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AFFIRM

A Randomized, Placebo-Controlled Trial of Natalizumab for Relapsing Multiple Sclerosis

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Year of Publication: 2006

Authors: Chris H. Polman, Paul W. O'Connor, Eva Havrdova, ..., Alfred W. Sandrock

Journal: New England Journal of Medicine

Citation: N Engl J Med 2006;354:899-910

PDF: https://www.researchgate.net/publication...tiple_sclerosis

Clinical Question

Does natalizumab, an α4 integrin antagonist, reduce disability progression and relapse rate in patients with relapsing multiple sclerosis?

Bottom Line

Natalizumab significantly reduced the risk of sustained progression of disability by 42% and the annualized relapse rate by 68% in patients with relapsing multiple sclerosis, representing a major advancement in MS treatment efficacy compared to existing therapies.

        Major Points
        First-in-class α4 integrin antagonist that blocks lymphocyte migration across blood-brain barrier
Dramatic 42% reduction in sustained disability progression over 2 years (HR 0.58, 95% CI 0.43-0.77)
68% reduction in annualized relapse rate at 1 year (0.26 vs 0.81 relapses/year)
Unprecedented MRI improvements: 83% reduction in new/enlarging T2 lesions, 92% reduction in gadolinium-enhancing lesions
Safety profile acceptable as monotherapy over 2 years, with fatigue and allergic reactions more common
9% of patients developed persistent antibodies with loss of efficacy

      

Design

Study Type: Multicenter, randomized, double-blind, placebo-controlled phase 3 trial

Randomization: 1

Blinding: Double-blind with identical infusion procedures

Enrollment Period: November 6, 2001 to study completion

Follow-up Duration: Up to 116 weeks (approximately 2.25 years)

Centers: 99

Countries: Europe, North America, Australia, New Zealand

Sample Size: 942

Analysis: Intention-to-treat analysis using Cox proportional-hazards model for disability progression, Poisson regression for relapse rate, logistic regression for secondary endpoints

Inclusion Criteria

Age 18-50 years
Diagnosis of relapsing multiple sclerosis per McDonald criteria
EDSS score 0-5.0
MRI showing lesions consistent with multiple sclerosis
At least one medically documented relapse within 12 months before study
Written informed consent

Exclusion Criteria

Primary progressive, secondary progressive, or progressive relapsing MS
Relapse within 50 days before first study drug dose
Treatment with cyclophosphamide or mitoxantrone within previous year
Treatment with interferon beta, glatiramer acetate, cyclosporine, azathioprine, methotrexate, or IVIG within previous 6 months
Prior treatment with interferon beta or glatiramer acetate for >6 months

Baseline Characteristics

Characteristic	Control	Active
Mean age	36.7 years	35.6 years
Female	67%	72%
Mean disease duration	6.0 years	5.0 years
Mean EDSS	2.3	2.3
Mean relapses in past year	1.50	1.53
Gadolinium-enhancing lesions present	46%	51%

Arms

Field	Natalizumab	Control
Intervention	Intravenous natalizumab 300 mg every 4 weeks	Intravenous placebo every 4 weeks
Duration	Up to 116 weeks	Up to 116 weeks

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Sustained progression of disability (≥1.0 point EDSS increase from baseline ≥1.0 or ≥1.5 point increase from baseline 0, sustained for 12 weeks)	Primary	29% cumulative probability of progression	17% cumulative probability of progression	0.58	<0.001
Annualized relapse rate at 1 year	Secondary	0.81 relapses per year	0.26 relapses per year	68% relative reduction	<0.001
New or enlarging T2 lesions over 2 years	Secondary	Mean 11.0 lesions	Mean 1.9 lesions	83% reduction	<0.001
Gadolinium-enhancing lesions at 2 years	Secondary	Mean 1.2 lesions	Mean 0.1 lesions	92% reduction	<0.001
Relapse-free patients at 2 years	Secondary	41%	67%		<0.001
Fatigue	Adverse	21%	27%		0.048
Allergic reaction	Adverse	4%	9%		0.012
Hypersensitivity reactions	Adverse	0%	4% (25 patients)		Not specified
Serious hypersensitivity	Adverse	0%	1% (8 patients)		Not specified

Subgroup Analysis

Sensitivity analysis for 24-week sustained progression showed 54% risk reduction (HR 0.46, 95% CI 0.33-0.64). Results consistent across all sensitivity analyses and secondary endpoints.

