PDF: PREEMPT 2
(2010)Objective
OnabotulinumtoxinA - To evaluate the efficacy and safety of onabotulinumtoxinA (Botox) for the prophylaxis of headaches in adults with chronic migraine.
Study Summary
• Showed consistent benefit across multiple headache severity and quality-of-life endpoints.
• Safe and well tolerated with low discontinuation rates.
• Supported use for chronic migraine prevention in patients with high baseline burden.
Intervention
Phase 3, randomized, double-blind, placebo-controlled trial (PREEMPT 2). Patients (n=705) received intramuscular onabotulinumtoxinA (155–195 U) or placebo every 12 weeks for 24 weeks. Primary endpoint was reduction in headache days. Also evaluated migraine days, headache-related disability (HIT-6), and quality of life (MSQ).
Inclusion Criteria
Adults aged 18–65 years with chronic migraine (≥15 headache days/month) and ≥50% of days with migraine features. Excluded those with recent use of other prophylactics or prior exposure to botulinum toxin.
Study Design
Arms: OnabotulinumtoxinA vs. Placebo
Patients per Arm: OnabotulinumtoxinA: 347; Placebo: 358
Outcome
• Migraine days: -8.7 vs. -6.3; p<0.001
• Moderate/severe headache days: -8.3 vs. -5.8; p<0.001
• Total cumulative headache hours: -132.4 vs. -90.0; p<0.001
• HIT-6 score ≥60 (severe disability): 66.3% vs. 76.5%; p=0.003
• Reduction in triptan use: -3.0 vs. -1.7 doses/month; p<0.001
• Adverse events: 65.1% (Botox) vs. 56.4% (Placebo), most mild; discontinuations due to AEs: 3.5% vs. 1.4%
Bottom Line
OnabotulinumtoxinA (155-195U administered every 12 weeks) is statistically superior to placebo for reducing headache days in adults with chronic migraine, with significant benefits across multiple headache symptom measures and quality of life assessments, and is safe and well tolerated with repeated treatments
Major Points
- PREEMPT 2 was a phase 3, double-blind, placebo-controlled trial conducted at 66 global sites (50 North American, 16 European) from February 2006 to August 2008
- 705 patients with chronic migraine were randomized 1:1 to onabotulinumtoxinA (155-195U) or placebo every 12 weeks for 2 cycles (24-week double-blind phase)
- Primary endpoint: onabotulinumtoxinA significantly reduced headache days per 28 days (-9.0 vs -6.7 placebo, mean difference -2.3, p<.001)
- All five ranked secondary endpoints significantly favored onabotulinumtoxinA: migraine days, moderate/severe headache days, cumulative headache hours, proportion with severe HIT-6 scores, and headache episodes
- Approximately two-thirds of patients had medication overuse at baseline; treatment efficacy was maintained in this challenging population
- Treatment significantly improved headache-related disability (HIT-6) and quality of life (MSQ) measures
- Safety profile was favorable with 89.6% onabotulinumtoxinA patients completing the 24-week phase; most adverse events were mild-moderate in severity
- Only 3.5% onabotulinumtoxinA vs 1.4% placebo patients discontinued due to adverse events
- High diary compliance rate (>93%) throughout the study using interactive voice response system
- Post-hoc analysis showed significant reduction in triptan usage with onabotulinumtoxinA (-3.0 vs -1.7, p<.001)
Study Design
- Study Type
- Phase 3, randomized, double-blind, placebo-controlled, parallel-group trial with 24-week double-blind phase followed by 32-week open-label phase
- Randomization
- Yes
- Blinding
- Double-blind: patients, investigators who administered study treatment and assessed outcomes, and sponsor study management personnel were all masked to treatment assignment
- Sample Size
- 705
- Follow-up
- 24 weeks (double-blind phase primary analysis); 56 weeks total including open-label phase
- Centers
- 66
- Countries
- United States, Canada, European countries (Germany, Croatia, and others)
Primary Outcome
Definition: Mean change from baseline in frequency of headache days per 28 days for the period ending with week 24 (weeks 21-24 post-treatment). Headache day defined as calendar day (00:00 to 23:59) when patient reported ≥4 continuous hours of headache
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| -6.7 days | -9.0 days | - (-3.25 to -1.31) | <.001 |
Limitations & Criticisms
- No active comparator was included; only placebo control used as no agents were approved for chronic migraine prophylaxis at the time
- Large placebo response observed (6.7 day reduction in headache days), which is common in migraine prophylaxis trials
- Potential unblinding: patients receiving onabotulinumtoxinA might have detected muscle relaxation in forehead, though presence of placebo response suggests blind was maintained
- Post-hoc change in primary endpoint (from headache episodes to headache days) after PREEMPT 1 results known but before PREEMPT 2 unblinding could inflate type 1 error, though conservative Bonferroni correction still showed significance
- Results may not extrapolate to patients with episodic migraine, chronic tension-type headache, or secondary headache disorders as these were excluded
- Discrepancy between reduction in headache days and no significant difference in overall acute pain medication usage, though post-hoc analysis showed significant reduction in triptan use specifically
- Modified LOCF imputation method for missing data could introduce bias, though sensitivity analyses with observed data were performed
- Study population was predominantly female (85%) and Caucasian (90%), limiting generalizability
- Investigators were trained not to enroll frequent opioid users, so results may not apply to that population
- Follow-up limited to 24 weeks for double-blind phase; longer-term efficacy and safety data from open-label phase needed
Citation
Cephalalgia OnlineFirst, published on March 17, 2010 as doi:10.1177/0333102410364677