab.cfm

Efficacy evaluation not performed or not valid

104

73 (11.6%)

60

45 (14.3%)

164

118 (12.5%)

Only data from the first year of study is reported. Data for all the duration of the trial is not available.

No other detail is available.

Center for drug evaluation and research. Medical Review. November 23, 2004 ‐ Drug Approval Package ‐ http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/125104s000_Natalizumab.cfm

Safety evaluation not performed or not valid

162

103 (16.4%)

95

53 (16.8%)

257

156 (16.6%)

Only data from the first year of study is reported. Data for all the duration of the trial is not available.

No other detail is available.

Center for drug evaluation and research. Medical Review. November 23, 2004 ‐ Drug Approval Package ‐ http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/125104s000_Natalizumab.cfm

Outside acceptable visit window

1239

406 (64.8%)

692

218 (69.2)

1931

624 (66.2%)

Only data from the first year of study are reported. Data for all the duration of the trial are not available.

No other detail is available.

Center for drug evaluation and research. Medical Review. November 23, 2004 ‐ Drug Approval Package ‐ http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/125104s000_Natalizumab.cfm

Missed study visit

38

25 (4.0%)

22

13 (4.1%)

60

38 (4.0%)

Only data from the first year of study is reported. Data for all the duration of the trial is not available.

No other detail is available.

Center for drug evaluation and research. Medical Review. November 23, 2004 ‐ Drug Approval Package ‐ http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/125104s000_Natalizumab.cfm

Discontinuation of study treatment in patients who had HSRs

2

2

0

0

2

2 (≺1%)

Two NTZ patients were redosed after experiencing a hypersensitivity reaction (per protocol, study drug was
to be discontinued in all patients who had HSRs).

Phillips 2006 AFFIRM 2006

Missed MRI scan

n.a.

n.a.

n.a.

n.a.

n.a.

87 (9.0%)

According to Miller and collaborators the main reason for missing data (>80%) was the scan not being performed because the patient withdrew from the study; in the remainder (<20%), although the patient was still in the study, the scan was either not performed, had not been received at the Central MRI Analysis Center, or had been received but was of inadequate quality for analysis.

Miller 2007 AFFIRM 2006

Other (according to the Center for drug evaluation and research)

996

401 (63.9%)

529

208 (66.0%)

1525

609 (64.6%)

Only data from the first year of study is reported. Data for all the duration of the trial is not available.

No other detail is available.

Center for drug evaluation and research. Medical Review. November 23, 2004 ‐ Drug Approval Package ‐ http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/125104s000_Natalizumab.cfm

All violations according to the Center for drug evaluation and research

2955

554 (88.4%)

1593

291 (92.4%)

4548

845

Only data from the first year of study is reported. Data for all the duration of the trial is not available.

Center for drug evaluation and research. Medical Review. November 23, 2004 ‐ Drug Approval Package ‐ http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/125104s000_Natalizumab.cfm

Figuras y tablas -
Table 3. Protocol violations in AFFIRM trial
Ir a la tabla de la revisión
Table 4. Protocol violations in GLANCE trial

Type of protocol violation

N of violations in NTZ group

N of patients with at least one protocol violation in NTZ group

N of violations in control group

N of patients with at least one protocol violation in control group

Total N of violations in all randomised patients

Total N of patients with at least one protocol violation in all randomised patients

Details

Reference

Incusion criteria: at least one medically documented relapse within 12 months before randomisation.

n.a.

n.a.

n.a.

n.a.

n.a.

n.a.

the minimum of N of relapses in previous 12 mo is 0 In the baseline characteristics of NTZ + GA group (i.e. at least one patient was included with no relapse in previous 12 mo)

Goodman 2009 GLANCE 2009

Other

n.a.

n.a.

n.a.

n.a.

n.a.

n.a.

n.a.
Figuras y tablas -
Table 4. Protocol violations in GLANCE trial
Ir a la tabla de la revisión
Table 5. Protocol violations in SENTINEL trial

Type of protocol violation

N of violations in NTZ group

N of patients with at least one protocol violation in NTZ group

N of violations in control group

N of patients with at least one protocol violation in control group

Total N of violations in all randomised patients

Total N of patients with at least one protocol violation in all randomised patients

Details

Reference

Inclusion criteria: at least one medically documented relapse within 12 months before randomisation

0

0

1

1 (≺1%)

1

1 (≺1%)

no relapse in past 12 mo.

Rudick 2006 SENTINEL 2006

Prohibited concomitant medication

69

55 (9.3%)

72

53 (9.1%)

141

108 (9.2%)

Only data from the first year of study is reported. Data for all the duration of the trial is not available.

