Clinical Trial Results:
An open, prospective, single arm study investigating efficacy and safety of human hepatitis B immunoglobulin Zutectra in liver transplanted patients - the ZEUS Study
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Summary
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EudraCT number |
2012-002516-51 |
Trial protocol |
GB IT ES |
Global end of trial date |
24 Sep 2014
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Results information
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Results version number |
v1(current) |
This version publication date |
13 Dec 2021
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First version publication date |
13 Dec 2021
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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 |
987
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Biotest AG
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Sponsor organisation address |
Landsteinerstr. 5, Dreieich, Germany, 63303
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Public contact |
Vice President Corporate Clinical Research & Development, Biotest AG, 49 61038010, andrea.wartenberg-demand@biotest.com
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Scientific contact |
Vice President Corporate Clinical Research & Development, Biotest AG, 49 61038010, andrea.wartenberg-demand@biotest.com
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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 |
24 Sep 2014
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
24 Sep 2014
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Global end of trial reached? |
Yes
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Global end of trial date |
24 Sep 2014
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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 |
To investigate the efficacy and safety of Zutectra in orthotopic liver transplanted patients with the therapeutic goal to prevent hepatitis B virus re-infection in HBV-DNA negative patients ≥ one week after liver transplantation.
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Protection of trial subjects |
To facilitate home administration including patient compliance, patients or caregivers needed to be adequately trained by the investigator/site staff and appropriate control measures were to be performed during the study, i.e. regular checks of anti-HBs levels and of the documentation in the patient diary.
Patients or caregivers who complied with the injection technique and patients that presented sufficiently high ( > 100 IU/L ) trough serum HBs antibody concentrations at fixed dosage regimen could begin home administration after assessments in the transplantation unit during the 4 weeks following Orthotopic Liver Transplantation.
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Background therapy |
Concomitant medication other than immunoglobulins could be administered as medically required. The concomitant use of adequate virostatic agents was to be considered, if appropriate, as standard of hepatitis B re-infection prophylaxis. Virostatic agents were to be used according to the standard of care at each site. | ||
Evidence for comparator |
Not applicable | ||
Actual start date of recruitment |
15 Dec 2012
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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 |
Spain: 4
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Country: Number of subjects enrolled |
United Kingdom: 2
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Country: Number of subjects enrolled |
France: 2
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Country: Number of subjects enrolled |
Italy: 41
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Worldwide total number of subjects |
49
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EEA total number of subjects |
49
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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) |
46
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From 65 to 84 years |
3
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85 years and over |
0
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Recruitment
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Recruitment details |
The recruitment period (Informed consent initial date) lasted from 15DEC2012 to 01APR2014. Seventeen out of 18 initiated sites in Spain, France, United Kingdom and Italy recruited 75 patients by signing the informed consent form. Of these, 56 patients were screened and 49 patients were eligible for study treatment. | ||||||||||||
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Pre-assignment
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Screening details |
Included were male and female adult patients with hepatitis B infection requiring liver transplantation ≥ one week after OLT (also re-transplantation) with undetectable HBV-DNA at time point of informed consent (IC) signature and at OLT, being HBsAg negative at pre-dose, and showing serum HBs antibody concentration ≥ 400 IU/L at pre-dose. | ||||||||||||
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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 |
Not applicable
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Blinding used |
Not blinded | ||||||||||||
Blinding implementation details |
Not applicable
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Arms
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Arm title
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Zutectra | ||||||||||||
Arm description |
Subcutaneous injections of human hepatitis B immunoglobulin Zutectra | ||||||||||||
Arm type |
Experimental | ||||||||||||
Investigational medicinal product name |
Zutectra
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Investigational medicinal product code |
BT088
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Other name |
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Pharmaceutical forms |
Solution for injection in pre-filled syringe
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Subcutaneous injections of 500 IU (1mL) or 1,000 IU (2mL) Zutectra were administered weekly or fortnightly until 24 weeks after transplantation, according to the serum anti-HBs concentrations and at the discretion of the physician in charge according to local practice to maintain antibody levels above 100 - 150 IU/L.
