Safety and efficacy of subcutaneous night-time only apomorphine infusion to treat insomnia in patients with Parkinson's disease (APOMORPHEE): a multicentre, randomised, controlled, double-blind crossover study.

BACKGROUND

Insomnia is a frequent complaint of patients with Parkinson's disease, and it negatively affects quality of life. Drugs that improve both sleep and parkinsonism would be of major benefit to patients with Parkinson's disease-related insomnia. We aimed to test the safety and efficacy of subcutaneous night-time only apomorphine infusion in patients with Parkinson's disease and insomnia.

METHODS

We did a randomised, multicentre, double-blind, placebo-controlled, crossover trial in 11 expert centres in Parkinson's disease and sleep centres in France. Participants aged 35-90 years with fluctuating Parkinson's disease and moderate to severe insomnia (Insomnia Severity Index score ≥15) were randomly assigned to either first receive night-time subcutaneous apomorphine (up to 5 mg/h) or matching placebo. Randomisation was done using a computer-generated plan in blocks of four, stratified by centre. This first intervention was followed by a 14-night washout period, then crossover to the other intervention. The treatment periods consisted of a 10-night titration phase followed by a 7-night fixed-dose phase. The dose was adjusted during the titration phase on the basis of a daily telephone call assessing sleep quality and treatment tolerability. The primary efficacy endpoint was the difference in Parkinson's disease sleep scale (PDSS) scores from the beginning to the end of each treatment period. Analysis was done on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, NCT02940912.

FINDINGS

Between Jan 31, 2017, and Jan 29, 2021, 46 participants were enrolled. 25 (54%) patients were randomly assigned to receive apomorphine first and 21 (46%) patients to receive placebo first. Mean change in PDSS score was significantly greater with night-time apomorphine infusion (15·18 [SD 24·34]) compared with placebo (5·23 [21·52]; treatment effect 9·95 [95% CI 0·88-19·03]; p=0·041). Adverse events were reported in 25 (54%) participants during the apomorphine period and in 17 (37%) participants during the placebo period (p=0·16). Apomorphine was associated with more frequent dizziness than was placebo (seven [15%] vs 0; p=0·041).

INTERPRETATION

Subcutaneous night-time only apomorphine infusion improved sleep disturbances according to difference on PDSS score, with an overall safety profile consistent with previous studies in Parkinson's disease. This treatment might be useful to manage sleep disturbances in patients with advanced Parkinson's disease and moderate to severe insomnia.

FUNDING

Orkyn and Aguettant Pharma.

TRANSLATION

For the French translation of the abstract see Supplementary Materials section.

Informations de copyright

Copyright © 2022 Elsevier Ltd. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests SLS has received travel grants from UCB Pharma. VCDC has served on a scientific advisory board for Jazz Pharma and received honoraria for speeches from Orkyn, Aguettant and LVL medical; received research support from Orkyn and Aguettant; and received travel grants from Orkyn and Aguettant. IA has received consultancy fees from IDORSIA Pharma, ONO Pharma, and Roche Pharma, and payment for a lecture by UCB Pharma. ER has served on scientific advisory boards for Orkyn, Aguettant, Merz-Pharma, and Allergan; received honoraria for speeches from Orkyn, Aguettant, Merz-Pharma, Everpharma, Elivie, and the International Parkinson and Movement Disorders Society; received research support from Merz-Pharma, Orkyn, Aguettant, Elivie, Ipsen, Allergan, Everpharma, Fondation Desmarest, AMADYS, Fonds de Dotation Brou de Laurière, ADCY5.org, Agence Nationale de la Recherche, and Societé Française de Médecine Esthétique; received travel grants from Vitalaire, PEPS development, Aguettant, Merz-Pharma, Ipsen, Merck, Orkyn, Elivie, Adelia Medical, Dystonia Medical Research Foundation, International Parkinson and Movement Disorders Society, European Academy of Neurology, and the International Association of Parkinsonism and Related Disorders. MA declares honoraria and travel grants from AbbVie, Teva, Merz, Orkyn, Aguettant, Actelion Pharmaceuticals, and Johnson and Johnson. PD has received support from UCB Pharma for attending a meeting, and speaker's honoraria from Roche. CA has received travel grants from Merz, and honoraria for presentations from Abbvie and Orkyn. LLV has received travel grants from UCB Pharma and Bioprojet. SD has received support for attending meetings from Aguettant, Orkyn, LVL, Homeperf, Elivie, and Boston Scientific; honoraria for presentations from Aguettant, Orkyn, LVL, Medtronic, Homeperf, Elivie, and Boston Scientific; and consulting fees from Aguettant, Orkyn, and Boston Scientific. DD has received consultancy fees for a scientific advisory board for Abbvie, Alterity, Orkyn, Air Liquide, Apopharma, Lundbeck, Everpharma, Boston Scientific, and the Cure Parkinson Trust; grants from the French Ministry of Health: projet hospitalier de recherche clinique grants; French Ministry of Research: ANR; European Preclinical Research: Coen; European Clinical Research: Horizon 2020, charities from France Parkinson, ARSLA Foundation; Foundations: University of Lille, CA; and has equity stake from InBrain Pharma; InVenis biotherapies. All other authors declare no competing interests.