LARGO
(2005)Objective
To determine the safety and efficacy of rasagiline (1 mg once daily) as an adjunct to levodopa in patients with Parkinson's disease and motor fluctuations, with entacapone as an active comparator
Study Summary
• On-time without troublesome dyskinesia increased by 0.85 h with both rasagiline and entacapone vs 0.03 h with placebo (P=0.0005 for both), with no increase in troublesome dyskinesia
• Rasagiline uniquely improved UPDRS-PIGD, freezing, and motor scores in the practically defined off-state — effects not seen with entacapone
Intervention
Rasagiline 1 mg once daily orally vs entacapone 200 mg with every levodopa dose vs placebo, as adjunct to optimized levodopa therapy, for 18 weeks (double-dummy design)
Inclusion Criteria
Idiopathic PD (≥2 cardinal signs), modified Hoehn and Yahr <5 in off-state, optimum levodopa therapy stable ≥14 days, motor fluctuations with ≥1 h daily off-time (excluding morning akinesia), 3–8 daily levodopa doses, ability to keep 24-h diaries
Study Design
Arms: Rasagiline 1 mg/d, Entacapone 200 mg with each levodopa dose, Placebo
Patients per Arm: Rasagiline 231, Entacapone 227, Placebo 229
Outcome
• All secondary endpoints met hierarchically: CGI (P<0.0001), UPDRS-ADL off-state (P<0.0001), UPDRS-motor on-state (P<0.0001) for rasagiline
• Rasagiline significantly improved PIGD (P=0.034) and freezing (P=0.045) scores, effects not seen with entacapone; safety profile similar to placebo
Bottom Line
Rasagiline 1 mg once daily reduced mean daily off-time by 0.78 hours more than placebo (P=0.0001), with a magnitude similar to entacapone (0.80 h; P<0.0001). Both drugs increased on-time without troublesome dyskinesia by 0.82 hours vs placebo without increasing troublesome dyskinesia. All hierarchical secondary endpoints (CGI, UPDRS-ADL off-state, UPDRS-motor on-state) were significantly improved. Rasagiline uniquely improved PIGD and freezing scores — effects not achieved by entacapone — possibly reflecting its sustained dopaminergic action from irreversible MAO-B inhibition. Safety was similar to placebo, with convenient once-daily dosing without titration.
Major Points
- LARGO was an 18-week, randomized, double-blind, placebo-controlled, double-dummy, three-arm trial of 687 patients across 74 sites in Europe, Israel, and Argentina
- Primary endpoint met: rasagiline reduced mean daily off-time by 1.18 h vs 0.40 h with placebo (difference −0.78 h; 95% CI −1.18 to −0.39; P=0.0001); entacapone reduced by 1.20 h (difference −0.80 h; 95% CI −1.20 to −0.41; P<0.0001)
- On-time without troublesome dyskinesia increased by 0.85 h for both rasagiline and entacapone vs 0.03 h placebo (P=0.0005 for both); no increase in on-time with troublesome dyskinesia with either drug
- All hierarchical secondary endpoints significant for rasagiline: CGI improvement −0.86 vs −0.37 placebo (P<0.0001); UPDRS-ADL off-state −1.71 (P<0.0001); UPDRS-motor on-state −2.94 (P<0.0001)
- Responder analysis (≥1 h off-time reduction): 51% rasagiline, 45% entacapone, 32% placebo (OR 2.5 rasagiline vs placebo; P<0.0001)
- Rasagiline significantly improved UPDRS-PIGD (−0.31; P=0.034), freezing (−0.16; P=0.045), and motor score in the practically defined off-state (−5.64; P=0.013) — none of these reached significance with entacapone
- UPDRS-dyskinesia scores showed no significant increase with either active treatment vs placebo, and levodopa dose was only minimally reduced (−24 mg rasagiline, −19 mg entacapone)
- Efficacy was independent of age (<70 vs ≥70 years) and unaffected by concomitant dopamine agonist use (~60% of patients)
- Fewer early discontinuations in rasagiline group (10%) vs entacapone (13%) and placebo (15%); fewer discontinuations due to adverse events with rasagiline (7) vs entacapone (16) and placebo (11)
- Although not powered for direct comparison between rasagiline and entacapone, results showed similar clinical effects on all primary and secondary endpoints
Study Design
- Study Type
- Randomized, double-blind, placebo-controlled, double-dummy, parallel-group, multicenter phase 3 trial with active comparator
- Randomization
- Yes
- Blinding
- Double-blind, double-dummy. All patients received one tablet once daily (rasagiline or matching placebo) and one capsule with every levodopa dose (entacapone or matching placebo). Randomized block design (block size 6, 2 per group).
- Sample Size
- 687
- Follow-up
- 18 weeks (with 2–4 week levodopa optimization run-in phase)
- Centers
- 74
- Countries
- Israel, Argentina, Austria, Belgium, France, Germany, Hungary, Italy, Netherlands, Portugal, Romania, Spain, UK
Primary Outcome
Definition: Change from baseline to treatment in mean total daily off-time (24-hour diary, hours/day)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| −0.40 (SE 0.15) h | - | - | - |
Limitations & Criticisms
- Not powered for direct comparison between rasagiline and entacapone; the similar effect sizes are suggestive but not conclusive
- 18-week duration is relatively short for evaluating long-term adjunctive therapy in a chronic progressive disease
- Sample size was increased from ~450 to 700 after masked variance reassessment, which may raise concerns about adaptive design
- PIGD and freezing improvements with rasagiline (but not entacapone) are intriguing but based on exploratory/post-hoc analyses with small effect sizes
- The substudy assessing motor scores in practically defined off-state included only 105 patients, limiting statistical power
- Levodopa dose adjustments were allowed in the first 6 weeks, introducing variability in effective levodopa exposure across arms
- Approximately 60% of patients were on concomitant dopamine agonists, making it difficult to isolate rasagiline's incremental benefit
- The study population was predominantly European/Israeli; limited racial/ethnic diversity
- Entacapone's effect may be underestimated as it was not combined with levodopa in a single tablet (Stalevo), potentially affecting compliance
- All authors received honoraria from Teva Pharmaceuticals (rasagiline manufacturer)
Citation
Lancet 2005; 365: 947-54