Criticisms

Study population limited to ages 18-50, excluding older MS patients
Excluded patients with prior exposure to disease-modifying therapies >6 months
2:1 randomization ratio may have introduced imbalance in statistical power
Safety evaluation limited to 2 years - longer-term safety unknown at time of publication
9% dropout rate overall, with some patients discontinuing due to adverse events
Development of neutralizing antibodies in 6% of patients with loss of efficacy
Study was suspended in 2005 due to PML cases discovered in combination therapy trials

Funding

Supported by Biogen Idec and Elan Pharmaceuticals. Data were analyzed by Biogen Idec and Elan Pharmaceuticals.

Based on: AFFIRM (New England Journal of Medicine, 2006)

Authors: Chris H. Polman, Paul W. O'Connor, Eva Havrdova, ..., Alfred W. Sandrock

Citation: N Engl J Med 2006;354:899-910

Content summarized and formatted by NeuroTrials.ai.

AFFIRM

(2006)

Objective

Natalizumab - To confirm the efficacy of natalizumab in relapsing multiple sclerosis and evaluate the safety of long-term treatment with this α4 integrin antagonist

Study Summary

• Natalizumab reduced risk of sustained disability progression by 42% over 2 years (HR 0.58, P<0.001)
• 68% reduction in annualized relapse rate at 1 year (0.26 vs 0.81, P<0.001)
• 83% reduction in new/enlarging T2 lesions and 92% reduction in gadolinium-enhancing lesions

Intervention

Randomized, double-blind, placebo-controlled trial of intravenous natalizumab 300mg every 4 weeks versus placebo for up to 116 weeks in patients with relapsing multiple sclerosis

Inclusion Criteria

Age 18-50 years, relapsing multiple sclerosis diagnosis, EDSS score 0-5.0, MRI lesions consistent with MS, at least one documented relapse within 12 months before study

Study Design

Arms: Natalizumab 300mg IV every 4 weeks (n=627) vs Placebo IV every 4 weeks (n=315)

Patients per Arm: 627 natalizumab, 315 placebo

Outcome

• Disability progression: 17% natalizumab vs 29% placebo (42% risk reduction)
• Relapse rate: 0.26/year natalizumab vs 0.81/year placebo (68% reduction)
• MRI lesions: 83% reduction in T2 lesions, 92% reduction in Gd-enhancing lesions

Bottom Line

Major Points

First-in-class α4 integrin antagonist that blocks lymphocyte migration across blood-brain barrier
Dramatic 42% reduction in sustained disability progression over 2 years (HR 0.58, 95% CI 0.43-0.77)
68% reduction in annualized relapse rate at 1 year (0.26 vs 0.81 relapses/year)
Unprecedented MRI improvements: 83% reduction in new/enlarging T2 lesions, 92% reduction in gadolinium-enhancing lesions
Safety profile acceptable as monotherapy over 2 years, with fatigue and allergic reactions more common
9% of patients developed persistent antibodies with loss of efficacy

Study Design

Study Type: Multicenter, randomized, double-blind, placebo-controlled phase 3 trial
Randomization: Yes
Blinding: Double-blind with identical infusion procedures
Sample Size: 942
Follow-up: Up to 116 weeks (approximately 2.25 years)
Centers: 99
Countries: Europe, North America, Australia, New Zealand

Primary Outcome

Definition: Sustained progression of disability (≥1.0 point EDSS increase from baseline ≥1.0 or ≥1.5 point increase from baseline 0, sustained for 12 weeks)

Control	Intervention	HR/OR	P-value
29% cumulative probability of progression	17% cumulative probability of progression	0.58 (0.43-0.77)	<0.001

Limitations & Criticisms

Study population limited to ages 18-50, excluding older MS patients
Excluded patients with prior exposure to disease-modifying therapies >6 months
2:1 randomization ratio may have introduced imbalance in statistical power
Safety evaluation limited to 2 years - longer-term safety unknown at time of publication
9% dropout rate overall, with some patients discontinuing due to adverse events
Development of neutralizing antibodies in 6% of patients with loss of efficacy
Study was suspended in 2005 due to PML cases discovered in combination therapy trials

Citation

N Engl J Med 2006;354:899-910

View Original Publication →

AFFIRM

A Randomized, Placebo-Controlled Trial of Natalizumab for Relapsing Multiple Sclerosis

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Baseline Characteristics

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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