PMID- 35429481 OWN - NLM STAT- MEDLINE DCOM- 20220419 LR - 20220531 IS - 1474-4465 (Electronic) IS - 1474-4422 (Linking) VI - 21 IP - 5 DP - 2022 May TI - 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. PG - 428-437 LID - S1474-4422(22)00085-0 [pii] LID - 10.1016/S1474-4422(22)00085-0 [doi] AB - 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. CI - Copyright (c) 2022 Elsevier Ltd. All rights reserved. FAU - De Cock, Valerie Cochen AU - De Cock VC AD - Sleep and Neurology Department, Beau Soleil Clinic and EuroMov, Digital Health in Motion, University of Montpellier, Montpellier, France. Electronic address: valerie.cochen@gmail.com. FAU - Dodet, Pauline AU - Dodet P AD - Sleep Disorders Unit, Pitie-Salpetriere University Hospital, Paris, France. FAU - Leu-Semenescu, Smaranda AU - Leu-Semenescu S AD - Sleep Disorders Unit, Pitie-Salpetriere University Hospital, Paris, France. FAU - Aerts, Cecile AU - Aerts C AD - Sleep and Neurology Department, Beau Soleil Clinic and EuroMov, Digital Health in Motion, University of Montpellier, Montpellier, France. FAU - Castelnovo, Giovanni AU - Castelnovo G AD - Department of Neurology, University Hospital of Nimes, Nimes, France. FAU - Abril, Beatriz AU - Abril B AD - Sleep Department, University Hospital of Nimes, Nimes, France. FAU - Drapier, Sophie AU - Drapier S AD - Department of Neurology, Pontchaillou University Hospital, Universite de Rennes 1, Rennes, France. FAU - Olivet, Helene AU - Olivet H AD - Sleep Department, Polyclinique Rennes Saint-Laurent, Rennes, France. FAU - Corbille, Anne-Gaelle AU - Corbille AG AD - University Hospital of Nantes, INSERM, CIC1413, Nantes, France. FAU - Leclair-Visonneau, Laurene AU - Leclair-Visonneau L AD - Clinical Neurophysiology Department, INSERM, CIC1413, Nantes, France. FAU - Sallansonnet-Froment, Magali AU - Sallansonnet-Froment M AD - Hopital d'Instruction des Armees Percy, Clamart, France. FAU - Lebouteux, Marie AU - Lebouteux M AD - Hopital d'Instruction des Armees Percy, Clamart, France. FAU - Anheim, Mathieu AU - Anheim M AD - Department of Neurology, University Hospital of Strasbourg, Strasbourg, France; Genetic Institute and Molecular and Cellular Biology (IGBMC), INSERM-U964/CNRS-UMR7104 Strasbourg University, Illkirch, France. FAU - Ruppert, Elisabeth AU - Ruppert E AD - Federation of Translational Medicine of Strasbourg (FMTS), Strasbourg University, Strasbourg, France. FAU - Vitello, Nicolas AU - Vitello N AD - Sleep Department, Pergola Clinic, Vichy, France. FAU - Eusebio, Alexandre AU - Eusebio A AD - APHM, CHU Timone, Department of Neurology and Movement Disorders, and Aix-Marseille Universite, CNRS, INT, Institute of Neuroscience, Timone, Marseille, France. FAU - Lambert, Isabelle AU - Lambert I AD - Sleep Unit, Epileptology Department, Timone Hospital, Marseille, France. FAU - Marques, Ana AU - Marques A AD - EA 7280, UFR Medicine, University of Clermont Auvergne, Clermont-Ferrand, France; Neurology Department, CHU, and INP, Institut Pascal, Clermont-Ferrand France. FAU - Fantini, Maria Livia AU - Fantini ML AD - EA 7280, UFR Medicine, University of Clermont Auvergne, Clermont-Ferrand, France; Neurology Department, CHU, and INP, Institut Pascal, Clermont-Ferrand France. FAU - Devos, David AU - Devos D AD - University of Lille, INSERM, CHU Lille, LilNCog, Lille Neuroscience and Cognition, INSERM, UMR-S1172, Lille, France. FAU - Monaca, Christelle AU - Monaca C AD - University of Lille, INSERM, CHU Lille, LilNCog, Lille Neuroscience and Cognition, INSERM, UMR-S1172, Lille, France. FAU - Benard-Serre, Nicolas AU - Benard-Serre N AD - Department of Epidemiology and Biostatistics, Beau Soleil Clinic, Montpellier, France. FAU - Lacombe, Sandy AU - Lacombe S AD - Department of Epidemiology and Biostatistics, Beau Soleil Clinic, Montpellier, France. FAU - Vidailhet, Marie AU - Vidailhet M AD - AP-HP, Salpetriere Hospital, DMU Neuroscience 6, Paris, France; Sorbonne University, Paris Brain Institute, INSERM, CNRS, Paris, France. FAU - Arnulf, Isabelle AU - Arnulf I AD - Sleep Disorders Unit, Pitie-Salpetriere University Hospital, Paris, France; Sorbonne University, Paris Brain Institute, INSERM, CNRS, Paris, France. FAU - Doulazmi, Mohamed AU - Doulazmi M AD - Adaptation Biologique et Vieillissement (UMR8256), Institut de Biologie Paris Seine, Sorbonne University, CNRS, Paris France. FAU - Roze, Emmanuel AU - Roze E AD - AP-HP, Salpetriere Hospital, DMU Neuroscience 6, Paris, France; Sorbonne University, Paris Brain Institute, INSERM, CNRS, Paris, France. LA - eng SI - ClinicalTrials.gov/NCT02940912 PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PL - England TA - Lancet Neurol JT - The Lancet. Neurology JID - 101139309 RN - N21FAR7B4S (Apomorphine) SB - IM CIN - Lancet Neurol. 2022 May;21(5):395-398. PMID: 35429469 MH - Adult MH - Aged MH - Aged, 80 and over MH - Apomorphine/adverse effects MH - Cross-Over Studies MH - Double-Blind Method MH - Humans MH - Middle Aged MH - *Parkinson Disease/complications/drug therapy MH - Quality of Life MH - *Sleep Initiation and Maintenance Disorders/drug therapy/etiology MH - *Sleep Wake Disorders MH - Treatment Outcome COIS- 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 Lauriere, ADCY5.org, Agence Nationale de la Recherche, and Societe Francaise de Medecine Esthetique; 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. EDAT- 2022/04/17 06:00 MHDA- 2022/04/20 06:00 CRDT- 2022/04/16 20:09 PHST- 2021/11/10 00:00 [received] PHST- 2022/02/15 00:00 [revised] PHST- 2022/02/21 00:00 [accepted] PHST- 2022/04/16 20:09 [entrez] PHST- 2022/04/17 06:00 [pubmed] PHST- 2022/04/20 06:00 [medline] AID - S1474-4422(22)00085-0 [pii] AID - 10.1016/S1474-4422(22)00085-0 [doi] PST - ppublish SO - Lancet Neurol. 2022 May;21(5):428-437. doi: 10.1016/S1474-4422(22)00085-0.