Zibotentan in systemic sclerosis-associated chronic kidney disease: a phase II randomised placebo-controlled trial

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Abstract

Background

We report results from a phase II randomised placebo-controlled trial assessing zibotentan, a highly selective endothelin receptor antagonist (ERA), in chronic kidney disease (CKD) secondary to systemic sclerosis (SSc).

Methods

This trial included three sub-studies: ZEBRA 1—a randomised placebo-controlled, double-blind trial of zibotentan in SSc patients with CKD2 or CKD3 (and glomerular filtration rate (GFR) >45 ml/min) over 26 weeks; ZEBRA 2A—a 26-week placebo-controlled, single-blind trial of zibotentan in scleroderma renal crisis patients not requiring dialysis; and ZEBRA 2B—an open label pharmacokinetic study of zibotentan in patients on haemodialysis.

Results

Sixteen patients were screened for ZEBRA 1. Of these, 6 patients were randomised to zibotentan and 7 to placebo. In ZEBRA 1, there were 47 non-serious adverse events (AE) during the trial. Twenty-seven occurred in the placebo group and 20 in the zibotentan group. One serious adverse event (SAE) occurred during ZEBRA1, in the placebo arm. Descriptive statistics did not suggest an effect of study drug on serum sVCAM1. Estimated GFR numerically declined in patients treated with placebo at 26 weeks and 52 weeks. In contrast, average eGFR increased in zibotentan-treated cases.

The 4 patients in ZEBRA 2A experienced 8 non-serious AEs, distributed equally between placebo and zibotentan. There was one SAE each in placebo and zibotentan groups, both unrelated to study medication.

ZEBRA 2B recruited 8 patients, 6 completed first dosing, and 2 completed a second dosing visit. Pharmacokinetic analysis confirmed zibotentan levels within the therapeutic range. Three patients experienced 3 non-serious AEs. One SAE occurred and was unrelated to study drug.

Conclusions

Zibotentan was generally well-tolerated. ZEBRA 1 did not show any effect of zibotentan on serum sVCAM-1 but was associated with numerical improvement in eGFR at 26 weeks that was more marked at 52 weeks. ZEBRA 2B suggested a feasible dose regimen for haemodialysis patients.

Trial registration

EudraCT no: 2013-003200-39 (first posted January 28, 2014)

ClinicalTrials.gov Identifier: NCT02047708

Sponsor protocol number: 13/0077

Related collections

Most cited references 26

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Systemic sclerosis.

Christopher P. Denton, Dinesh Khanna (2017)

Systemic sclerosis, also called scleroderma, is an immune-mediated rheumatic disease that is characterised by fibrosis of the skin and internal organs and vasculopathy. Although systemic sclerosis is uncommon, it has a high morbidity and mortality. Improved understanding of systemic sclerosis has allowed better management of the disease, including improved classification and more systematic assessment and follow-up. Additionally, treatments for specific complications have emerged and a growing evidence base supports the use of immune suppression for the treatment of skin and lung fibrosis. Some manifestations of the disease, such as scleroderma renal crisis, pulmonary arterial hypertension, digital ulceration, and gastro-oesophageal reflux, are now treatable. However, the burden of non-lethal complications associated with systemic sclerosis is substantial and is likely to become more of a challenge. Here, we review the clinical features of systemic sclerosis and describe the best practice approaches for its management. Furthermore, we identify future areas for development.

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Causes and risk factors for death in systemic sclerosis: a study from the EULAR Scleroderma Trials and Research (EUSTAR) database.

Gabriele Valentini, Ulf Müller-Ladner, P Peña … (2010)

To determine the causes and predictors of mortality in systemic sclerosis (SSc). Patients with SSc (n=5860) fulfilling the American College of Rheumatology criteria and prospectively followed in the EULAR Scleroderma Trials and Research (EUSTAR) cohort were analysed. EUSTAR centres completed a structured questionnaire on cause of death and comorbidities. Kaplan-Meier and Cox proportional hazards models were used to analyse survival in SSc subgroups and to identify predictors of mortality. Questionnaires were obtained on 234 of 284 fatalities. 55% of deaths were attributed directly to SSc and 41% to non-SSc causes; in 4% the cause of death was not assigned. Of the SSc-related deaths, 35% were attributed to pulmonary fibrosis, 26% to pulmonary arterial hypertension (PAH) and 26% to cardiac causes (mainly heart failure and arrhythmias). Among the non-SSc-related causes, infections (33%) and malignancies (31%) were followed by cardiovascular causes (29%). Of the non-SSc-related fatalities, 25% died of causes in which SSc-related complications may have participated (pneumonia, sepsis and gastrointestinal haemorrhage). Independent risk factors for mortality and their HR were: proteinuria (HR 3.34), the presence of PAH based on echocardiography (HR 2.02), pulmonary restriction (forced vital capacity below 80% of normal, HR 1.64), dyspnoea above New York Heart Association class II (HR 1.61), diffusing capacity of the lung (HR 1.20 per 10% decrease), patient age at onset of Raynaud's phenomenon (HR 1.30 per 10 years) and the modified Rodnan skin score (HR 1.20 per 10 score points). Disease-related causes, in particular pulmonary fibrosis, PAH and cardiac causes, accounted for the majority of deaths in SSc.

