Increased dose of carbidopa with levodopa and entacapone improves "off" time in a randomized trial

Abstract

Objective: To investigate whether increased fixed carbidopa doses of 65 or 105 mg (ODM-101/65 and ODM-101/105) in combination with 75, 100, 125, or 150 mg of levodopa and 200 mg of entacapone might improve "off" time in fluctuating Parkinson disease (PD) compared to the standard combination of 4:1 levodopa/carbidopa with the usual 200 mg of entacapone (LCE) during a 4-week treatment period.

Methods: This was a randomized, double-blind, double-dummy, active-controlled, crossover, multicenter, phase II, proof-of-concept study in patients with fluctuating PD.

Results: One hundred seventeen patients were randomized into the study (mean age 67.0 years; daily "off" time 5.3 hours; mean daily levodopa dose 610 mg). Carryover-adjusted mean changes from baseline "off" times were during ODM-101/65, -1.53 hours (p = 0.02 vs LCE), during ODM-101/105, -1.57 hours (p = 0.01 vs LCE), and during LCE -0.91 hours. Changes in daily "on" time without dyskinesia were 1.54 hours (p = 0.005 vs LCE), 1.38 hours (p = 0.0214 vs LCE), and 0.69 hours, respectively. Changes in "on" time with troublesome dyskinesia were <0.1 hours and not significantly different between treatments. In patients with high-activity COMT genotypes Val/Met or Val/Val, "off" time was reduced more with ODM-101/65 and ODM-101/105 than with LCE (p = 0.015 and p = 0.006). No difference between the treatments was seen in safety and tolerability. The most common treatment-related adverse effects were nausea, dizziness, drug-effect decrease, and dyskinesia, which were in most cases mild or moderate in severity. Treatment-related serious adverse events were diarrhea (ODM-101/105 and LCE), and myocardial ischemia and blood creatine kinase increase (LCE).

Conclusion: Increasing the dose of carbidopa in combination with levodopa and entacapone should be considered in the treatment of fluctuating PD to improve daily "off" times. Genotyping patients with PD according to COMT activity may improve individual treatment strategies.

Clinicaltrialsgov identifier: NCT01766258.

Classification of evidence: This study provides Class II evidence that an increased dose of carbidopa improves motor fluctuations when administered with levodopa and entacapone.

Figure 1. Study participant disposition and treatment allocations

AE = adverse event; LCE = levodopa/carbidopa/entacapone.

Figure 2. Effect of carbidopa increase on “off” and “on” times

(A) Mean changes (−SEM) from baseline in daily “off” time. (B) Mean changes (+SEM) from baseline in daily “on” time without dyskinesia. 65 mg = ODM-101/65; 105 mg = ODM-101/105; LCE = levodopa/carbidopa/entacapone.