Clinical Trial Results:
Single centre, open-label, randomized, controlled, cross over study to evaluate the pharmacokinetic and bioavailability of Envarsus® in comparison to Advagraf® in de novo liver transplant recipients
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Summary
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EudraCT number |
2015-002935-16 |
Trial protocol |
DE |
Global end of trial date |
01 Apr 2019
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Results information
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Results version number |
v1(current) |
This version publication date |
13 Nov 2020
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First version publication date |
13 Nov 2020
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Other versions |
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Summary report(s) |
PAKT CSR Synopsis 2020_04_07 |
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 |
PAKT CTC 151043
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03241043 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
University Medical Center Hamburg-Eppendorf (UKE)
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Sponsor organisation address |
Martinistr. 52, Hamburg, Germany, 20246
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Public contact |
Study Coordinator, University Medical Center Hamburg-Eppendorf, Department of Visceral Transplant Surgery, 0049 40741056640, transplant-studien@uke.de
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Scientific contact |
Study Coordinator, University Medical Center Hamburg-Eppendorf, Department of Visceral Transplant Surgery, 0049 40741056640, transplant-studien@uke.de
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Sponsor organisation name |
University Medical Center Hamburg-Eppendorf
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Sponsor organisation address |
Martinistr. 52, Hamburg, Germany, 20246
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Public contact |
Prof. Dr. med. Uta Herden, University Medical Center Hamburg-Eppendorf, 040 741050822, uta.herden@uke.de
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Scientific contact |
Prof. Dr. med. Uta Herden, University Medical Center Hamburg-Eppendorf, 040 741050822, uta.herden@uke.de
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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 |
17 Mar 2020
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
01 Apr 2019
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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 assess the equivalent dose of Envarsus® to achieve the same target trough level as achieved with Advagraf and to assess the conversion ratios Envarsus® ↔ Advagraf®.
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Protection of trial subjects |
All patients included in the clinical trial underwent previous liver transplantation and required an immunosuppressive therapy normally based on a calcineurine inhibitor e.g. tacrolimus. Both IMPs (Envarsus® and Advagraf®) contained tacrolimus as active substance and were approved and have been used ac-cording to marketing authorization. Based on available information and the design of the clinical trial, the Sponsor and the PI considerd the trial to be ethically acceptable. The duration of confinement and the medical surveillance during the whole trial, especially at the points of treatment switch, were considered adequate to ensure safety of the patients.
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Background therapy |
Induction therapy with Simulect® (Basiliximab); treatment with corticosteroids according to center practice; combined immunosuppressive therapy with an mTOR-inhibitor (everolimus/sirolimus) or combined immunosuppressive therapy with mycophenolate mofetil was allowed prior to randomisation, but had to be stopped during Envarsus®/Advagraf® treatment period. | ||
Evidence for comparator |
A cross-over design is the most powerful design for a bioavailability and pharmacokinetic clinical trial because it removes the inter-subject variability from the comparison of the average bioavailability and pharmacokinetic profiles between the formulations and allows for the adjustment of period effects. In this design, each patient functioned as his own control when comparisons between different treatments/ medications were realized between the two subsequent treatment periods exclusively as opposed to comparisons in different patients. | ||
Actual start date of recruitment |
31 Aug 2016
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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 |
Germany: 20
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Worldwide total number of subjects |
20
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EEA total number of subjects |
20
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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) |
18
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From 65 to 84 years |
2
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85 years and over |
0
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Recruitment
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Recruitment details |
First patient first visit (FPFV) was performed 31-Aug-2016. In total, 20 de novo liver transplant recipients have been enrolled. The patients have been recruited from the involved medical center, University Medical Center Hamburg-Eppendorf (UKE), Department for Hepatobiliary and Transplant Surgery, Germany. | ||||||||||||||||||
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Pre-assignment
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Screening details |
Selection of study population: de novo liver transplant recipients. 20 patients were screened and randomized in treatment group 1 or 2 between liver transplantation (Ltx) and postoperative day (pod) 30 after Ltx. | ||||||||||||||||||
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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 |
Not blinded | ||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Group 1: Envarsus® -> Advagraf® | ||||||||||||||||||
Arm description |
Two treatments have been investigated, separated without a wash-out period. Group 1: Envarsus® -> Advagraf®. After randomization the previous tacrolimus medication was stopped and Envarsus® therapy was started the same morning. Therapy was given for 14 days plus eventually a longer interval in case the target level has not been reached in time. On Visit 7 (day 15 + n) therapy was switched to Advagraf® for further 14 days plus eventually a longer interval in case of not reaching the target level in a specified timeframe. | ||||||||||||||||||
Arm type |
cross over | ||||||||||||||||||
Investigational medicinal product name |
Envarsus®
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Investigational medicinal product code |
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Other name |
Tacrolimus
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Pharmaceutical forms |
Prolonged-release tablet
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Routes of administration |
Oral use
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Dosage and administration details |
The Tacrolimus target levels have been between 6 and 10 ng/mL. They have been defined individually for each patient based on clinical experience. The decision for the target level was based on the same principles and considerations as in all patients, whether they participated in this study or not. The starting dose after randomization was according to the conversion ratio 0.7 mg of Envarsus® per 1 mg Tacrolimus premedication. Once daily, the dose have been administered fasted in the morning in 24 hours interval. It should have been administered at the same time each day. Dose have been adjusted until the target level was reached.
