ADAGIO
(2009)Objective
The ADAGIO study tested whether early initiation of rasagiline provides disease-modifying benefits in Parkinson's disease using a delayed-start design.
Study Summary
• No benefit observed with 2 mg/day, failing to meet the hierarchical endpoints
• UPDRS score worsened less in 1 mg early-start group vs delayed-start
Intervention
1176 early Parkinson's disease patients were randomized to early-start or delayed-start rasagiline (1 mg or 2 mg/day). Early-start groups received 72 weeks of active drug; delayed-start groups received placebo for 36 weeks then rasagiline for 36 weeks. No other antiparkinsonian therapy was allowed.
Inclusion Criteria
• Age 30–80 years
• Untreated idiopathic Parkinson's disease diagnosed within 18 months
• At least two cardinal features (tremor, rigidity, bradykinesia)
• Hoehn & Yahr stage ≤2.5
Study Design
Arms: Early-start rasagiline 1 mg, Delayed-start rasagiline 1 mg, Early-start rasagiline 2 mg, Delayed-start rasagiline 2 mg
Patients per Arm: Approximately 290 per group
Outcome
• Rate of worsening (weeks 12–36): 0.09 vs 0.14 points/week, P=0.01
• 2 mg dose failed to show difference: 3.47 vs 3.11, P=0.60
• Secondary endpoint: 1.26 vs 4.27 points UPDRS (1 mg vs placebo), P<0.001
Bottom Line
Rasagiline 1 mg/day met the delayed-start superiority criteria in early PD, suggesting possible disease-modifying effect (UPDRS total: -1.7; P=0.01 at 72 weeks). However, 2 mg/day did NOT meet criteria. Published NEJM 2009. 1176 patients. The inconsistent dose-response weakened the disease-modification interpretation.
Major Points
- Rasagiline 1mg met all 3 delayed-start criteria: superiority of early vs delayed start at 72 weeks (-1.7; P=0.01).
- Rasagiline 2mg did NOT meet criteria — inconsistent dose-response undermined disease-modification claim.
- 1176 early PD patients. Delayed-start design: 36 weeks rasagiline vs placebo → 36 weeks all on rasagiline.
- Three hierarchical endpoints: (1) superiority at 72 weeks, (2) superiority at 36 weeks, (3) non-inferiority slope test.
- 1mg met all 3; 2mg met endpoints 2 and 3 but failed endpoint 1.
- Symptomatic benefit at 36 weeks: -2.82 (1mg) and -3.64 (2mg) vs placebo (both P<0.001).
- FDA ultimately did not grant disease-modification label due to dose inconsistency.
- Published NEJM 2009 (Olanow et al.). Teva sponsored.
- Rasagiline: irreversible MAO-B inhibitor. 1mg/day is the approved PD dose.
- Highlighted challenges of demonstrating disease modification in PD using delayed-start designs.
Study Design
- Study Type
- Randomized, double-blind, placebo-controlled delayed-start trial
- Randomization
- Yes
- Blinding
- Participants and investigators were blinded
- Sample Size
- 1176
- Follow-up
- 72 weeks
- Centers
- 129
- Countries
- 14 countries (not listed)
Primary Outcome
Definition: Change in total UPDRS from baseline to 72 weeks
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 4.50 (delayed-start 1 mg) | 2.82 (early-start 1 mg) | - (-3.15 to -0.21) | 0.02 |
Limitations & Criticisms
- 1 mg showed positive results while 2 mg did not, raising questions about consistency
- Placebo phase might have been too short to reveal disease modification
- Primary endpoint (slope analysis) not widely validated
- Post hoc subgroup analysis supports 2 mg but is exploratory
Citation
N Engl J Med 2009;361:1268-1278