BIPARK-2
(2017)Objective
To evaluate the efficacy and safety of 25- and 50-mg/d dosages of opicapone compared with placebo as adjunct to levodopa therapy in patients with Parkinson disease experiencing end-of-dose motor fluctuations.
Study Summary
• Off-time reduction was sustained throughout a 1-year open-label extension phase (-126.3 minutes from double-blind baseline), and opicapone was well tolerated with no relevant hepatotoxicity or diarrhea
Intervention
Opicapone 25 mg/d or 50 mg/d taken once daily in the evening as adjunct to levodopa/DDCI therapy vs matching placebo
Inclusion Criteria
Adults aged 30-83 years with clinical diagnosis of Parkinson disease for at least 3 years, Hoehn-Yahr stage 1-3 (on state), at least 1-year history of clinical improvement with levodopa/DDCI therapy, stable optimized regimen of 3-8 daily doses of levodopa/DDCI for at least 4 weeks, signs of end-of-dose deterioration for at least 4 weeks, mean total awake off-time of at least 1.5 hours excluding morning akinesia, and ability to keep reliable diaries
Study Design
Arms: Placebo, Opicapone 25 mg/d, Opicapone 50 mg/d
Patients per Arm: Placebo: 144, Opicapone 25 mg/d: 129, Opicapone 50 mg/d: 154
Outcome
• Off-time responder rates (>=1 h reduction) were significantly higher for both opicapone 25 mg/d (62.4%, P = .04) and 50 mg/d (66.0%, P = .009) vs placebo (50.4%); on-time responder rates were also significantly higher for both doses
• Most common adverse events with opicapone vs placebo were dyskinesia (24.0% vs 8.1%), constipation (9.6%/6.7% vs 1.5%), and dry mouth (10.4%/4.0% vs 0.7%); no relevant hepatotoxicity or diarrhea was observed
Bottom Line
Treatment with opicapone 50 mg once daily as adjunct to levodopa significantly reduced mean daily off-time by 54.3 minutes compared with placebo in patients with Parkinson disease and motor fluctuations. This effect was sustained for at least 1 year. Opicapone was safe and well tolerated with no relevant hepatotoxicity or diarrhea.
Major Points
- Opicapone 50 mg/d significantly reduced off-time vs placebo (treatment effect -54.3 min; 95% CI -96.2 to -12.4; P = .008), while the 25 mg/d dose did not reach significance (treatment effect -37.2 min; 95% CI -80.8 to 6.4; P = .11)
- Off-time responder rates (>=1 h reduction) were significantly higher for opicapone 25 mg/d (62.4%, P = .04) and 50 mg/d (66.0%, P = .009) compared with placebo (50.4%)
- On-time responder rates (>=1 h increase) were significantly higher for opicapone 25 mg/d (63.2%, P = .004) and 50 mg/d (61.9%, P = .006) compared with placebo (45.2%)
- Off-time reduction was sustained throughout the 1-year open-label extension phase (-126.3 min from double-blind baseline at 1-year open-label endpoint)
- The most common adverse events with opicapone vs placebo were dyskinesia (24.0% vs 8.1%), constipation (9.6%/6.7% vs 1.5%), and dry mouth (10.4%/4.0% vs 0.7%); no relevant liver function abnormalities or diarrhea were observed
- The higher-than-expected placebo response (64.5 min vs assumed 30 min) may have contributed to the 25 mg/d dose not reaching significance, suggesting the study may have been underpowered for that comparison
- Most of the gain in on-time with opicapone was without troublesome dyskinesia; increases in on-time with troublesome dyskinesia were not significantly different from placebo
Study Design
- Study Type
- Phase 3 randomized, double-blind, placebo-controlled trial with 1-year open-label extension
- Randomization
- Yes
- Blinding
- Double-blind (double-blind phase); Open-label (extension phase)
- Sample Size
- 427
- Follow-up
- 14-15 weeks (double-blind phase) plus 52 weeks (open-label extension)
- Centers
- 71
- Countries
- Belgium, United Kingdom, Israel, Estonia, Czech Republic, Russia, South Africa, Australia, South Korea, India, Argentina, Chile
Primary Outcome
Definition: Change from baseline in absolute off-time (minutes) at the end of the double-blind phase based on patient diaries
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| -64.5 (14.4) min (LS mean [SE]) | Opicapone 25 mg/d: -101.7 (14.9) min; Opicapone 50 mg/d: -118.8 (13.8) min (LS mean [SE]) | - (50 mg/d vs placebo: -96.2 to -12.4 min; 25 mg/d vs placebo: -80.8 to 6.4 min) | 50 mg/d vs placebo: P = .008; 25 mg/d vs placebo: P = .11 |
Limitations & Criticisms
- The study may have been underpowered due to a higher-than-expected placebo response (64.5 min vs assumed 30 min), particularly for detecting differences with the 25 mg/d dose
- UPDRS motor scores and other scale-based outcomes did not show significant between-group differences, though the study was only powered to address motor fluctuations
- The placebo group had slightly fewer male patients and more Asian patients compared with active treatment groups, introducing potential baseline imbalance
- The open-label extension phase lacked a placebo comparator, limiting conclusions about long-term efficacy beyond maintenance of effect
- Discontinuation rate due to adverse events was higher in the 50 mg/d opicapone group (12.0%) compared with placebo (7.4%) during the double-blind phase
- Two of the authors are employed by the study sponsor (BIAL), which participated in study design, conduct, data collection, data management, and interpretation
Citation
JAMA Neurol. 2017;74(2):197-206