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Baseline characteristics reporting groups
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Reporting group title |
overall trial
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Safety Set
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Subject analysis set type |
Safety analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
All patients who received the study medication at least once
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Subject analysis set title |
Full-Analysis Set
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Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
All patients who received at least one dose of study medication and had at least one post dose efficacy assessment
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Subject analysis set title |
Per-Protocol Set
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Subject analysis set type |
Per protocol | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
All patients of the FAS who completed the whole study period until assessment of treatment failure or Closing Visit (whichever comes first) without major protocol deviations
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End points reporting groups
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Reporting group title |
Zutectra
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Reporting group description |
Subcutaneous injections of human hepatitis B immunoglobulin Zutectra | ||
Subject analysis set title |
Safety Set
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
All patients who received the study medication at least once
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Subject analysis set title |
Full-Analysis Set
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
All patients who received at least one dose of study medication and had at least one post dose efficacy assessment
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Subject analysis set title |
Per-Protocol Set
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
All patients of the FAS who completed the whole study period until assessment of treatment failure or Closing Visit (whichever comes first) without major protocol deviations
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End point title |
Treatment Failure | |||||||||
End point description |
The definition of treatment failure (primary efficacy variable) is based on any trough
level of serum anti-HBs ≤ 100 IU/L and/or diagnosed hepatitis B related re-infection in
patients with trough levels of serum anti-HBs > 100 IU/L during the period between first
study drug administration and end of study.
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End point type |
Primary
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End point timeframe |
Period between first study drug administration and end of study.
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Statistical analysis title |
Treatment Failure | |||||||||
Statistical analysis description |
A two-sided 95% confidence interval (using the Clopper-Pearson method) was
calculated for the primary efficacy variable as well as for its components. The time to
failure from Day 0 = Day of OLT was to be analyzed for the combined endpoint and its
components using survival time methods (Kaplan-Meier).
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Comparison groups |
Zutectra v Full-Analysis Set
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Number of subjects included in analysis |
98
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Analysis specification |
Pre-specified
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Analysis type |
superiority [1] | |||||||||
P-value |
< 0.169 [2] | |||||||||
Method |
Compared to upper CL of CI | |||||||||
Parameter type |
rate | |||||||||
Point estimate |
0
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Confidence interval |
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level |
95% | |||||||||
sides |
1-sided
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lower limit |
- | |||||||||
upper limit |
0.0725 | |||||||||
| Notes [1] - The 95% confidence interval should be below the upper confidence limit (CL) of a 5% failure rate, which would result in a upper CL of 16.9%. [2] - No P-value was calculated; compared to upper limit of confidence interval |
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End point title |
Hepatitis B related Infections | ||||||
End point description |
The number of all patients with hepatitis B related infection.
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End point type |
Secondary
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End point timeframe |
Period between first study drug administration and end of study.
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| No statistical analyses for this end point | |||||||
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Adverse events information
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Timeframe for reporting adverse events |
During active treatment phase, from first dose until closing visit.
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Adverse event reporting additional description |
Patients were asked about adverse events (AEs) that occurred during the SC Zutectra injection or since the last visit. Patients kept a diary to document any discomfort during the course of the trial which was reviewed regularly. Treatment emergent AEs are AEs not present at baseline or present at baseline, but worsening during the treatment period.
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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 |
16.0
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Reporting groups
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Reporting group title |
Zutectra
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Reporting group description |
Subcutaneous injections of human hepatitis B immunoglobulin Zutectra | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 4.1% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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28 Feb 2013 |
Amendment No. 1 of 28 February 2013 was implemented to clarify inclusion and exclusion criteria, expand the time window for study visits, increase the number of participating countries and sites, correct minor mistakes in the study flowchart and protocol, and adapt the definition of AEs/IRAEs.
Main changes were:
• The study population could also include hepatocellular carcinoma patients with
hepatitis B requiring liver transplantation. Such patients are not always viewed as
having liver failure
• The time-window for the pre-dose assessment, the start of Zutectra study treatment,
and treatment days was extended to allow increased flexibility in study visit
arrangements
• To improve recruitment into the study, additional centers were included, including
centers in Spain |
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03 Apr 2014 |
Amendment No. 2 of 03 April 2014 was implemented to prolong the study duration, decrease the required patient number, adapt inclusion criterion 2, update information on completed studies with Zutectra, change AE reporting requirements before start of treatment with study drug, and introduce some clarifications and administrative changes.
Main changes were:
• The number of evaluable patients (ITT population) required was decreased to 40
• The study duration was extended due to slow patient recruitment
• The time-window for the historical HBV-DNA test required by inclusion criterion 2
was extended to reflect the common practice
• To change reporting requirements for AEs before start of treatment with IMP
• To change reporting requirements for study procedure related AEs
• To delete chloride assessment from the safety parameters
• Updated information on studies 974 and 978 |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
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. | |||
| None reported | |||
