Parkinson’s disease: More hours of good on-time with extended- vs immediate-release carbidopa-levodopa

IPX203, a new oral extended-release (ER) carbidopa-levodopa (CD-LD) combination, provides more hours of good on-time per day than immediate-release (IR) CD-LD, according to results of a phase III clinical trial in patients with Parkinson’s disease (PD).

“Levodopa is the most effective oral therapy for symptomatic treatment of PD, but it has a short half-life and a limited window of opportunity for absorption in the proximal small intestine. IPX203 [which contains IR granules and ER coated beads] was developed to address these limitations,” wrote the researchers. [Eur Neurol 2009;62:1-8; Mov Disord 2015;30:64-72; Clin Neuropharmacol 2019;42:149-156; Clin Neuropharmacol 2019;42:4-8]

RISE-PD was a 20-week, randomized, double-blind, double-dummy, active-controlled, parallel-group, phase III trial conducted across 105 academic and clinical centres in the US and Europe. A total of 222 patients randomized to receive IPX203 and 227 patients randomized to receive IR CD-LD completed the study. [JAMA Neurol 2023;doi:10.1001/jamaneurol.2023.2679]

Although, on average, IPX203 was dosed three times per day and IR CD-LD was dosed five times per day, the study met its primary endpoint of statistically significant improvement in number of good on-time hours per day with IPX203 vs IR CD-LD (least squares [LS] mean change from baseline, -0.50 vs -1.03; difference in LS means, 0.53; 95 percent confidence interval [CI], 0.09–0.97; p=0.02).

“Good on-time is an appropriate outcome measure in clinical trials of PD patients who are experiencing motor complications, as it is associated with patients’ perceived duration of a good response throughout the day and provides an index of their motor status that reflects the effects of both parkinsonism and dyskinesia,” explained the researchers. “IPX203 resulted in 0.53 more hours of good on-time per day than IR CD-LD when comparing change from baseline to end of our study.”

The secondary endpoint of change from baseline in off-time hours per day showed that IPX203 treatment resulted in significantly less off-time vs IR CD-LD (difference in LS means, -0.48; 95 percent CI, -0.90 to -0.06; p=0.03). Furthermore, a significantly greater proportion of patients treated with IPX203 vs IR CD-LD rated themselves as much improved or very much improved on the Patient Global Impression of Change scale (29.7 percent vs 18.8 percent; p=0.002). “These results are consistent with the notion that maintenance of LD plasma concentration translates into more sustained clinical benefit in patients with motor fluctuations,” remarked the researchers.

Post hoc analysis of mean duration of efficacy per dose showed that IPX203 increased good on-time per dose by 1.55 hours more than IR CD-LD, representing a 70 percent increase (95 percent CI, 1.37–1.73; p<0.001). “This provides additional important evidence of clinical efficacy and may help guide clinicians in making medication management decisions. In addition, studies have shown that taking fewer doses per day is associated with greater compliance,” noted the researchers. [Neurotherapeutics 2020;17:1339-1365]