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MIGR-001

Topiramate for Migraine Prevention: A Randomized Controlled Trial

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Year of Publication: 2004

Authors: Brandes JL, Saper JR, Diamond M, ..., Jacobs D; MIGR-001 Study Group

Journal: JAMA

Citation: JAMA 2004;291(8):965-973

Link: https://doi.org/10.1001/jama.291.8.965

PDF: https://jamanetwork.com/journals/jama/fullarticle/198286

Clinical Question

Does topiramate reduce monthly migraine frequency compared with placebo in adults and adolescents with migraine?

Bottom Line

In adults and adolescents with episodic migraine, topiramate 100 mg/d (p<0.001) and 200 mg/d (p<0.001) significantly reduced monthly migraine frequency compared with placebo; the 50 mg/d dose was not significantly better than placebo. 100 mg/d provided optimal efficacy-tolerability balance and established topiramate as a first-line preventive migraine drug, supporting FDA approval in 2004.

        Major Points
        Phase 3 multicenter randomized double-blind placebo-controlled parallel-group trial at 52 North American clinical centers
483 patients aged 12-65 with 3-12 migraines per month during 28-day baseline
Randomized to placebo or topiramate 50, 100, or 200 mg/d
8-week titration + 18-week maintenance (26 weeks total)
Primary endpoint: change from baseline in mean monthly migraine frequency
Mean reduction in monthly migraines: 0.8 (placebo), 1.3 (50 mg), 2.1 (100 mg), 2.4 (200 mg)
100 mg/d vs placebo: p<0.001
200 mg/d vs placebo: p<0.001
50 mg/d did not reach statistical significance
≥50% responder rates: 23% (placebo) vs 36% (50 mg), 54% (100 mg), 52% (200 mg)
Onset of benefit within 1 month of reaching target dose
Most common AEs: paresthesias, fatigue, weight loss, anorexia, somnolence, cognitive difficulties
Discontinuation due to AEs: 8%, 14%, 21%, 29% (dose-dependent)
Cognitive/language difficulties ("word-finding") reported in ~12% on 100 mg, ~18% on 200 mg
Together with MIGR-002, supported FDA approval of topiramate for migraine prevention in 2004
100 mg/d became standard target dose in practice

      

Design

Study Type: Phase 3 multicenter randomized double-blind placebo-controlled parallel-group trial

Randomization: 1

Blinding: Double-blind

Follow-up Duration: 26 weeks (8-week titration + 18-week maintenance)

Centers: 52

Countries: USA, Canada

Sample Size: 487

Analyzed: 483

Analysis: Intention-to-treat; last-observation-carried-forward

Inclusion Criteria

Age 12-65 years
History of migraine per IHS-II criteria ≥6 months
3-12 migraine headaches per month during 28-day baseline
No more than 15 total headache days per month
Otherwise healthy

Exclusion Criteria

Chronic migraine or >15 headache days/month
Medication overuse (>15 days acute/month)
Significant psychiatric comorbidity
Prior failure of topiramate
Renal stone history (topiramate can cause stones)
Pregnancy or lactation

Baseline Characteristics

Characteristic	Control	Active
N	114	386
Age mean	~40	~40
Sex female	~88%	~88%
Baseline monthly migraines	~5.5	~5.5

Arms

Field	Control	Topiramate 50 mg/d	Topiramate 100 mg/d	Topiramate 200 mg/d
N	114	125	128	133
Intervention	Matching placebo tablets	Topiramate titrated to 50 mg/d	Topiramate titrated to 100 mg/d (divided BID)	Topiramate titrated to 200 mg/d (divided BID)
Duration	26 weeks	26 weeks	26 weeks	26 weeks