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Investigational medicinal product name |
Advagraf®
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Investigational medicinal product code |
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Other name |
Tacrolimus
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Pharmaceutical forms |
Prolonged-release tablet
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Routes of administration |
Oral use
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Dosage and administration details |
The Tacrolimus target levels have been between 6 and 10 ng/mL. They have been defined individually for each patient based on clinical experience. The decision for the target level was based on the same principles and considerations as in all patients, whether they participated in this study or not. The starting dose after randomization was according to the conversion ratio 1.0 mg of Advagraf® per 1 mg Tacrolimus premedication. Once daily, the dose have been administered fasted in the morning in 24 hours interval. It should have been administered at the same time each day. Dose have been adjusted until the target level was reached.
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Arm title
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Group 2: Advagraf® -> Envarsus® | ||||||||||||||||||
Arm description |
Two treatments have been investigated, separated without a wash-out period. Group 2: Advagraf® -> Envarsus®. After randomization the previous tacrolimus medication was stopped and Advagraf® therapy was started the same morning. Therapy was given for 14 days plus eventually a longer interval in case the target level has not been reached in time. On Visit 7 (day 15 + n) therapy was switched to Envarsus® for further 14 days plus eventually a longer interval in case of not reaching the target level in a specified timeframe. | ||||||||||||||||||
Arm type |
cross over | ||||||||||||||||||
Investigational medicinal product name |
Advagraf®
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Investigational medicinal product code |
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Other name |
Tacrolimus
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Pharmaceutical forms |
Prolonged-release tablet
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Routes of administration |
Oral use
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Dosage and administration details |
The Tacrolimus target levels have been between 6 and 10 ng/mL. They have been defined individually for each patient based on clinical experience. The decision for the target level was based on the same principles and considerations as in all patients, whether they participated in this study or not. The starting dose after randomization was according to the conversion ratio 1.0 mg of Advagraf® per 1 mg Tacrolimus premedication. Once daily, the dose have been administered fasted in the morning in 24 hours interval. It should have been administered at the same time each day. Dose have been adjusted until the target level was reached.
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Investigational medicinal product name |
Envarsus®
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Investigational medicinal product code |
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Other name |
Tacrolimus
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Pharmaceutical forms |
Prolonged-release tablet
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Routes of administration |
Oral use
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Dosage and administration details |
The Tacrolimus target levels have been between 6 and 10 ng/mL. They have been defined individually for each patient based on clinical experience. The decision for the target level was based on the same principles and considerations as in all patients, whether they participated in this study or not. The starting dose after randomization was according to the conversion ratio 0.7 mg of Envarsus® per 1 mg Tacrolimus premedication. Once daily, the dose have been administered fasted in the morning in 24 hours interval. It should have been administered at the same time each day. Dose have been adjusted until the target level was reached.
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Baseline characteristics reporting groups
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Reporting group title |
Group 1: Envarsus® -> Advagraf®
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Reporting group description |
Two treatments have been investigated, separated without a wash-out period. Group 1: Envarsus® -> Advagraf®. After randomization the previous tacrolimus medication was stopped and Envarsus® therapy was started the same morning. Therapy was given for 14 days plus eventually a longer interval in case the target level has not been reached in time. On Visit 7 (day 15 + n) therapy was switched to Advagraf® for further 14 days plus eventually a longer interval in case of not reaching the target level in a specified timeframe. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Group 2: Advagraf® -> Envarsus®
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Reporting group description |
Two treatments have been investigated, separated without a wash-out period. Group 2: Advagraf® -> Envarsus®. After randomization the previous tacrolimus medication was stopped and Advagraf® therapy was started the same morning. Therapy was given for 14 days plus eventually a longer interval in case the target level has not been reached in time. On Visit 7 (day 15 + n) therapy was switched to Envarsus® for further 14 days plus eventually a longer interval in case of not reaching the target level in a specified timeframe. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Group 1 safety population
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Subject analysis set type |
Safety analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
NA
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Subject analysis set title |
Group 2 safety population
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Subject analysis set type |
Safety analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
NA
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Subject analysis set title |
PK population
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Subject analysis set type |
Per protocol | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
NA
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End points reporting groups
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Reporting group title |
Group 1: Envarsus® -> Advagraf®
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Reporting group description |
Two treatments have been investigated, separated without a wash-out period. Group 1: Envarsus® -> Advagraf®. After randomization the previous tacrolimus medication was stopped and Envarsus® therapy was started the same morning. Therapy was given for 14 days plus eventually a longer interval in case the target level has not been reached in time. On Visit 7 (day 15 + n) therapy was switched to Advagraf® for further 14 days plus eventually a longer interval in case of not reaching the target level in a specified timeframe. | ||
Reporting group title |
Group 2: Advagraf® -> Envarsus®
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Reporting group description |
Two treatments have been investigated, separated without a wash-out period. Group 2: Advagraf® -> Envarsus®. After randomization the previous tacrolimus medication was stopped and Advagraf® therapy was started the same morning. Therapy was given for 14 days plus eventually a longer interval in case the target level has not been reached in time. On Visit 7 (day 15 + n) therapy was switched to Envarsus® for further 14 days plus eventually a longer interval in case of not reaching the target level in a specified timeframe. | ||
Subject analysis set title |
Group 1 safety population
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
NA
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Subject analysis set title |
Group 2 safety population
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
NA
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Subject analysis set title |
PK population
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
NA
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End point title |
Pharmacokinetic characteristics: C0/dose ss [µg / mg L] Envarsus® [1] | ||||||||
End point description |
The pharmacokinetic profiles of Envarsus® and Advagraf® were evaluated as a surrogate for the efficacy. In total, 19 plasma samples (9 subjects with 9 x 2 plasma samples each and one subjects who dropped out with one sample) are available. All 9 patients having both plasma profiles have been analyzed.
