Objective: Use heatmap analysis to quantify and examine diurnal patterns of OFF and GOOD ON time periods throughout the day, and changes in the number and duration of these periods with CSAI treatment compared to placebo.

Background: TOLEDO was the first phase 3, randomized, double-blind, placebo-controlled trial to demonstrate efficacy of CSAI for Parkinson disease (PD) motor fluctuations. Treatment effects showed a 1.89 h placebo-adjusted reduction in OFF time, and 1.97 h placebo-adjusted increase in GOOD ON time after 12-weeks maintenance treatment.¹ Here we evaluate the effects of CSAI treatment on patterns of these motor states throughout the day.

Method: Patients experiencing ≥3 h of OFF time per day (Hauser diary) despite optimized levodopa and adjunctive medications received titrated apomorphine infusions (3–8 mg/h) or placebo while awake (~14–18 h/d). Patterns of motor states, including number/duration of OFF and GOOD ON periods, were evaluated for patients with valid diaries at baseline and Week12/endpoint, comparing groups receiving CSAI vs. placebo. Patients could reduce medication based on adverse events.

Results: Of 106 (53 CSAI; 53 placebo) participants in the full analysis set, 73 (68.9%; 41 CSAI, 32 placebo) had valid diary data at Baseline and Endpoint. Heat maps showed little difference between treatment groups at Baseline but longer mean duration of GOOD ON episodes in the CSAI group at Week 12 (7.4 h vs.3.6 h, P=0.001), with 9 CSAI participants (vs. 1 placebo) recording only GOOD ON motor states at Endpoint. The CSAI group showed fewer mean OFF episodes relative to the placebo group (2.2 vs. 3.1, P=0.01), shorter mean duration of OFF episodes (1.3 h vs. 2.2 h, P=0.04), greater mean reduction in other PD medication use (levodopa equivalent dose: ‑27.9% vs. -9.0%, P=0.0003), and more patients rating themselves improved on the Patient Global Impression of Change scale (79.1% vs.23.5%, P<0.0001).

Conclusion: In addition to overall reduction in OFF time and increased GOOD ON time, this analysis of TOLEDO study data showed that participants maintained on CSAI therapy exhibited more prolonged periods of GOOD ON time uninterrupted by OFF episodes relative to placebo.  These changes in the pattern of motor states are accompanied by increased patient perceptions of improvement.

References: 1 Katzenschlager, Poewe, Rascol et al. Apomorphine subcutaneous infusion in patients with Parkinson’s disease with persistent motor fluctuations (TOLEDO): a multicentre, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2018;17(9):749-759.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/continuous-subcutaneous-apomorphine-infusion-csai-reduces-off-periods-and-extends-periods-of-good-on-time-heatmap-analysis-of-the-toledo-study/