Medications prohibited: any approved disease modifying therapy other than IFNß‐1a im once a week, experimental drugs.

Center for drug evaluation and research. Medical Review. November 23, 2004 ‐ Drug Approval Package ‐ http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/125104s000_Natalizumab.cfm

Other eligibility criteria

88

70 (11.9%)

87

66 (11.3%)

175

136 (11.6%)

Only data from the first year of study is reported. Data for all the duration of the trial is not available.

No other detail is available.

Center for drug evaluation and research. Medical Review. November 23, 2004 ‐ Drug Approval Package ‐ http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/125104s000_Natalizumab.cfm

Missed, partial or incorrect dosing

868

306 (52.0%)

918

310 (53.3%)

1786

616 (52.6%)

Only data from the first year of study is reported. Data for all the duration of the trial is not available.

No other detail is available.

Center for drug evaluation and research. Medical Review. November 23, 2004 ‐ Drug Approval Package ‐ http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/125104s000_Natalizumab.cfm

Efficay evaluation not performed or not valid

189

113 (19.2%)

197

107 (18.4%)

386

220 (18.8%)

Only data from the first year of study is reported. Data for all the duration of the trial is not available.

No other detail is available.

Center for drug evaluation and research. Medical Review. November 23, 2004 ‐ Drug Approval Package ‐ http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/125104s000_Natalizumab.cfm

Safety evaluation not performed or not valid

185

101 (17.1%)

213

120 (20.6%)

398

221 (18.9%)

Only data from the first year of study is reported. Data for all the duration of the trial is not available.

No other detail is available.

Center for drug evaluation and research. Medical Review. November 23, 2004 ‐ Drug Approval Package ‐ http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/125104s000_Natalizumab.cfm

Outside acceptable visit window

1423

418 (71.0%)

1504

430 (73.9%)

2927

848 (72.4%)

Only data from the first year of study is reported. Data for all the duration of the trial is not available.

No other detail is available.

Center for drug evaluation and research. Medical Review. November 23, 2004 ‐ Drug Approval Package ‐ http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/125104s000_Natalizumab.cfm

Missed study visit

39

29 (4.9%)

54

39 (6.7%)

93

68 (5.8%)

Only data from the first year of study is reported. Data for all the duration of the trial is not available.

No other detail is available.

Center for drug evaluation and research. Medical Review. November 23, 2004 ‐ Drug Approval Package ‐ http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/125104s000_Natalizumab.cfm

Other (according to the Center for drug evaluation and research)

1639

411 (69.8%)

1799

425 (73.0%)

3438

836 (71.4%)

Only data from the first year of study is reported. Data for all the duration of the trial is not available.

No other detail is available.

Center for drug evaluation and research. Medical Review. November 23, 2004 ‐ Drug Approval Package ‐ http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/125104s000_Natalizumab.cfm

All violations according to the Center for drug evaluation and research

4500

569 (96.6%)

4855

568 (97.6%)

9355

1137 (97.1%)

Center for drug evaluation and research. Medical Review. November 23, 2004 ‐ Drug Approval Package ‐ http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/125104s000_Natalizumab.cfm

Figuras y tablas -
Table 5. Protocol violations in SENTINEL trial
Ir a la tabla de la revisión
Table 6. Other trials sponsored by the Pharmaceutical Industry

Study

label

Phase

Aims

Population

Design

Dose regimen

N of participants

Duration

Planned N of doses

Outcome measures

Main references

200

1

Safety

Tolerability

RRMS and SPMS subjects

Randomised, Double‐blind, Placebo‐controlled, Dose‐escalation

0.03 (n=3) ‐ 0.1 (n=3) 0.3 (n=3) 1.0 (n=6) 3.0 (n=6) mg/Kg; (placebo n=7)

28

n.a.

1

Safety

Tolerability

Sheremata 1999

221

1

Safety

Pharmacokinetics

Pharmacodynamics

RRMS and SPMS subjects

Randomised, Placebo‐controlled

1‐3‐6 mg/Kg

39

n.a.

1

Safety

Pharmacodynamics

Center for drug evaluation and research. Medical Review ‐ Drug Approval Package ‐ http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/125104s000_Natalizumab.cfm

study quoted by Rudick 2004

224

1

Safety

Pharmacokinetics

Interaction with IFNß‐1a

RRMS subjects treated with intramuscular IFNß‐1a

Open label

3 (n=15) ‐ 6 (n=23) mg/Kg

38

n.a.

