E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Renal complications of systemic sclerosis (scleroderma renal crisis and chronic kidney disease). |
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E.1.1.1 | Medical condition in easily understood language |
Kidney disease in scleroderma |
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E.1.1.2 | Therapeutic area | Diseases [C] - Skin and Connective Tissue Diseases [C17] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10064848 |
E.1.2 | Term | Chronic kidney disease |
E.1.2 | System Organ Class | 100000004857 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061087 |
E.1.2 | Term | Connective tissue disorder |
E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10018124 |
E.1.2 | Term | Generalized scleroderma |
E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10069339 |
E.1.2 | Term | Acute kidney injury |
E.1.2 | System Organ Class | 100000004857 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The main objectives for this study is to see how safe Zibotentan is in patients with scleroderma and kidney damage and whether it has any effect on their kidney function |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives for this study are: •To test whether the zibotentan is safe in patients who have had scleroderma renal crisis (not requiring dialysis) in the last 12 months, and whether it improves their kidney function. (ZEBRA 2A) •To see how patients with scleroderma and kidney damage (not on dialysis) respond when they stop taking Zibotentan after 6 months of treatment. (ZEBRA 1 and 2A) •To explore how Zibotentan affects other new “biomarkers” of kidney damage in the blood and urine of patients in the study. To see how kidney damage from scleroderma affects blood levels of Zibotentan, compared with people with normal kidney function. •To test a single dose of Zibotentan in patients with severe kidney damage from scleroderma who are on dialysis and see how well it is tolerated, how safe it is and how blood levels of the drug differ from people with normal kidney function.
The exploratory objectives for this study are to discover new “biomarkers” of kidney damage in s |
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E.2.3 | Trial contains a sub-study | No |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Study consits of three parallel investigations Zebra 1,2a,2b as detailed above
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E.3 | Principal inclusion criteria |
Inclusion criteria (all substudies) 1)Patients with either diffuse or limited systemic sclerosis of any disease duration 2)Male or female age 18 or older. 3)Women must be either surgically sterilized or post-menopausal or use a highly effective method of birth control. 4)Females of childbearing potential and males must be willing to use one highly effective and one other method of contraception from the time consent is signed until 6 weeks after treatment discontinuation. 5)Females of childbearing potential must have a negative pregnancy test within 7 days prior to being registered for trial treatment. NOTE: Subjects are considered not of child bearing potential if they are surgically sterile (i.e. they have undergone a hysterectomy, bilateral tubal ligation, or bilateral ophorectomy) or they are postmenopausal. 6)Provision of signed and dated informed consent prior to any study specific procedures. Specific inclusion criteria for ZEBRA1 1)Patients with CKD2 or CKD3A, with GFR>45 mL/min WHO definitions for chronic kidney disease will be used in this study. Stage 2: mildly reduced kidney function AND already known to have some kidney damage or disease. People with an eGFR of 60-89 (inclusive) without any known kidney damage or disease are not considered to have CKD2/3. Stage 3: moderately reduced kidney function. (With or without a known kidney disease. For example, an elderly person with ageing kidneys may have reduced kidney function without a specific known kidney disease.) 45 mL/min to 59 mL/min (3A) 30 mL/min to 44 ml/min (3B) 2)Patients who have not had a renal crisis within the previous 12 months at Visit 0. Specific inclusion criteria for For ZEBRA 2A and B. 1)Patients who have experienced a Scleroderma renal crisis. Scleroderma renal crisis will be defined as follows, requiring both of: •A new onset of blood pressure >150/85 obtained at least twice over a consecutive 24 hour period. This blood pressure is chosen because it is that defined by the New York Heart Association as significant hypertension. •Decline in renal function as defined by an increase of at least 10% from a baseline serum creatinine measured within the previous 12 months. When possible a repeat serum creatinine should be obtained to corroborate the initial result. In order to corroborate further the occurrence of acute renal crisis, it would be desirable to have any of the following, if available: •Microangiopathic haemolytic anaemia on blood smear •Retinopathy typical of acute hypertensive crisis •New onset of urinary RBCs (excluding other causes) •Flash pulmonary oedema •Oliguria or anuria •Renal biopsy findings consistent with SRC . Specific inclusion criteria for ZEBRA2A Patients should have experienced an SRC within 1-12 months of the study start. Patients should not be receiving renal dialysis Specific inclusion criteria for ZEBRA2B Patients should be undergoing regular renal dialysis after experiencing an SRC – any form of dialysis is acceptable.
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E.4 | Principal exclusion criteria |
Exclusion criteria (all substudies) 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 after a month of washout period (as long as they are still within 1-12 months of the onset of the Scleroderma renal crisis for ZEBRA2A). 12.Active malignancy or neoplastic disease in the previous 12 months 13.Women who rely on oestrogen-containing contraceptives (due to potential drug interaction with Zibotentan). 14.Females who are pregnant or breastfeeding.
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E.5 End points |
E.5.1 | Primary end point(s) |
•To assess the tolerability, safety and effect of Zibotentan treatment over 6 months on renal biomarkers (sVCAM1) in patients with scleroderma associated with CKD2 and CKD3 (GFR>45 mL/min). (ZEBRA1) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Adverse Events (AEs) Electrocardiogram (ECG) Physical examination Haematology Clinical chemistry Urinalysis Vital signs sVCAM-1 |
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E.5.2 | Secondary end point(s) |
The secondary objectives for this study are: •To assess the tolerability, safety and effect of Zibotentan treatment over 6 months on renal function, (GFR) in patients who have experienced an SRC not requiring dialysis (ZEBRA2A) •To assess the efficacy of Zibotentan treatment over 6 months on disease outcome measures in patients with scleroderma associated with CKD2 and CKD3 (GFR>45ml/min) and in patients with scleroderma who have experienced a renal crisis within 1-12 months of the start of treatment not requiring dialysis. (ZEBRA1 and 2A only) •To assess response to Zibotentan withdrawal after 6 months treatment (ZEBRA1 and 2A only) •To explore the impact of Zibotentan on novel candidate biomarkers of renal involvement in patients with scleroderma. •To evaluate the effect of renal impairment in scleroderma on the PK of Zibotentan •To evaluate the effect of severe renal dysfunction and dialysis on the tolerability, safety and pharmacokinetic profile of a single dose of Zibotentan in patients with scleroderma (ZEBRA 2B only)
The exploratory objectives for this study are •To compare the biomarkers and clinical outcome measures between the patients in ZEBRA1 and ZEBRA2, and with other existing datasets (e.g. the BIRD1 dataset (Penn 2013) •Additional exploratory biomarkers relevant to renal disease and scleroderma may be measured and are to be defined based on an ongoing observational cross sectional study
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
As per CKD2/3 patients above Glomerular filtration rate at 6 and 12 months (assessed by eGFR or isotope GRF if clinically indicated) HAQ-DI with Scleroderma specific VAS Scleroderma Functional score SF-36 Physician and patient global disease activity score Digital ulcers will be counted and recorded and skin involvement assessed by modified Rodnan skin score Examination of proteinuria (tubular, glomerular), creatinine clearance and eGFR Maintenance anti-hypertensive therapy Mortality, frequency and duration of dialysis, at 6 and 12 months Blood pressure, ET1, eGFR, need for additional use of anti-hypertensive treatment and biomarkers at 1 and 4 weeks after stopping Zibotentan treatment. (Biomarkers at 4 weeks only) sVCAM-1 Serum Nt-pro-BNP VEGF, vWF, ET-1, creatinine, sIC
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | Yes |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |