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Clinical Trial
. 2022 Jun 1;24(1):130.
doi: 10.1186/s13075-022-02818-6.

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

Edward P Stern  1 , Lauren V Host  1 , Ivy Wanjiku  1 , K Jane Escott  2 , Peter S Gilmour  2 , Rachel Ochiel  1 , Robert Unwin  1   3 , Aine Burns  1 , Voon H Ong  1 , Helen Cadiou  4 , Aidan G O'Keeffe  4   5 , Christopher P Denton  6   7
Affiliations
Clinical Trial

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

Edward P Stern et al. Arthritis Res Ther. .

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.

Keywords: Chronic kidney disease; Endothelin; Renal crisis; Scleroderma; Zibotentan.

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Conflict of interest statement

CD reports grants and personal fees from Acceleron, Janssen, Arxx Therapeutics, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galapagos, GlaxoSmithKline, Horizon, Roche, and Abbvie, all outside the submitted work. PG, KJE, and RU are employees of AstraZeneca. The other authors declare no competing interests.

Figures

Fig. 1
Fig. 1
CONSORT diagram showing flow of patients through the ZEBRA 1 sub-study. The diagram provides a summary of the flow of patients through the ZEBRA 1 sub-study including screened cases and 13 patients randomised
Fig. 2
Fig. 2
Representative primary and secondary endpoint data for ZEBRA 1 sub-study. A Endpoint data for serum VCAM-1 and eGFR in ZEBRA 1. Upper panels show the serum VCAM-1 levels at baseline, 26 weeks, and 52 weeks for the patients in placebo and zibotentan groups. Mean and SD are indicated. There was no apparent difference between treatment groups. The lower panel shows that eGFR (ml/min/1.73m2) decreased in the placebo arm and increased in the zibotentan arm at 52 weeks. B Candidate CKD-SSc urinary biomarker data for ZEBRA 1. Secondary endpoint data for candidate urinary biomarkers of SSc-CKD identified in a previous cohort study [8]. For urinary ICAM-1 to creatinine ratio, there is no difference between treatment groups or timepoints. For MCP-1 to creatinine ratio, the placebo group shows increasing level at 52 weeks compared to a numerical reduction for the zibotentan group although distribution of data is wide as shown by SD for each time point
Fig. 3
Fig. 3
Pharmacokinetic data following single oral dose zibotentan for patients in ZEBRA 2B. A Zibotentan blood plasma levels for all patients after 2.5 mg single oral dose. The upper panel shows the concentration of zibotentan (ng/ml) at 6 after a single oral dose of 2.5 mg zibotentan in six patients on haemodialysis. The final samples were taken pre- and post-dialysis to explore clearance of zibotentan. B Zibotentan blood plasma levels for patients receiving 5 mg single oral dose. Concentration of zibotentan (ng/ml) for the two patients that were re-dosed with 5 mg oral zibotentan is plotted against time with the final two samples being pre- and post-haemodialysis
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