1

Safety

Pharmacokinetics

Center for drug evaluation and research. Medical Review ‐ Drug Approval Package ‐ http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/125104s000_Natalizumab.cfm

Vollmer 2004

201

UK Antegren Study

2

Preliminary efficacy

RRMS and SPMS subjects

Randomised, Double‐blind, Placebo‐controlled

3 mg/Kg

72

(placebo n=35)

24 wks

2

MRI parameters

UK Antegren Study 1999

202

Natalizumab Multiple Sclerosis Trial

2

Preliminary efficacy (on relapse)

RRMS and SPMS subjects in relapse

Randomised, Double‐blind, Placebo‐controlled

1‐3 mg/Kg

180

14 wks

1

MRI parameters

EDSS

Scripp
Neurologic Rating Scale

Patient’s own
assessment of well‐being

O'Connor  2004

Figuras y tablas -
Table 6. Other trials sponsored by the Pharmaceutical Industry
Ir a la tabla de la revisión
Comparison 1. Primary Efficacy Outcome (Natalizumab vs Control)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 N of pts with at least one relapse at 2 yrs Show forest plot

2

2113

Risk Ratio (M‐H, Random, 95% CI)

0.57 [0.47, 0.69]

1.1 Natalizumab vs Placebo

1

942

Risk Ratio (M‐H, Random, 95% CI)

0.51 [0.44, 0.61]

1.2 Natalizumab + IFN vs IFN

1

1171

Risk Ratio (M‐H, Random, 95% CI)

0.62 [0.55, 0.70]

2 N of pts who progressed at 2 yrs Show forest plot

2

2113

Risk Ratio (M‐H, Random, 95% CI)

0.74 [0.62, 0.89]

2.1 Natalizumab vs Placebo

1

942

Risk Ratio (M‐H, Random, 95% CI)

0.67 [0.55, 0.81]

2.2 Natalizumab + IFN vs IFN

1

1171

Risk Ratio (M‐H, Random, 95% CI)

0.80 [0.69, 0.93]

3 PCS Change in Short Form (SF‐36) follow up 2 years Show forest plot

2

2113

Mean Difference (IV, Random, 95% CI)

1.98 [1.05, 2.91]

3.1 Natalizumab vs Placebo

1

942

Mean Difference (IV, Random, 95% CI)

2.01 [0.48, 3.54]

3.2 Natalizumab + IFN vs IFN

1

1171

Mean Difference (IV, Random, 95% CI)

1.96 [0.79, 3.13]

4 MCS Change in Short Form (SF‐36) follow up 2 years Show forest plot

2

2113

Mean Difference (IV, Random, 95% CI)

1.38 [0.33, 2.42]

4.1 Natalizumab vs Placebo

1

942

Mean Difference (IV, Random, 95% CI)

2.53 [0.00, 5.06]

4.2 Natalizumab + IFN vs IFN

1

1171

Mean Difference (IV, Random, 95% CI)

1.14 [‐0.00, 2.28]
Figuras y tablas -
Comparison 1. Primary Efficacy Outcome (Natalizumab vs Control)
Ir a la tabla de la revisión
Comparison 2. Secondary Efficacy Outcome (Natalizumab vs Control)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Change in Well‐being (VAS) at 2 yrs Show forest plot

1

942

Mean Difference (IV, Random, 95% CI)

6.4 [1.76, 11.04]

1.1 Natalizumab vs Placebo

1

942

Mean Difference (IV, Random, 95% CI)

6.4 [1.76, 11.04]

2 Gd‐enhacing lesion (at least one) at 2 yrs Show forest plot

2

2113

Risk Ratio (M‐H, Random, 95% CI)

0.12 [0.09, 0.17]

2.1 Natalizumab vs Placebo

1

942

Risk Ratio (M‐H, Random, 95% CI)

0.11 [0.07, 0.17]

2.2 Natalizumab + IFN vs IFN

1

1171

Risk Ratio (M‐H, Random, 95% CI)

0.14 [0.09, 0.22]

3 Change of MRI T2 total lesion load at 2 yrs Show forest plot

1

855

Mean Difference (IV, Random, 95% CI)

‐3796.20 [‐5849.43, ‐1742.97]

3.1 Natalizumab vs Placebo

1

855

Mean Difference (IV, Random, 95% CI)

‐3796.20 [‐5849.43, ‐1742.97]
Figuras y tablas -
Comparison 2. Secondary Efficacy Outcome (Natalizumab vs Control)
Ir a la tabla de la revisión
Comparison 3. Primary Safety Outcome (Natalizumab vs Control)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 N of pts with Severe AE over 2 yrs Show forest plot

