Objective: ND012 is a drug-device combination delivering liquid L-dopa/carbidopa (LD/CD) via continuous SC infusion. This secondary analysis evaluated the efficacy of 2 dosing regimens (R1: 24h infusion & R2: 14h daytime infusion) on early morning OFF (EMO) and nocturnal symptoms in fluctuating PD.

Background: Nocturnal symptoms and EMO periods are significant contributors to poor quality of life in PD patients with motor fluctuations. Primary results from this Phase-2 study have been previously reported and showed ND0612 reduced total daily OFF time (R1: -2.8h, p=0.004 & R2: -1.3h, p=0.158).

Methods: After 1 day of standard oral LD/CD treatment, 38 subjects with fluctuating PD (mean age: 63.5y; OFF-time 5.3h/day) were randomized to 2 ND0612 dosing regimens for 28 days: R1 (total LD/CD dose: 720/90 mg) or R2 (total dose: 538/68mg + 1 morning dose of standard oral LD/CD [150/15 mg]). Change from baseline in percent of subjects with full ON at 8 & 9 AM, nighttime sleep quality (assessed using PDSS-2) and early morning (8 AM) UPDRS motor scores (post-hoc) were assessed by a blinded rater.

Results: In R1, the proportion of subjects with full ON increased at 8AM (from 11% at baseline to 50% at Day 28, p=0.02) and 9AM (from 32% to 75%, p=0.007). Early morning UPDRS motor scores improved from a baseline of 37.4 to 20.3 at Day 28 (mean [95%CI] improvement of -19.1 [-25.6, -12.5] points, p<0.0001); mean PDSS-2 scores also significantly improved from baseline to Day 27 (-4.1 [-8.0, -0.2]; p=0.042). In R2, dosing began in the morning and thus no improvement in the proportion of patients with full ON was found at either 8AM or 9AM; indeed none was expected as this was before many of the subjects began their daily therapy. Daytime dosing had no significant effect on sleep quality, but 8 AM UPDRS motor scores significantly improved by -10.7 [-16.8, -4.6] points (p=0.001).

Conclusions: 24h ND0612 infusion significantly decreased EMO periods, with an associated improvement in motor status. Sleep quality also improved, indicating that patients tolerated the overnight infusion. R2 was not optimized because treatment initiation was delayed until a nurse started the pump. A longer 16h daytime infusion regimen with higher doses (LD/CD 720/90 mg) starting immediately upon waking up is under evaluation. ND0612 may provide a minimally invasive option of continuous LD delivery for PD patients experiencing nocturnal and early morning motor fluctuations.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/efficacy-of-nd0612-for-nocturnal-problems-and-early-morning-off/