Outcomes

Outcome	Type	Control	Intervention	P-value
Change from baseline in mean monthly migraine frequency over the double-blind period	Primary	-0.8 migraines/month (placebo)	-1.3 (50 mg, NS); -2.1 (100 mg); -2.4 (200 mg)	100 mg: p<0.001; 200 mg: p<0.001; 50 mg: not significant
≥50% responder rate (primary endpoint)	Secondary	23%	36% (50 mg); 54% (100 mg); 52% (200 mg)	100 mg and 200 mg p<0.001
Reduction in monthly migraine days	Secondary	Baseline	Greater with higher doses	Consistent favorable
Reduction in acute medication days	Secondary	Baseline	Greater with higher doses	Consistent
MIDAS disability score	Secondary	Baseline	Improvement with active doses	Favorable
MSQ quality of life	Secondary	Baseline	Improvement with active doses	Favorable
Paresthesias	Adverse	6%	35% (50 mg), 51% (100 mg), 49% (200 mg)	Dose-dependent
Fatigue	Adverse	11%	15% (50 mg), 15% (100 mg), 20% (200 mg)	Dose-dependent
Anorexia (decreased appetite)	Adverse	6%	9% (50 mg), 12% (100 mg), 13% (200 mg)	Dose-dependent
Nausea	Adverse	4%	8% (50 mg), 10% (100 mg), 12% (200 mg)	Dose-dependent
Somnolence	Adverse	3%	4% (50 mg), 6% (100 mg), 8% (200 mg)	Dose-dependent
Weight loss	Adverse	0%	7% (50 mg), 10% (100 mg), 15% (200 mg)	Dose-dependent
Cognitive/language difficulties	Adverse	2%	8% (50 mg), 12% (100 mg), 18% (200 mg)	Dose-dependent
Discontinuation due to AEs	Adverse	8%	14% (50 mg), 21% (100 mg), 29% (200 mg)	Dose-dependent
Serious adverse events	Adverse	Low	Low across doses	Similar overall

Subgroup Analysis

Efficacy was consistent across subgroups by age, sex, and baseline migraine frequency. Dose-response observed for both efficacy and tolerability; 100 mg/d emerged as the optimal dose balancing efficacy and tolerability. 50 mg/d not recommended as target dose given failed primary endpoint.

Criticisms

Modest effect size: ~1.3 fewer migraines per month at 100 mg/d
Dose-dependent AEs (particularly cognitive/language and paresthesias) limit real-world tolerability
Renal stone risk (especially at higher doses) requires patient counseling
Weight loss may be desirable (headache population often overweight) but unwanted in underweight patients
Teratogenicity (cleft lip/palate risk) limits use in pregnancy-age women
Short 26-week follow-up does not assess long-term tolerability or durability

Funding

Ortho-McNeil Pharmaceuticals (manufacturer of topiramate/Topamax)

Based on: MIGR-001 (JAMA, 2004)

Authors: Brandes JL, Saper JR, Diamond M, ..., Jacobs D; MIGR-001 Study Group

Citation: JAMA 2004;291(8):965-973

Content summarized and formatted by NeuroTrials.ai.

MIGR-001

(2004)

Objective

Topiramate 50, 100, or 200 mg/d — to evaluate efficacy and safety for preventive treatment of migraine.

Study Summary

• Topiramate 100 mg/d and 200 mg/d significantly reduced monthly migraine frequency; 50 mg/d did not meet the primary endpoint.
• Mean reduction in monthly migraine days: 0.8 (placebo), 1.3 (50 mg), 2.1 (100 mg, p<0.001), 2.4 (200 mg, p<0.001).
• ≥50% responder rates: 23% (placebo) vs 36% (50 mg), 54% (100 mg), 52% (200 mg).
• Tolerability best at 100 mg/d; 200 mg/d had highest AE-driven discontinuation.
• Common AEs: paresthesias, fatigue, weight loss, anorexia, cognitive/language difficulties.
• Established topiramate as a first-line migraine preventive; 100 mg/d became the standard target dose with FDA approval in 2004.