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Macitentan and morbidity and mortality in pulmonary arterial hypertension.

Tomás Pulido, Igor Adzerikho, Richard N Channick … (2013)

Current therapies for pulmonary arterial hypertension have been adopted on the basis of short-term trials with exercise capacity as the primary end point. We assessed the efficacy of macitentan, a new dual endothelin-receptor antagonist, using a primary end point of morbidity and mortality in a long-term trial. We randomly assigned patients with symptomatic pulmonary arterial hypertension to receive placebo once daily, macitentan at a once-daily dose of 3 mg, or macitentan at a once-daily dose of 10 mg. Stable use of oral or inhaled therapy for pulmonary arterial hypertension, other than endothelin-receptor antagonists, was allowed at study entry. The primary end point was the time from the initiation of treatment to the first occurrence of a composite end point of death, atrial septostomy, lung transplantation, initiation of treatment with intravenous or subcutaneous prostanoids, or worsening of pulmonary arterial hypertension. A total of 250 patients were randomly assigned to placebo, 250 to the 3-mg macitentan dose, and 242 to the 10-mg macitentan dose. The primary end point occurred in 46.4%, 38.0%, and 31.4% of the patients in these groups, respectively. The hazard ratio for the 3-mg macitentan dose as compared with placebo was 0.70 (97.5% confidence interval [CI], 0.52 to 0.96; P=0.01), and the hazard ratio for the 10-mg macitentan dose as compared with placebo was 0.55 (97.5% CI, 0.39 to 0.76; P<0.001). Worsening of pulmonary arterial hypertension was the most frequent primary end-point event. The effect of macitentan on this end point was observed regardless of whether the patient was receiving therapy for pulmonary arterial hypertension at baseline. Adverse events more frequently associated with macitentan than with placebo were headache, nasopharyngitis, and anemia. Macitentan significantly reduced morbidity and mortality among patients with pulmonary arterial hypertension in this event-driven study. (Funded by Actelion Pharmaceuticals; SERAPHIN ClinicalTrials.gov number, NCT00660179.).

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Author and article information

Contributors

Christopher P. Denton: c.denton@ucl.ac.uk

Journal

Journal ID (nlm-ta): Arthritis Res Ther

Journal ID (iso-abbrev): Arthritis Res Ther

Title: Arthritis Research & Therapy

Publisher: BioMed Central (London )

ISSN (Print): 1478-6354

ISSN (Electronic): 1478-6362

Publication date (Electronic): 1 June 2022

Publication date PMC-release: 1 June 2022

Publication date (Print): 2022

Volume: 24

Electronic Location Identifier: 130

Affiliations

[1 ]GRID grid.83440.3b, ISNI 0000000121901201, Division of Medicine, , University College London, Royal Free Campus, ; London, UK

[2 ]GRID grid.417815.e, ISNI 0000 0004 5929 4381, Emerging Innovations Unit, , BioPharmaceuticals R&D, AstraZeneca, ; Cambridge, UK

[3 ]GRID grid.417815.e, ISNI 0000 0004 5929 4381, Early Clinical Development, Cardiovascular, Renal & Metabolism, , BioPharmaceuticals R&D, AstraZeneca, ; Cambridge, UK

[4 ]GRID grid.83440.3b, ISNI 0000000121901201, Joint Research Office, , University College London, ; London, UK

[5 ]GRID grid.4563.4, ISNI 0000 0004 1936 8868, School of Mathematical Sciences, , University of Nottingham, ; Nottingham, UK

[6 ]GRID grid.83440.3b, ISNI 0000000121901201, UCL Centre for Rheumatology and Connective Tissue Diseases, ; 2nd Floor – UCL Medical School Building, Royal Free Campus, Rowland Hill Street, London, NW3 2PF UK

Article

Publisher ID: 2818

DOI: 10.1186/s13075-022-02818-6

PMC ID: 9158153

PubMed ID: 35650639

SO-VID: bf567cc6-de08-486d-8c12-47ba47be4be8

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 7 April 2022

Date accepted : 21 May 2022

Custom metadata

ScienceOpen disciplines: Orthopedics

Keywords: scleroderma,renal crisis,chronic kidney disease,endothelin,zibotentan

Data availability:

ScienceOpen disciplines: Orthopedics

Keywords: scleroderma, renal crisis, chronic kidney disease, endothelin, zibotentan

Zibotentan in systemic sclerosis-associated chronic kidney disease: a phase II randomised placebo-controlled trial

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Abstract

Background

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Results

Conclusions

Trial registration

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UCL: UN SDG 03 Good Health and Well-Being

Most cited references 26

Systemic sclerosis.

Causes and risk factors for death in systemic sclerosis: a study from the EULAR Scleroderma Trials and Research (EUSTAR) database.

Macitentan and morbidity and mortality in pulmonary arterial hypertension.

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