Clinical Trial Results:
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
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Summary
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EudraCT number |
2013-003200-39 |
Trial protocol |
GB |
Global end of trial date |
19 Oct 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
05 Jul 2019
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First version publication date |
05 Jul 2019
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
13/0077
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02047708 | ||
WHO universal trial number (UTN) |
- | ||
Other trial identifiers |
IRAS number : 136274 | ||
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Sponsors
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Sponsor organisation name |
UCL
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Sponsor organisation address |
Joint Research Office , Gower Street , London , United Kingdom, WC1E 6BT
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Public contact |
Dr Edward Stern, UCL Joint Research office , +44 02073177544, e.stern@ucl.ac.uk
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Scientific contact |
Dr Edward Stern, UCL Joint Research office , +44 02073177544, e.stern@ucl.ac.uk
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
03 Jan 2019
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
19 Oct 2017
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Global end of trial reached? |
Yes
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Global end of trial date |
19 Oct 2017
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Was the trial ended prematurely? |
No
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General information about the trial
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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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Protection of trial subjects |
Zibotentan has been well tolerated but has been associated with minor side effects including headache, low blood pressure, nausea, vomiting and nasal congestion.These side effects were minimised by keeping within the dosage range as well as regular safety monitoring while on the study.
Participants with severe hepatic impairment were excluded as a clinical study detailed in the Zibotentan Investigator's Brochure indicated reduced clearance of Zibotentan in these patients.
Participants may experience some local discomfort whilst blood samples are taken. This may include pain,
inflammation, infection or a small bruise at the puncture site. The study doctor will follow up if any of these side effects occur.
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Background therapy |
Immunosuppressants such as mycophenolate, cyclophosphamide, and methotrexate are prescribed to manage disease symptoms as there is currently no approved medication. | ||
Evidence for comparator |
This is a phase II, single centre, randomised, placebo controlled, 3 part trial designed to evaluate the safety, tolerability and efficacy of Zibotentan in patients with renal disease secondary to scleroderma . As there is no approved drug for DcSSC, a placebo arm is the relevant comparator. | ||
Actual start date of recruitment |
03 Feb 2014
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 23
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Worldwide total number of subjects |
23
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EEA total number of subjects |
23
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
14
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From 65 to 84 years |
9
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85 years and over |
0
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Recruitment
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Recruitment details |
Recruitment window was 02/10/2014 to 02/02/2017 | |||||||||||||||
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Pre-assignment
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Screening details |
28 participants screened for trial. 5 were screening failures therefore 23 participants randomized. 1 participant withdrew. | |||||||||||||||
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Pre-assignment period milestones
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Number of subjects started |
23 | |||||||||||||||
Number of subjects completed |
23 | |||||||||||||||
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Period 1
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Period 1 title |
Overall Trial (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||
Roles blinded |
Subject, Investigator | |||||||||||||||
Blinding implementation details |
Zebra 1- Double blind
Zebra 2A- Single blind
Zebra 2B- Open label
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Active treatment | |||||||||||||||
Arm description |
Zibotentan 2.5, 5, 7.5, 10 mg od | |||||||||||||||
Arm type |
Experimental | |||||||||||||||
Investigational medicinal product name |
Zibotentan 2.5, 5, 7.5, 10 mg
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Zibotentan 2.5, 5, 7.5, 10 mg taken orally
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Arm title
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Placebo | |||||||||||||||
Arm description |
- | |||||||||||||||
Arm type |
Placebo | |||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
2.5, 5, 7.5, 10 mg taken orally
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Investigational medicinal product name |
Zibotentan 2.5, 5, 7.5, 10 mg
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Zibotentan 2.5, 5, 7.5, 10 mg taken orally
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Baseline characteristics reporting groups
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Reporting group title |
Active treatment
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Reporting group description |
Zibotentan 2.5, 5, 7.5, 10 mg od | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Zebra 1
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Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
A 1:1 randomised parallel group placebo-controlled, double-blind, single centre trial comparing Zibotentan 10 mg once daily orally (with possible dose reductions to a minimum dose of 5mg once daily) with matched placebo in Scleroderma patients with CKD2 and CKD3 (and GFR >45 ml/min) over 26 weeks with a 26 weeks follow up.
