Phase 1/2 Study of Lumasiran for Treatment of Primary Hyperoxaluria Type 1: A Placebo-Controlled Randomized Clinical Trial
| العنوان: | Phase 1/2 Study of Lumasiran for Treatment of Primary Hyperoxaluria Type 1: A Placebo-Controlled Randomized Clinical Trial |
|---|---|
| المؤلفون: | William van’t Hoff, David Erbe, Pierre Cochat, Daniella Magen, Patrick Haslett, Jaap W. Groothoff, Jiandong Lu, Yaacov Frishberg, Pushkal Garg, Georges Deschênes, Akshay Vaishnaw, Sandeep Talamudupula, Ulrike Lorch, Sally-Anne Hulton, Jérôme Harambat, Tracy L. McGregor, John C. Lieske, Dawn S. Milliner, Bahru A. Habtemariam |
| المساهمون: | Shaare Zedek Medical Center [Jerusalem, Israel], Hôpital Robert Debré, University of Amsterdam [Amsterdam] (UvA), Birmingham Women's and Children's NHS Foundation Trust, Ruth Children's Hospital [Haifa, Israel] (RCH), CHU Bordeaux [Bordeaux], Great Ormond Street Hospital for Children [London] (GOSH), Richmond Pharmacology Ltd [London, United Kingdom] (RP), Mayo Clinic [Rochester], Alnylam Pharmaceuticals [Cambridge, MA, USA], Hospices Civils de Lyon (HCL), Université de Lyon, study collaborators: Asela Bandara, Jonathan Bowen, Wei Li Chong, Simon Coates, Patrick De Barr, Janine De Beer, Juleen Gayed, Timothy Hill, Alex Kotak, Junko Ono, Jorg Taubel, Meera Thayalan, Robynne Wong, Christoph Coch, Martin Coenen, Markus Feldkotter, Nils Henning Heiland, Maximilian Hohenadel, Bernd Hoppe, Henriette Kyrieleis, Gesa Schalk, Lucy Cooper, Asheeta Gupta, David Milford, Mordi Muorah, Justine Bacchetta, Delphine Bernoux, Aurelia Bertholet-Thomas, Elodie Cheyssac, Aurelie Portefaix, Bruno Ranchin, Anne-Laure Sellier-Leclerc, Brigitte Llanas, Veronique Baudouin, Anne Couderc, Julien Hogan, Florentia Kaguelidou, Theresa Kwon, Anne Maisin, David Sas, Rachel Becker-Cohen, Efrat Ben-Shalom, Choni Rinat, Shimrit Tzvi Behr, Detlef Bockenhauer, Bshara Mansour, Shirley Pollack, Sander Garrelfs, Michiel Oosterveld, Shabbir Moochhala, Stephen Walsh, Lavanya Kamesh, Graham Lipkin, Admin, Oskar, Paediatric Nephrology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, ARD - Amsterdam Reproduction and Development |
| المصدر: | Clinical Journal of the American Society of Nephrology Clinical Journal of the American Society of Nephrology, American Society of Nephrology, 2021, pp.CJN.14730920. ⟨10.2215/cjn.14730920⟩ Clinical journal of the American Society of Nephrology, 16(7), 1025-1036. American Society of Nephrology Clin J Am Soc Nephrol |
| بيانات النشر: | HAL CCSD, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Male, Epidemiology, 030232 urology & nephrology, Renal Agents, Critical Care and Intensive Care Medicine, Gastroenterology, Oxalosis, law.invention, Primary hyperoxaluria, 0302 clinical medicine, Randomized controlled trial, law, Medicine, Single-Blind Method, RNA, Small Interfering, Child, Oxalates, 0303 health sciences, Plasma oxalate, 16. Peace & justice, 3. Good health, Nephrocalcinosis, Nephrology, Female, Adult, medicine.medical_specialty, Lumasiran, Adolescent, Urinary system, Kidney stones, Placebo, Young Adult, 03 medical and health sciences, Internal medicine, Primary hyperoxaluria type 1, Humans, Adverse effect, 030304 developmental biology, Transplantation, business.industry, Urinary oxalate, RNAi therapeutics, Original Articles, medicine.disease, Glycolates, Clinical trial, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, RNAi, Hyperoxaluria, Primary, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business |
| الوصف: | International audience; BACKGROUND AND OBJECTIVES: In the rare disease primary hyperoxaluria type 1, overproduction of oxalate by the liver causes kidney stones, nephrocalcinosis, kidney failure, and systemic oxalosis. Lumasiran, an RNA interference therapeutic, suppresses glycolate oxidase, reducing hepatic oxalate production. The objective of this first-in-human, randomized, placebo-controlled trial was to evaluate the safety, pharmacokinetic, and pharmacodynamic profiles of lumasiran in healthy participants and patients with primary hyperoxaluria type 1. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This phase 1/2 study was conducted in two parts. In part A, healthy adults randomized 3:1 received a single subcutaneous dose of lumasiran or placebo in ascending dose groups (0.3-6 mg/kg). In part B, patients with primary hyperoxaluria type 1 randomized 3:1 received up to three doses of lumasiran or placebo in cohorts of 1 or 3 mg/kg monthly or 3 mg/kg quarterly. Patients initially assigned to placebo crossed over to lumasiran on day 85. The primary outcome was incidence of adverse events. Secondary outcomes included pharmacokinetic and pharmacodynamic parameters, including measures of oxalate in patients with primary hyperoxaluria type 1. Data were analyzed using descriptive statistics. RESULTS: Thirty-two healthy participants and 20 adult and pediatric patients with primary hyperoxaluria type 1 were enrolled. Lumasiran had an acceptable safety profile, with no serious adverse events or study discontinuations attributed to treatment. In part A, increases in mean plasma glycolate concentration, a measure of target engagement, were observed in healthy participants. In part B, patients with primary hyperoxaluria type 1 had a mean maximal reduction from baseline of 75% across dosing cohorts in 24-hour urinary oxalate excretion. All patients achieved urinary oxalate levels ≤1.5 times the upper limit of normal. CONCLUSIONS: Lumasiran had an acceptable safety profile and reduced urinary oxalate excretion in all patients with primary hyperoxaluria type 1 to near-normal levels. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Study of Lumasiran in Healthy Adults and Patients with Primary Hyperoxaluria Type 1, NCT02706886. |
| اللغة: | English |
| تدمد: | 1555-9041 1555-905X |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1739805a88aa63ffcc6bf79348807932Test https://hal.archives-ouvertes.fr/hal-03279682Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....1739805a88aa63ffcc6bf79348807932 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15559041 1555905X |
|---|