The summaries are free for public
use. The Chronic Liver Disease
Foundation will continue to add and
archive summaries of articles deemed
relevant to CLDF by the Board of
Trustees and its Advisors.
Abstract Details
Trientine tetrahydrochloride versus penicillamine for maintenance therapy in Wilson disease (CHELATE): a randomised, open-label, non-inferiority, phase 3 trial
1Department of Medicine, Section of Digestive Diseases, and Department of Surgery, Section of Transplant and Immunology, Yale School of Medicine, New Haven, CT, USA. Electronic address: michael.schilsky@yale.edu.
22nd Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland.
3UO Medicina Generale Epatologia e Gastroenterologia Medica ASST Santi Paolo e Carlo, Milano, Italy.
4Department of Gastroenterology-Hepatology and Department of Chronic Diseases and Metabolism, University Hospitals, Leuven, Belgium.
5Hospital Nossa Senhora das Graças, Curitiba, Brazil.
6Département de Neurologie, Centre de Référence de la Maladie de Wilson, Hôpital Fondation Adolphe de Rothschild, Paris, France.
7Nucleo de Pesquisa e Desenvolvimento de Medicamentos, Universidade Federal do Ceará, Fortaleza, Brazil.
8Medizinische Klinik und Poliklinik II/Transplantation Center, LMU Klinikum, München, Germany.
9Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
10Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
11Leeds Teaching Hospitals NHS Trust, Leeds, UK.
12Department of Gastroenterology and Hepatology, Royal Surrey NHS Foundation Trust, Surrey, UK; Department of Clinical and Experimental Medicine, Faculty of Health and Medical Sciences, University of Surrey, Surrey, UK; Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, UK.
13UOC Gastroenterologia Azienda Ospedaliera di Padova, Padova, Italy.
14Hospices Civils de Lyon - Hôpital Femme Mère Enfant - Hépatologie, Gastroentérologie et Nutrition Pédiatrique, Centre de Référence de la Maladie de Wilson, Bron, France.
15IDDI, Ottignies-Louvain-La-Neuve, Belgium.
16Orphalan, Paris, France.
17Department of Internal Medicine, Salem Medical Center, Heidelberg, Germany.
Abstract
Background: Wilson disease is an inherited disorder of copper transport. Whereas penicillamine is used therapeutically to re-establish copper balance, trientine is indicated for patients with penicillamine intolerance. We aimed to compare penicillamine with trientine tetrahydrochloride (TETA4) for maintenance therapy in patients with Wilson disease.
Methods: We conducted a randomised, open-label, non-inferiority, phase 3 trial at 15 health-care centres across nine countries (patients were recruited from 13 of these health-care centres across Brazil, Europe, and the USA). We enrolled patients aged 18-75 years with stable Wilson disease who were treated for at least 1 year with penicillamine. Patients entered a 12-week period to determine stability through clinical assessment by site investigators and predefined thresholds for serum non-caeruloplasmin-bound copper (NCC; by an exchangeable copper assay; 25-150 μg/L), 24 h urinary copper excretion (100-900 μg/24 h), and alanine aminotransferase (ALT; <2 × upper limit of normal). Stable patients were randomly assigned (1:1) to continue receiving the maintenance twice daily dose of oral penicillamine or switched mg-for-mg to oral TETA4 centrally with a web-based system using minimisation. The primary endpoint, assessed 24 weeks after randomisation, was NCC by speciation assay. The non-inferiority margin of mean difference in NCC by speciation assay was -50 μg/L, as estimated by a general linear model for repeated visits, adjusted for baseline values. Further data on safety and efficacy were collected during a 24-week extension period. Data were analysed using an intention-to-treat approach. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03539952 (active, not recruiting).
Findings: Between June 4, 2018, and March 10, 2020, 77 patients were screened. 53 patients were randomly assigned (27 to the penicillamine group and 26 to the TETA4 group). After 24 weeks, the mean difference in serum NCC by speciation assay between the penicillamine group and TETA4 group was -9·1 μg/L (95% CI -24·2 to 6·1), with the lower limit of the 95% CI within the defined non-inferiority margin. At 24 weeks, urinary copper excretion was lower with TETA4 than with penicillamine (mean difference 237·5 μg/24 h (99% CI 115·6 to 359·4). At 48 weeks, TETA4 remained non-inferior to penicillamine in terms of NCC by speciation assay (mean difference NCC -15·5 μg/L [95% CI -34·5 to 3·6]). Urinary copper excretion at 48 weeks remained in the expected range for well treated patients in both study groups, and the mean difference (124·8 μg/24 h [99% CI -37·6 to 287·1]) was not significantly different. At 24 weeks and 48 weeks, masked clinical adjudication of stability assessed by three independent clinicians confirmed clinical stability (100%) of all participants, in agreement with the stability seen with the NCC by speciation assay. There were no notable changes in either the Clinical Global Impression of Change or Unified Wilson Disease Rating Scale (neurological assessment) from baseline (pre-randomisation) at weeks 24 and 48. The mean change in serum total copper from baseline to 24 weeks was 17·6 μg/L (99% CI -9·5 to 44·7) with penicillamine and -6·3 μg/L (-34·7 to 22·1) with TETA4, and the mean change in serum total caeruloplasmin from baseline to 24 weeks was 1·8 mg/L (-19·2 to 22·8) with penicillamine and -2·2 mg/L (-6·1 to 1·7) with TETA4. All liver enzymes were similar at 24 weeks and 48 weeks, with the exception of elevated ALT concentration at 48 weeks for patients in the TETA4 group. Penicillamine was associated with three post-randomisation serious adverse events (leukopenia, cholangiocarcinoma, and hepatocellular cancer); none were reported for TETA4. The most common treatment-emergent adverse events were headache for penicillamine (five [19%] of 27 patients vs two [8%] of 26) and abdominal pain for TETA4 (one [4%] vs four [15%]); all treatment-emergent adverse events resolved and were mild to moderate. One patient developed a rash with TETA4 that resolved on discontinuation of therapy.
Interpretation: The efficacy of TETA4 as oral maintenance therapy was non-inferior to penicillamine and well tolerated in adults with Wilson disease.
Stay Informed!