2

2110

Risk Ratio (M‐H, Random, 95% CI)

0.92 [0.81, 1.04]

1.1 Natalizumab vs Placebo

1

939

Risk Ratio (M‐H, Random, 95% CI)

0.85 [0.68, 1.08]

1.2 Natalizumab + IFN vs IFN

1

1171

Risk Ratio (M‐H, Random, 95% CI)

0.95 [0.81, 1.10]

2 N of pts with Serious AE (irrespective of treatment duration) Show forest plot

3

2220

Risk Ratio (M‐H, Random, 95% CI)

0.83 [0.70, 0.98]

2.1 Natalizumab vs Placebo

1

939

Risk Ratio (M‐H, Random, 95% CI)

0.79 [0.61, 1.02]

2.2 Natalizumab + IFN vs IFN

1

1171

Risk Ratio (M‐H, Random, 95% CI)

0.87 [0.69, 1.09]

2.3 Natalizumab + GA vs GA

1

110

Risk Ratio (M‐H, Random, 95% CI)

0.5 [0.05, 5.36]

3 N of pts with serious AE (irrespective of treatment duration ‐ MS relapses excluded) Show forest plot

3

2220

Risk Ratio (M‐H, Random, 95% CI)

1.13 [0.90, 1.43]

3.1 Natalizumab vs Placebo

1

939

Risk Ratio (M‐H, Random, 95% CI)

1.19 [0.81, 1.73]

3.2 Natalizumab + IFN vs IFN

1

1171

Risk Ratio (M‐H, Random, 95% CI)

1.10 [0.81, 1.49]

3.3 Natalizumab + GA vs GA

1

110

Risk Ratio (M‐H, Random, 95% CI)

1.0 [0.06, 15.59]
Figuras y tablas -
Comparison 3. Primary Safety Outcome (Natalizumab vs Control)
Ir a la tabla de la revisión
Comparison 4. Secondary Safety Outcome (Natalizumab vs Control)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 N of pts with at least one AE (irrespective of treatment duration) Show forest plot

3

2220

Risk Ratio (M‐H, Random, 95% CI)

1.00 [0.99, 1.01]

1.1 Natalizumab vs Placebo

1

939

Risk Ratio (M‐H, Random, 95% CI)

0.99 [0.96, 1.02]

1.2 Natalizumab + IFN vs IFN

1

1171

Risk Ratio (M‐H, Random, 95% CI)

1.00 [0.99, 1.01]

1.3 Natalizumab + GA vs GA

1

110

Risk Ratio (M‐H, Random, 95% CI)

0.98 [0.88, 1.10]

2 Treatment Discontinuation caused by AE (irrespective of treatment duration) Show forest plot

3

2220

Risk Ratio (M‐H, Random, 95% CI)

1.14 [0.82, 1.59]

2.1 Natalizumab vs Placebo

1

939

Risk Ratio (M‐H, Random, 95% CI)

1.58 [0.84, 2.97]

2.2 Natalizumab + IFN vs IFN

1

1171

Risk Ratio (M‐H, Random, 95% CI)

1.01 [0.68, 1.50]

2.3 Natalizumab + GA vs GA

1

110

Risk Ratio (M‐H, Random, 95% CI)

1.0 [0.06, 15.59]
Figuras y tablas -
Comparison 4. Secondary Safety Outcome (Natalizumab vs Control)
Ir a la tabla de la revisión
Comparison 5. Adverse Event Analysis

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Headache Show forest plot

3

2220

Risk Ratio (M‐H, Random, 95% CI)

1.08 [0.97, 1.20]

1.1 Natalizumab vs Placebo

1

939

Risk Ratio (M‐H, Random, 95% CI)

1.15 [0.95, 1.39]

1.2 Natalizumab IFN vs IFN

1

1171

Risk Ratio (M‐H, Random, 95% CI)

1.05 [0.92, 1.19]

1.3 Natalizumab + GA vs GA

1

110

Risk Ratio (M‐H, Random, 95% CI)

1.13 [0.63, 2.03]

2 Pain in arms or legs ‐ Arthralgia Show forest plot

3

2220

Risk Ratio (M‐H, Fixed, 95% CI)

1.17 [0.98, 1.40]

2.1 Natalizumab vs Placebo

1

939

Risk Ratio (M‐H, Fixed, 95% CI)

1.35 [0.98, 1.85]