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End point type |
Primary
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End point timeframe |
descriptive statistics of all considered pharmacokinetic characteristics
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Original static evaluation not possible because target number of cases not reached. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Pharmacokinetic characteristics: AUC 0-24/dose ss [µg h/ mg L] Envarsus® [2] | ||||||||
End point description |
The pharmacokinetic profiles of Envarsus® and Advagraf® were evaluated as a surrogate for the efficacy. In total, 19 plasma samples (9 subjects with 9 x 2 plasma samples each and one subjects who dropped out with one sample) are available. All 9 patients having both plasma profiles have been analyzed.
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End point type |
Primary
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End point timeframe |
descriptive statistics of all considered pharmacokinetic characteristics
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| Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Original static evaluation not possible because target number of cases not reached. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Pharmacokinetic characteristics: AUC 0-24/dose ss [µg h / mg L] Advagraf® [3] | ||||||||
End point description |
The pharmacokinetic profiles of Envarsus® and Advagraf® were evaluated as a surrogate for the efficacy. In total, 19 plasma samples (9 subjects with 9 x 2 plasma samples each and one subjects who dropped out with one sample) are available. All 9 patients having both plasma profiles have been analyzed.
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End point type |
Primary
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End point timeframe |
descriptive statistics of all considered pharmacokinetic characteristics
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| Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Original static evaluation not possible because target number of cases not reached. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Pharmacokinetic characteristics: C0/dose ss [µg / mg L] Advagraf® [4] | ||||||||
End point description |
The pharmacokinetic profiles of Envarsus® and Advagraf® were evaluated as a surrogate for the efficacy. In total, 19 plasma samples (9 subjects with 9 x 2 plasma samples each and one subjects who dropped out with one sample) are available. All 9 patients having both plasma profiles have been analyzed.
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End point type |
Primary
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End point timeframe |
descriptive statistics of all considered pharmacokinetic characteristics
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| Notes [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Original static evaluation not possible because target number of cases not reached. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Pharmacokinetic characteristics: C max/dose ss [µg / mg L] Envarsus® | ||||||||
End point description |
The pharmacokinetic profiles of Envarsus® and Advagraf® were evaluated as a surrogate for the efficacy. In total, 19 plasma samples (9 subjects with 9 x 2 plasma samples each and one subjects who dropped out with one sample) are available. All 9 patients having both plasma profiles have been analyzed.
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End point type |
Secondary
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End point timeframe |
descriptive statistics of all considered pharmacokinetic characteristics
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| No statistical analyses for this end point | |||||||||
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End point title |
Pharmacokinetic characteristics: C max/dose ss [µg / mg L] Advagraf® | ||||||||
End point description |
The pharmacokinetic profiles of Envarsus® and Advagraf® were evaluated as a surrogate for the efficacy. In total, 19 plasma samples (9 subjects with 9 x 2 plasma samples each and one subjects who dropped out with one sample) are available. All 9 patients having both plasma profiles have been analyzed.
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End point type |
Secondary
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End point timeframe |
descriptive statistics of all considered pharmacokinetic characteristics
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| No statistical analyses for this end point | |||||||||
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Adverse events information [1]
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Timeframe for reporting adverse events |
All AEs, including those associated with the protocol, were collected from the time that the patient was randomized, regardless of the relationship to the IMP. All AEs had to be recorded until the last trial day according to the clinical trial protocol.
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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 |
NA
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| Frequency threshold for reporting non-serious adverse events: 5% | |||
| Notes [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported. Justification: All AEs, including those associated with the protocol, were collected from the time that the patient was randomized, regardless of the relationship to the IMP. All AEs had to be recorded until the last trial day according to the clinical trial protocol. |
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? No | |||
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 | |||