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Subject analysis set title |
Zebra 2A
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Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
A parallel group placebo-controlled, single blind, single centre trial comparing Zibotentan once daily orally over 26 weeks, with a 26 week follow up, with matched placebo using 2:1 (active:placebo) randomisation in patients within 1-12 months of SRC (Scleroderma Renal Crisis) not requiring ongoing dialysis. Individual patients will start at 2.5 mg once daily and following weekly monitoring will be dose escalated by 2.5 mg weekly to a maximum of 10 mg once daily over the course of the first 4 weeks.
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Subject analysis set title |
Zebra 2B
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Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
An open label single ascending dose administration pharmacokinetic study of Zibotentan 2.5 mg to 10 mg orally in patients requiring dialysis. Individual patients can receive up to two single doses of Zibotentan (at different dose levels).
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End points reporting groups
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Reporting group title |
Active treatment
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Reporting group description |
Zibotentan 2.5, 5, 7.5, 10 mg od | ||
Reporting group title |
Placebo
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Reporting group description |
- | ||
Subject analysis set title |
Zebra 1
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
A 1:1 randomised parallel group placebo-controlled, double-blind, single centre trial comparing Zibotentan 10 mg once daily orally (with possible dose reductions to a minimum dose of 5mg once daily) with matched placebo in Scleroderma patients with CKD2 and CKD3 (and GFR >45 ml/min) over 26 weeks with a 26 weeks follow up.
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Subject analysis set title |
Zebra 2A
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
A parallel group placebo-controlled, single blind, single centre trial comparing Zibotentan once daily orally over 26 weeks, with a 26 week follow up, with matched placebo using 2:1 (active:placebo) randomisation in patients within 1-12 months of SRC (Scleroderma Renal Crisis) not requiring ongoing dialysis. Individual patients will start at 2.5 mg once daily and following weekly monitoring will be dose escalated by 2.5 mg weekly to a maximum of 10 mg once daily over the course of the first 4 weeks.
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Subject analysis set title |
Zebra 2B
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
An open label single ascending dose administration pharmacokinetic study of Zibotentan 2.5 mg to 10 mg orally in patients requiring dialysis. Individual patients can receive up to two single doses of Zibotentan (at different dose levels).
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End point title |
sVCAM-1 serum level | ||||||||||||||||||
End point description |
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).
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End point type |
Primary
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End point timeframe |
26 weeks after baseline
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Statistical analysis title |
VCAM1 urine /creatinine | ||||||||||||||||||
Statistical analysis description |
Descriptive statistical analysis did not show any difference between active treatment and placebo
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Comparison groups |
Active treatment v Placebo
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Number of subjects included in analysis |
13
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||
P-value |
< 0.1 [1] | ||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||
Confidence interval |
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| Notes [1] - less than 0.1 |
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End point title |
Number and severity of adverse events Zebra 1 | ||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
24 weeks from baseline
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Statistical analysis title |
Number of AE's | ||||||||||||
Comparison groups |
Placebo v Active treatment
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Number of subjects included in analysis |
13
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Analysis specification |
Pre-specified
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Analysis type |
superiority [2] | ||||||||||||
P-value |
> 0.1 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Confidence interval |
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| Notes [2] - Descriptive analysis did not show significant difference at 24 weeks between treatment arms |
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End point title |
eGFR level Zebra 2A | ||||||||||||||||||
End point description |
The primary analysis will be to graphically evaluate GFR changes in the 26 weeks from baseline. This will be compared using eGFR as a continuous variable.