2.2 Natalizumab + IFN vs IFN

1

1171

Risk Ratio (M‐H, Fixed, 95% CI)

1.05 [0.85, 1.31]

2.3 Natalizumab + GA vs GA

1

110

Risk Ratio (M‐H, Fixed, 95% CI)

5.0 [0.60, 41.42]

3 Depression Show forest plot

3

2220

Risk Ratio (M‐H, Random, 95% CI)

1.18 [0.98, 1.41]

3.1 Natalizumab vs Placebo

1

939

Risk Ratio (M‐H, Random, 95% CI)

1.18 [0.88, 1.60]

3.2 Natalizumab + IFN vs IFN

1

1171

Risk Ratio (M‐H, Random, 95% CI)

1.17 [0.92, 1.47]

3.3 Natalizumab + GA vs GA

1

110

Risk Ratio (M‐H, Random, 95% CI)

1.5 [0.26, 8.63]

4 Anxiety Show forest plot

1

1171

Risk Ratio (M‐H, Random, 95% CI)

1.49 [1.05, 2.12]

4.1 Natalizumab + IFN vs IFN

1

1171

Risk Ratio (M‐H, Random, 95% CI)

1.49 [1.05, 2.12]

5 Insomnia Show forest plot

1

1171

Risk Ratio (M‐H, Random, 95% CI)

1.06 [0.82, 1.36]

5.1 Natalizumab + IFN vs IFN

1

1171

Risk Ratio (M‐H, Random, 95% CI)

1.06 [0.82, 1.36]

6 Influenza Like Illness Show forest plot

1

1171

Risk Ratio (M‐H, Random, 95% CI)

1.05 [0.83, 1.33]

6.1 Natalizumab + IFN vs IFN

1

1171

Risk Ratio (M‐H, Random, 95% CI)

1.05 [0.83, 1.33]

7 Nasopharyngitis Show forest plot

2

1281

Risk Ratio (M‐H, Fixed, 95% CI)

1.09 [0.94, 1.26]

7.1 Natalizumab + IFN vs IFN

1

1171

Risk Ratio (M‐H, Fixed, 95% CI)

1.11 [0.96, 1.29]

7.2 Natalizumab + GA vs GA

1

110

Risk Ratio (M‐H, Fixed, 95% CI)

0.64 [0.27, 1.52]

8 Pharyngitis Show forest plot

2

2110

Risk Ratio (M‐H, Random, 95% CI)

1.41 [0.98, 2.04]

8.1 Natalizumab vs Placebo

1

939

Risk Ratio (M‐H, Random, 95% CI)

1.20 [0.81, 1.79]

8.2 Natalizumab + IFN vs IFN

1

1171

Risk Ratio (M‐H, Random, 95% CI)

1.76 [1.07, 2.90]

9 Sinusitis Show forest plot

2

1281

Risk Ratio (M‐H, Random, 95% CI)

1.29 [0.88, 1.88]

9.1 Natalizumab + IFN vs IFN

1

1171

Risk Ratio (M‐H, Random, 95% CI)

1.20 [0.93, 1.56]

9.2 Natalizumab + GA vs GA

1

110

Risk Ratio (M‐H, Random, 95% CI)

2.25 [0.74, 6.87]

10 Sinus Congestion Show forest plot

1

1171

Risk Ratio (M‐H, Random, 95% CI)

2.03 [1.15, 3.59]

10.1 Natalizumab + IFN vs IFN

1

1171

Risk Ratio (M‐H, Random, 95% CI)

2.03 [1.15, 3.59]

11 Sinus Headache Show forest plot

1

1171

Risk Ratio (M‐H, Random, 95% CI)

1.69 [0.94, 3.03]

11.1 Natalizumab + IFN vs IFN

1

1171

Risk Ratio (M‐H, Random, 95% CI)

1.69 [0.94, 3.03]

12 Upper Respiratory Infection Show forest plot

3

2220

Risk Ratio (M‐H, Random, 95% CI)

1.05 [0.87, 1.28]

12.1 Natalizumab vs Placebo

1

939

Risk Ratio (M‐H, Random, 95% CI)

1.00 [0.80, 1.26]

12.2 Natalizumab + IFN vs IFN

1

1171

Risk Ratio (M‐H, Random, 95% CI)

1.13 [0.76, 1.69]

12.3 Natalizumab + GA vs GA

1

110

Risk Ratio (M‐H, Random, 95% CI)

1.8 [0.64, 5.03]

13 Influenza Show forest plot

1

1171

Risk Ratio (M‐H, Random, 95% CI)

1.14 [0.87, 1.48]

13.1 Natalizumab + IFN vs IFN

1

1171

Risk Ratio (M‐H, Random, 95% CI)

1.14 [0.87, 1.48]

14 Cough Show forest plot

1

1171

Risk Ratio (M‐H, Random, 95% CI)

1.24 [0.87, 1.75]

14.1 Natalizumab + IFN vs IFN

1

1171

Risk Ratio (M‐H, Random, 95% CI)

1.24 [0.87, 1.75]

15 Diarrhea Show forest plot

1

1171

Risk Ratio (M‐H, Random, 95% CI)

1.19 [0.93, 1.53]

15.1 Natalizumab + IFN vs IFN

1

1171

Risk Ratio (M‐H, Random, 95% CI)

1.19 [0.93, 1.53]

16 Nausea Show forest plot

2

1281

Risk Ratio (M‐H, Random, 95% CI)

1.13 [0.88, 1.46]

16.1 Natalizumab + IFN vs IFN

1

1171

Risk Ratio (M‐H, Random, 95% CI)

1.14 [0.87, 1.48]

16.2 Natalizumab + GA vs GA

1

110

Risk Ratio (M‐H, Random, 95% CI)

1.13 [0.47, 2.70]

17 Vomiting Show forest plot

1

1171

Risk Ratio (M‐H, Random, 95% CI)

1.40 [0.88, 2.22]

17.1 Natalizumab + IFN vs IFN

1

1171

Risk Ratio (M‐H, Random, 95% CI)

1.40 [0.88, 2.22]

18 Abdominal Pain or Discomfort Show forest plot

2

2110

Risk Ratio (M‐H, Random, 95% CI)

1.14 [0.84, 1.55]

18.1 Natalizumab vs Placebo

1

939

Risk Ratio (M‐H, Random, 95% CI)

1.11 [0.74, 1.65]

18.2 Natalizumab + IFN vs IFN

1

1171

Risk Ratio (M‐H, Random, 95% CI)

1.19 [0.74, 1.92]

19 Muscle Cramp Show forest plot

1

1171

Risk Ratio (M‐H, Random, 95% CI)

1.19 [0.74, 1.92]

19.1 Natalizumab + IFN vs IFN

1

1171

Risk Ratio (M‐H, Random, 95% CI)

1.19 [0.74, 1.92]

20 Myalgia Show forest plot

1

1171

Risk Ratio (M‐H, Random, 95% CI)

1.31 [0.95, 1.81]

20.1 Natalizumab + IFN vs IFN

1

1171

Risk Ratio (M‐H, Random, 95% CI)

1.31 [0.95, 1.81]

21 Seasonal Allergy Show forest plot

1

1171

Risk Ratio (M‐H, Random, 95% CI)

1.50 [0.90, 2.51]

21.1 Natalizumab + IFN vs IFN

1

1171

Risk Ratio (M‐H, Random, 95% CI)

1.50 [0.90, 2.51]

22 Peripheral Edema Show forest plot

1

1171

Risk Ratio (M‐H, Random, 95% CI)

4.78 [2.00, 11.42]

22.1 Natalizumab + IFN vs IFN

1

1171

Risk Ratio (M‐H, Random, 95% CI)

4.78 [2.00, 11.42]

23 Tremor Show forest plot

2

2110

Risk Ratio (M‐H, Random, 95% CI)

1.42 [0.89, 2.27]

23.1 Natalizumab vs Placebo

1

939

Risk Ratio (M‐H, Random, 95% CI)

1.05 [0.48, 2.29]

23.2 Natalizumab + IFN vs IFN

1

1171

Risk Ratio (M‐H, Random, 95% CI)

1.69 [0.94, 3.03]

24 Flushing Show forest plot

1

110

Risk Ratio (M‐H, Random, 95% CI)

6.00 [0.75, 48.21]

24.1 Natalizumab GA vs GA

1

110

Risk Ratio (M‐H, Random, 95% CI)

6.00 [0.75, 48.21]

25 Fatigue ‐ Myasthenia Show forest plot

1

939

Risk Ratio (M‐H, Random, 95% CI)

1.27 [0.99, 1.64]

25.1 Natalizumab vs Placebo

1

939

Risk Ratio (M‐H, Random, 95% CI)

1.27 [0.99, 1.64]

26 Urinary Urgency / Frequency Show forest plot

1

939

Risk Ratio (M‐H, Random, 95% CI)

1.27 [0.79, 2.03]

26.1 Natalizumab vs Placebo

1

939

Risk Ratio (M‐H, Random, 95% CI)

