TEMPO
(2002)Objective
To evaluate the efficacy, safety, and tolerability of rasagiline (selective irreversible MAO-B inhibitor) as monotherapy in patients with early Parkinson disease not requiring dopaminergic therapy
Study Summary
• Responder rates (less than 3-unit worsening) were significantly higher with rasagiline (66–67%) vs placebo (49%)
• No meaningful differences in adverse events between rasagiline and placebo; the drug was well tolerated with no cardiovascular safety signals
Intervention
Rasagiline mesylate 1 mg/d or 2 mg/d orally vs matching placebo, once daily for 26 weeks (1-week titration + 25-week maintenance)
Inclusion Criteria
Age >35 years, at least 2 cardinal signs of PD, Hoehn and Yahr stage ≤III, not requiring dopaminergic therapy, MMSE >23
Study Design
Arms: Rasagiline 1 mg/d, Rasagiline 2 mg/d, Placebo
Patients per Arm: Rasagiline 1 mg: 134, Rasagiline 2 mg: 132, Placebo: 138
Outcome
• Significant benefits on motor and ADL subscales and quality of life (PDQUALIF); no advantage of 2 mg over 1 mg
• No significant difference in time to need for levodopa (though not powered for this endpoint)
Bottom Line
Rasagiline at both 1 mg/d and 2 mg/d was effective as monotherapy in early PD, significantly improving total UPDRS scores compared to placebo over 26 weeks. The 1 mg dose showed a numerically larger effect (−4.20 units) than 2 mg (−3.56 units), with no advantage for the higher dose. The drug was well tolerated with an adverse event profile similar to placebo. The magnitude of symptomatic benefit was comparable to selegiline and lazabemide in prior studies, though more modest than dopamine agonists. No difference in time to need for levodopa was detected, but the study was not powered for this endpoint.
Major Points
- TEMPO was a 26-week, randomized, double-blind, placebo-controlled trial of rasagiline monotherapy in 404 patients with early PD across 32 sites in the US and Canada
- Both rasagiline doses significantly improved total UPDRS vs placebo: 1 mg effect size −4.20 (95% CI −5.66 to −2.73; P<.001); 2 mg effect size −3.56 (95% CI −5.04 to −2.08; P<.001)
- Significant benefits were also seen on UPDRS motor subscale (1 mg: −2.71; 2 mg: −1.68), ADL subscale (1 mg: −1.04; 2 mg: −1.22), and PDQUALIF quality of life scores
- Responder analysis (less than 3-unit total UPDRS worsening): 66% for 1 mg, 67% for 2 mg, vs 49% for placebo (P=.004 and P=.001)
- No significant difference in time to need for levodopa therapy: 11.2% (1 mg), 16.7% (2 mg), vs 16.7% (placebo); study was not powered for this secondary endpoint
- Adverse events were no more frequent with rasagiline than placebo; no cardiovascular safety concerns despite MAO-B inhibition
- Small but significant increase in supine systolic blood pressure with 2 mg (+4.04 mm Hg; P=.02) but not 1 mg
- Symptomatic benefit was comparable to selegiline in DATATOP (~3 UPDRS units at 3 months) and lazabemide (~2 units at 6 months)
- The magnitude of benefit was more modest than dopamine agonists (difference <4 UPDRS units), but with fewer adverse effects (particularly somnolence, edema, hallucinations)
Study Design
- Study Type
- Randomized, double-blind, placebo-controlled, parallel-group, multicenter phase 3 trial
- Randomization
- Yes
- Blinding
- Double-blind. All patients, investigators, and coordinating staff were kept unaware of treatment assignments.
- Sample Size
- 404
- Follow-up
- 26 weeks
- Centers
- 32
- Countries
- United States, Canada
Primary Outcome
Definition: Change in total UPDRS score from baseline to 26 weeks (last observation carried forward)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| Unadjusted mean change: +3.9 (SD 7.5) | - | - | - |
Limitations & Criticisms
- Relatively short 26-week duration limits ability to assess long-term efficacy and disease-modifying potential
- No advantage of 2 mg over 1 mg dosing; the 2 mg group had slightly higher baseline ADL and mental subscale impairment, potentially confounding comparisons between dose groups
- Not powered to detect differences in time to need for levodopa therapy, a clinically meaningful endpoint
- LOCF imputation method may introduce bias, particularly for patients requiring additional dopaminergic therapy
- Predominantly White (93–97%) and male (56–67%) population limits generalizability
- The symptomatic benefit (~3.5–4 UPDRS units) is modest compared to dopamine agonists, though with better tolerability
- Cannot distinguish symptomatic from disease-modifying effects with this study design; a delayed-start design would be needed
- Three new malignancies in the 2 mg group vs none in other groups raises a safety signal, though likely incidental given small numbers
- Anticholinergics were the only permitted concomitant PD therapy, which may not reflect contemporary real-world practice
Citation
Arch Neurol. 2002;59:1937-1943