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End point type |
Primary
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End point timeframe |
26 weeks after baseline visit
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Statistical analysis title |
eGFR level | ||||||||||||||||||
Statistical analysis description |
Drug levels provide information about potential dosing in dialysis patients in any future study
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Comparison groups |
Active treatment v Placebo
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Number of subjects included in analysis |
3
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Analysis specification |
Pre-specified
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Analysis type |
superiority [3] | ||||||||||||||||||
P-value |
< 0.1 [4] | ||||||||||||||||||
Method |
ANCOVA | ||||||||||||||||||
Confidence interval |
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| Notes [3] - The primary analysis will be to graphically evaluate GFR changes in the 26 weeks from baseline. This will be compared using eGFR as a continuous variable. [4] - less than 0.1 |
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End point title |
Number and severity of adverse events Zebra 2A | ||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
24 weeks from baseline
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Statistical analysis title |
Number and severity of adverse events Zebra 2A | ||||||||||||
Comparison groups |
Active treatment v Placebo
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Number of subjects included in analysis |
4
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.1 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Confidence interval |
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Adverse events information
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Timeframe for reporting adverse events |
Baseline to end of study
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Adverse event reporting additional description |
Safety and tolerability of Zibotentan in CKD2/3 patients assessed by ECG, Physical examination, vital signs, haematology, clinical chemistry and Urinalysis. Study doctor also enquired about adverse events at every study visit between baseline and end of study.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
19
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Reporting groups
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Reporting group title |
Zebra 1
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Reporting group description |
1:1 randomised parallel group placebo-controlled, double-blind, single centre trial comparing Zibotentan 10 mg once daily orally (with possible dose reductions to a minimum dose of 5mg once daily) with matched placebo in Scleroderma patients with CKD2 and CKD3 (and GFR >45 ml/min) over 26 weeks with a 26 weeks follow up. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Zebra 2A
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Reporting group description |
A parallel group placebo-controlled, single blind, single centre trial comparing Zibotentan once daily orally over 26 weeks, with a 26 week follow up, with matched placebo using 2:1 (active:placebo) randomisation in patients within 1-12 months of SRC (Scleroderma Renal Crisis) not requiring ongoing dialysis. Individual patients will start at 2.5 mg once daily and following weekly monitoring will be dose escalated by 2.5 mg weekly to a maximum of 10 mg once daily over the course of the first 4 weeks | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Zebra 2B
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Reporting group description |
An open label single ascending dose administration pharmacokinetic study of Zibotentan 2.5 mg to 10 mg orally in patients requiring dialysis. Individual patients can receive up to two single doses of Zibotentan (at different dose levels). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 1% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | ||||||||||
Date |
Amendment |
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19 May 2014 |
1. All patients will have pre and treatment echocardiogram in all parts of the study. Patients in ZEBRA 1 and ZEBRA 2A will also have an end of treatment echocardiogram. Updated following MHRA review.
2. All patients will have NT pro-BNP measured as part of the panel of monthly safety bloods. Updated following MHRA review.
3. End of treatment (week 26) pharmacokinetics analysis is to be omitted from ZEBRA 1 and ZEBRA 2A. Additional PK testing at this stage would not have any safety value for study participants or add to the scientific quality of the study.
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06 Jul 2016 |
1. Update to the Investigator’s brochure (current version 15).
2. Minor changes to the layout of the Scleroderma Health assessment questionnaire.
3. Updates to the Protocol to reflect change in named statistician and contact details as well as update to sponsor's representative's contact details.
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07 Dec 2016 |
1. Changes to the inclusion criteria for the ZEBRA 2B sub-study, removing the requirement that patients have a diagnosis of scleroderma or scleroderma renal crisis.
2. At all study visits where a 24-hour urine collection was mandated, will be replaced by a spot urine sample for protein:creatinine ratio. It is well established in clinical practice that this measurement method is at least as accurate as 24-hour collection and it is much better tolerated by patients.
3. The visit schedules for all three studies contain an error that has persisted through earlier protocol versions: as described in the endpoints for these studies, the trial design requires experimental biomarkers to be collected at start of treatment visit (visit 1), end of treatment visit (26 weeks) and end of follow-up visit (52 weeks), but the protocol shows biomarker sample collection at all study visits. This error been corrected in the latest version. Only routine safety blood and urine samples will be collected at interim study visits.
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25 Jul 2017 |
1. The removal of follow up visits for Zebra 2B renal crisis patients which are not relevant for either safety or research outcomes as well as clarification on dose escalation.
2. Updated the information sheet and Protocol in line with the previously REC approved substantial amendment 5 i.e. the removal of Echocardiograms for 2B patients which is not relevant for non-Scleroderma patients.
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Interruptions (globally) |
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| Were there any global interruptions to the trial? Yes | ||||||||||
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Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | ||||||||||
| Challenging to recruit patients within the recruitment window due to limitations mentioned above. Recruitment target in the 2 arms of the study therefore not met. Statistical analysis plan updated accordingly. | ||||||||||