1.27 [0.79, 2.03]

27 Hypersensitivity reactions Show forest plot

3

2220

Risk Ratio (M‐H, Random, 95% CI)

3.43 [0.33, 36.07]

27.1 Natalizumab vs Placebo

1

939

Risk Ratio (M‐H, Random, 95% CI)

25.42 [1.55, 416.15]

27.2 Natalizumab + IFN vs IFN

1

1171

Risk Ratio (M‐H, Random, 95% CI)

5.43 [1.21, 24.41]

27.3 Natalizumab GA vs GA

1

110

Risk Ratio (M‐H, Random, 95% CI)

0.2 [0.01, 4.07]

28 Chest Discomfort Show forest plot

1

939

Risk Ratio (M‐H, Random, 95% CI)

1.71 [0.83, 3.56]

28.1 Natalizumab vs Placebo

1

939

Risk Ratio (M‐H, Random, 95% CI)

1.71 [0.83, 3.56]

29 Local Bleeding Show forest plot

1

939

Risk Ratio (M‐H, Random, 95% CI)

1.58 [0.64, 3.91]

29.1 Natalizumab vs Placebo

1

939

Risk Ratio (M‐H, Random, 95% CI)

1.58 [0.64, 3.91]

30 Rigors Show forest plot

2

1049

Risk Ratio (M‐H, Random, 95% CI)

3.54 [1.16, 10.83]

30.1 Natalizumab vs Placebo

1

939

Risk Ratio (M‐H, Random, 95% CI)

3.15 [0.94, 10.57]

30.2 Natalizumab GA vs GA

1

110

Risk Ratio (M‐H, Random, 95% CI)

7.0 [0.37, 132.40]

31 Syncope Show forest plot

1

939

Risk Ratio (M‐H, Random, 95% CI)

1.05 [0.48, 2.29]

31.1 Natalizumab vs Placebo

1

939

Risk Ratio (M‐H, Random, 95% CI)

1.05 [0.48, 2.29]

32 Urinary Infection Show forest plot

2

1049

Risk Ratio (M‐H, Random, 95% CI)

0.99 [0.51, 1.93]

32.1 Natalizumab vs Placebo

1

939

Risk Ratio (M‐H, Random, 95% CI)

1.17 [0.88, 1.57]

32.2 Natalizumab GA vs GA

1

110

Risk Ratio (M‐H, Random, 95% CI)

0.5 [0.13, 1.90]

33 Lower Respiratory Infection Show forest plot

1

939

Risk Ratio (M‐H, Random, 95% CI)

1.06 [0.78, 1.45]

33.1 Natalizumab vs Placebo

1

939

Risk Ratio (M‐H, Random, 95% CI)

1.06 [0.78, 1.45]

34 Tonsillitis Show forest plot

1

939

Risk Ratio (M‐H, Random, 95% CI)

1.37 [0.78, 2.39]

34.1 Natalizumab vs Placebo

1

939

Risk Ratio (M‐H, Random, 95% CI)

1.37 [0.78, 2.39]

35 Gastroenteritis Show forest plot

1

939

Risk Ratio (M‐H, Random, 95% CI)

1.23 [0.81, 1.86]

35.1 Natalizumab vs Placebo

1

939

Risk Ratio (M‐H, Random, 95% CI)

1.23 [0.81, 1.86]

36 Vaginitis Show forest plot

1

939

Risk Ratio (M‐H, Random, 95% CI)

1.65 [1.01, 2.71]

36.1 Natalizumab vs Placebo

1

939

Risk Ratio (M‐H, Random, 95% CI)

1.65 [1.01, 2.71]

37 Menstrual disorders Show forest plot

1

939

Risk Ratio (M‐H, Random, 95% CI)

1.89 [1.09, 3.29]

37.1 Natalizumab vs Placebo

1

939

Risk Ratio (M‐H, Random, 95% CI)

1.89 [1.09, 3.29]

38 Skin Rash Show forest plot

2

1049

Risk Ratio (M‐H, Random, 95% CI)

1.94 [0.47, 7.99]

38.1 Natalizumab vs Placebo

1

939

Risk Ratio (M‐H, Random, 95% CI)

1.23 [0.81, 1.86]

38.2 Natalizumab + GA vs GA

1

110

Risk Ratio (M‐H, Random, 95% CI)

6.00 [0.75, 48.21]

39 Dermatitis Show forest plot

2

1049

Risk Ratio (M‐H, Random, 95% CI)

2.15 [0.96, 4.85]

