Zibotentan Better Renal Scleroderma Outcome Study (ZEBRA)

A Phase II, Single Centre, Randomised, Placebo-controlled, 3-part Trial to Assess the Safety, Tolerability and Efficacy of Zibotentan in Patients With Renal Disease Secondary to Scleroderma

Many patients with scleroderma have damage to their kidneys caused by the disease. There is limited evidence for treatments to prevent this damage or stop it progressing. Blocking a substance in the blood called endothelin has helped treat some aspects of scleroderma. The purpose of this study is to see how effective a new endothelin blocker called Zibotentan is in treating patients who have scleroderma and have gone on to develop reduced kidney function as a complication. It will be given in addition to the accepted treatments used for scleroderma. There will be three parts to this study each for a different group of patients:

• ZEBRA 1 for patients with mild or moderate kidney disease caused by scleroderma
• ZEBRA 2A for patients with a more severe, acute form of kidney disease caused by scleroderma (scleroderma renal crisis) who do not require dialysis
• ZEBRA 2B for patients who have had scleroderma renal crisis and are on dialysis

Study Overview

• Status: Completed
• Conditions: Chronic Kidney Disease; Scleroderma; Scleroderma Renal Crisis
• Intervention / Treatment: Drug: Zibotentan

Detailed Description

This is a 3-part study (Zebra 1, 2A and 2B) that will explore safety and therapeutic potential of Zibotentan in acute and chronic renal complications of Scleroderma. Trial duration will be 52 weeks for Zebra 1 and 2A (1 or 2 weeks for ZEBRA 2B with 1 year follow up data). Scleroderma (Systemic sclerosis) is a multisystem rheumatic disease that results in vascular damage and fibrosis of target organs.This project will focus specifically on the evaluation and treatment of renal disease in scleroderma.

Renal involvement in Scleroderma occurs with a variety of different pathologies; hypertensive scleroderma renal crisis (SRC) being the most dramatic manifestation but milder forms of chronic renal disease are frequent and represent an important clinical feature.

• Study Type: Interventional
• Enrollment (Actual): 27
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, NW32QG
    • Royal Free London NHS Foundation Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Adults with scleroderma and:
2. CKD 2/3 (ZEBRA 1)
3. Renal crisis not on dialysis (ZEBRA 2A)
4. Renal crisis on dialysis (ZEBRA 2B)

Exclusion Criteria:

1. Previous use of an endothelin receptor antagonist within 3 months of the study start
2. Significant abnormalities in liver function testing (ALT, ALP, Bilirubin) more than three times upper limit of normal)
3. Patients with body weight <40kg.
4. Patients with conditions which prevent compliance with the protocol or failure to adhere to therapy.
5. Patients with any other life threatening condition.
6. Patients with known hypersensitivity to Zibotentan or its excipients
7. Previous history of epilepsy or other CNS AEs, neurologic symptoms or signs consistent with acute or evolving spinal cord compression, and CNS metastases
8. Patients with a baseline left ventricular ejection fraction < 40% (prior to any scleroderma renal crisis), patients with acute myocardial infarction within six months or patients who are judged by the trial clinician to be at unacceptable risk from cardiac complications.
9. History of chronic alcohol or drug abuse or any condition associated with poor compliance as judged by the investigator
10. Patients receiving cyclosporin A within 1 week of screening or expecting to receive this agent during the study.
11. Patients who have received an investigational agent in the month prior to screening. These patients may be eligible if after a month of washout period, they are still within 112 months of the onset of the Scleroderma renal crisis.
12. Active malignancy or neoplastic disease in the previous 12 months
13. Women who rely on oestrogencontaining contraceptives (due to potential drug interaction with Zibotentan).
14. Females who are pregnant or breastfeeding.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: Quadruple

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
sVCAM 1 soluble Vascular Cell Adhesion Molecule	sVCAM1 is a biomarker of renal involvement in scleroderma	12 months

Collaborators and Investigators

• Sponsor: University College, London
• Collaborators: Medical Research Council

Publications and helpful links

General Publications

• Stern EP, Host LV, Wanjiku I, Escott KJ, Gilmour PS, Ochiel R, Unwin R, Burns A, Ong VH, Cadiou H, O'Keeffe AG, Denton CP. Zibotentan in systemic sclerosis-associated chronic kidney disease: a phase II randomised placebo-controlled trial. Arthritis Res Ther. 2022 Jun 1;24(1):130. doi: 10.1186/s13075-022-02818-6.

Study record dates

Study Major Dates

• Study Start: October 1, 2014
• Primary Completion (Actual): October 1, 2017
• Study Completion (Actual): October 1, 2017

Study Registration Dates

• First Submitted: January 22, 2014
• First Submitted That Met QC Criteria: January 27, 2014
• First Posted (Estimate): January 28, 2014

Study Record Updates

• Last Update Posted (Actual): October 31, 2017
• Last Update Submitted That Met QC Criteria: October 30, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Urologic Diseases; Renal Insufficiency; Connective Tissue Diseases; Kidney Diseases; Renal Insufficiency, Chronic; Scleroderma, Systemic; Scleroderma, Diffuse; Scleroderma, Localized
• Other Study ID Numbers: 2013-003200-39