Efficacy and safety of intravenous prasinezumab in individuals with early-stage Parkinson's disease on stable symptomatic monotherapy (PADOVA): a phase 2b, multicentre, randomised, double-blind, placebo-controlled study.
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BACKGROUND: Prasinezumab has previously shown potential for reducing the progression of motor signs (Movement Disorder Society-sponsored Revision of the Unified Parkinson's Disease Rating Scale [MDS-UPDRS] Part III) in patients with early-stage Parkinson's disease who were treatment-naive or receiving monoamine oxidase type B (MAO-B) inhibitors. The aim of the PADOVA trial was to evaluate the efficacy and safety of prasinezumab in a broader population of patients receiving stable symptomatic medication. METHODS: This phase 2b, multicentre, double-blind, parallel-group, placebo-controlled, randomised, superiority trial recruited participants with early-stage Parkinson's disease (age 50-85 years, 3 months to 3 years from diagnosis, Hoehn and Yahr stage 1 or 2) on stable symptomatic medication from 110 centres in nine countries in Europe and North America. Participants were individually randomly assigned (1:1) via permuted blocks (stratified by symptomatic medication [levodopa or MAO-B inhibitor]) to intravenous prasinezumab (1500 mg) or placebo every 4 weeks for at least 76 weeks and until the target number of motor progression events was reached. Participants, investigators, and clinical assessors were masked to group assignment. The primary endpoint was time to a confirmed motor progression event (≥5-point increase in MDS-UPDRS Part III off-medication score), assessed in the full analysis set (all randomly assigned participants according to the treatment to which they were assigned). Safety and tolerability were assessed in all randomly assigned participants who received at least one dose of study drug, with participants grouped according to treatment received. The trial is registered with ClinicalTrials.gov (NCT04777331) and EudraCT (2020-004997-23), and is active, not recruiting. FINDINGS: Between May 5, 2021, and March 22, 2023, 787 individuals were screened. 586 were enrolled and randomly assigned (n=293 per group; mean age 64·2 years [SD 7·3]; 214 [37%] female and 372 [63%] male); 550 completed double-blind treatment (prasinezumab, n=277; placebo, n=273). The primary endpoint was not met; the primary analysis showed a non-significant delay in motor progression with prasinezumab versus placebo (hazard ratio 0·84 [95% CI 0·69-1·01]; p=0·066); median time to confirmed motor progression in the prasinezumab group was 61·1 weeks (95% CI 52·3-71·9), compared with 49·7 weeks (40·1-58·1) in the placebo group. The incidence of one or more serious adverse events was similar between groups (prasinezumab, 34 [12%] of 292; placebo, 34 [12%] of 290) and three recorded deaths were unrelated to the study drug (prasinezumab, n=1 [<1%]; placebo, n=2 [1%]). INTERPRETATION: Although PADOVA did not meet the primary endpoint, prespecified exploratory evidence suggests clinical activity of prasinezumab in early-stage Parkinson's disease, supporting continued investigation in the ongoing phase 3 PARAISO trial (NCT07174310). FUNDING: F Hoffmann-La Roche.