39.1 Natalizumab vs Placebo

1

939

Risk Ratio (M‐H, Random, 95% CI)

1.82 [0.98, 3.40]

39.2 Natalizumab + GA vs GA

1

110

Risk Ratio (M‐H, Random, 95% CI)

6.00 [0.75, 48.21]

40 Pruritus Show forest plot

1

939

Risk Ratio (M‐H, Random, 95% CI)

2.07 [0.86, 5.00]

40.1 Natalizumab vs Placebo

1

939

Risk Ratio (M‐H, Random, 95% CI)

2.07 [0.86, 5.00]

41 Vertigo Show forest plot

1

939

Risk Ratio (M‐H, Random, 95% CI)

1.18 [0.67, 2.09]

41.1 Natalizumab vs Placebo

1

939

Risk Ratio (M‐H, Random, 95% CI)

1.18 [0.67, 2.09]

42 Infection Show forest plot

3

2220

Risk Ratio (M‐H, Random, 95% CI)

1.01 [0.97, 1.06]

42.1 Natalizumab vs Placebo

1

939

Risk Ratio (M‐H, Random, 95% CI)

1.00 [0.93, 1.07]

42.2 Natalizumab + IFN vs IFN

1

1171

Risk Ratio (M‐H, Random, 95% CI)

1.03 [0.97, 1.08]

42.3 Natalizumab + GA vs GA

1

110

Risk Ratio (M‐H, Random, 95% CI)

0.92 [0.69, 1.22]

43 Infusion reactions Show forest plot

3

2220

Risk Ratio (M‐H, Random, 95% CI)

1.24 [1.05, 1.47]

43.1 Natalizumab vs Placebo

1

939

Risk Ratio (M‐H, Random, 95% CI)

1.34 [1.01, 1.77]

43.2 Natalizumab + IFN vs IFN

1

1171

Risk Ratio (M‐H, Random, 95% CI)

1.20 [0.97, 1.49]

43.3 Natalizumab + GA vs GA

1

110

Risk Ratio (M‐H, Random, 95% CI)

0.86 [0.31, 2.39]

44 Back Pain Show forest plot

1

110

Risk Ratio (M‐H, Random, 95% CI)

2.25 [0.74, 6.87]

44.1 Natalizumab +GA vs GA

1

110

Risk Ratio (M‐H, Random, 95% CI)

2.25 [0.74, 6.87]

45 Fall Show forest plot

2

2110

Risk Ratio (M‐H, Random, 95% CI)

2.69 [0.32, 22.39]

46 Neoplasms Show forest plot

3

2220

Risk Ratio (M‐H, Random, 95% CI)

0.83 [0.19, 3.66]

46.1 Natalizumab vs Placebo

1

939

Risk Ratio (M‐H, Random, 95% CI)

2.49 [0.29, 21.20]

46.2 Natalizumab + IFN vs IFN

1

1171

Risk Ratio (M‐H, Random, 95% CI)

0.49 [0.19, 1.31]

46.3 Natalizumab + GA vs GA

1

110

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

47 Abnormal liver function tests Show forest plot

1

939

Risk Ratio (M‐H, Random, 95% CI)

1.29 [0.67, 2.47]

47.1 Natalizumab vs Placebo

1

939

Risk Ratio (M‐H, Random, 95% CI)

1.29 [0.67, 2.47]

48 Death Show forest plot

3

2220

Risk Ratio (M‐H, Random, 95% CI)

0.92 [0.14, 6.04]

48.1 Natalizumab vs Placebo

1

939

Risk Ratio (M‐H, Random, 95% CI)

2.49 [0.12, 51.75]

48.2 Natalizumab + GA vs GA

1

110

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

48.3 Natalizumab + IFN vs IFN

1

1171

Risk Ratio (M‐H, Random, 95% CI)

0.49 [0.04, 5.43]

49 MS relapse as a serious AE Show forest plot

3

2220

Risk Ratio (M‐H, Random, 95% CI)

0.50 [0.37, 0.68]

49.1 Natalizumab vs Placebo

1

939

Risk Ratio (M‐H, Random, 95% CI)

0.46 [0.30, 0.70]

49.2 Natalizumab + IFN vs IFN

1

1171

Risk Ratio (M‐H, Random, 95% CI)

0.55 [0.36, 0.86]

49.3 Natalizumab + GA vs GA

1

110

Risk Ratio (M‐H, Random, 95% CI)

0.33 [0.01, 8.01]
Figuras y tablas -
Comparison 5. Adverse Event Analysis
Ir a la tabla de la revisión