Intervention

Topiramate 50, 100, or 200 mg/d vs placebo; 8-week titration followed by 18-week maintenance in a 26-week double-blind study.

Inclusion Criteria

Patients 12–65 years with history of migraine per IHS-II criteria for ≥6 months; 3–12 migraines per month during 28-day baseline.

Study Design

Arms: Placebo vs Topiramate 50 mg vs 100 mg vs 200 mg (1:1:1:1)

Patients per Arm: Placebo 114; 50 mg 125; 100 mg 128; 200 mg 133 (N=487 randomized; 483 in ITT)

Outcome

• Primary: Mean reduction in monthly migraine frequency — 0.8 (placebo), 1.3 (50 mg; NS), 2.1 (100 mg; p<0.001), 2.4 (200 mg; p<0.001)
• ≥50% responder rates: 23% (placebo), 36% (50 mg), 54% (100 mg), 52% (200 mg)
• Onset of benefit within 1 month of reaching target dose
• AEs: paresthesias (most common), fatigue, weight loss, anorexia, somnolence, cognitive difficulties
• Discontinuation due to AEs: 8% (placebo), 14% (50 mg), 21% (100 mg), 29% (200 mg)

Clinical Question

Does topiramate reduce migraine frequency and improve migraine-related disability in adults and adolescents with episodic migraine?

Bottom Line

Major Points

Phase 3 multicenter randomized double-blind placebo-controlled parallel-group trial at 52 North American clinical centers
483 patients aged 12-65 with 3-12 migraines per month during 28-day baseline
Randomized to placebo or topiramate 50, 100, or 200 mg/d
8-week titration + 18-week maintenance (26 weeks total)
Primary endpoint: change from baseline in mean monthly migraine frequency
Mean reduction in monthly migraines: 0.8 (placebo), 1.3 (50 mg), 2.1 (100 mg), 2.4 (200 mg)
100 mg/d vs placebo: p<0.001
200 mg/d vs placebo: p<0.001
50 mg/d did not reach statistical significance
≥50% responder rates: 23% (placebo) vs 36% (50 mg), 54% (100 mg), 52% (200 mg)
Onset of benefit within 1 month of reaching target dose
Most common AEs: paresthesias, fatigue, weight loss, anorexia, somnolence, cognitive difficulties
Discontinuation due to AEs: 8%, 14%, 21%, 29% (dose-dependent)
Cognitive/language difficulties ("word-finding") reported in ~12% on 100 mg, ~18% on 200 mg
Together with MIGR-002, supported FDA approval of topiramate for migraine prevention in 2004
100 mg/d became standard target dose in practice

Study Design

Study Type: Phase 3 multicenter randomized double-blind placebo-controlled parallel-group trial
Randomization: Yes
Blinding: Double-blind
Sample Size: 487
Follow-up: 26 weeks (8-week titration + 18-week maintenance)
Centers: 52
Countries: USA, Canada

Primary Outcome

Definition: Change from baseline in mean monthly migraine frequency over the double-blind period

Control	Intervention	HR/OR	P-value
-0.8 migraines/month (placebo)	-1.3 (50 mg, NS); -2.1 (100 mg); -2.4 (200 mg)	-	100 mg: p<0.001; 200 mg: p<0.001; 50 mg: not significant

Limitations & Criticisms

Modest effect size: ~1.3 fewer migraines per month at 100 mg/d
Dose-dependent AEs (particularly cognitive/language and paresthesias) limit real-world tolerability
Renal stone risk (especially at higher doses) requires patient counseling
Weight loss may be desirable (headache population often overweight) but unwanted in underweight patients
Teratogenicity (cleft lip/palate risk) limits use in pregnancy-age women
Short 26-week follow-up does not assess long-term tolerability or durability

Citation

JAMA 2004;291(8):965-973

View Original Publication →

MIGR-001

Topiramate for Migraine Prevention: A Randomized Controlled Trial

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Baseline Characteristics

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

Ask about MIGR-001