Immunosuppression After Liver TransplantationPhase 4ConversionNCT02105155
Conversion Prograf® to Advagraf® at D7 Versus D90 After Liver Transplantation
A Phase 4 study testing Conversion at day 7 ± 3 Prograf® to Advagraf® and Conversion at day 90±5 Prograf® to Advagraf® in people with Immunosuppression After Liver Transplantation, run by Assistance Publique - Hôpitaux de Paris at 1 site in France.
Trial summary
The best period for the conversion from Prograf (tacrolimus administered twice daily) to Advagraf (once-daily prolonged-release tacrolimus) remains unknown. The aim of this prospective, randomized, multicenter trial is to prove the non-inferiority of the early conversion (at D7) versus the conversion at D90 after… Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Immunosuppression After Liver Transplantation
- What is being tested?
- Conversion at day 7 ± 3 Prograf® to Advagraf® and Conversion at day 90±5 Prograf® to Advagraf®
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 90 participants
- Where
- 1 siteFrance
- Study dates
- Nov 2014to 17 Oct 2016
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 18 to 75 years
- First liver transplantation
- No contra-indication to tacrolimus, mycophenolate mofetil or steroids
- Informed consent signed
- French Health Assurance
Who cannot join
- Combined transplantation
- Severe uncontrolled infection
- Hypersensitivity to tacrolimus or its excipients, to other macrolides, to mycophenolate mofetil or its excipients
- Pregnant or lactating woman, or women of childbearing potential without adequate method of contraception
- Cancer or pasthistory of cancer other than basal or squamous cell carcinoma or hepatocellular carcinoma suitable for liver transplantation
- Patients with renal impairment where GFR is less than 30ml/min
- HIV positivity
Trial locations and contacts
1 site in 1 country.
France1 site
Hôpital Pitié Salpêtrière unité médicale de transplantion hépatique
Paris, 75013
About this study
Official title: Non-inferiority and Tolerance of Conversion From Prograf® to Advagraf® at D7 Versus D90 After Liver Transplantation
The best period for the conversion from Prograf (tacrolimus administered twice daily) to Advagraf (once-daily prolonged-release tacrolimus) remains unknown. The aim of this prospective, randomized, multicenter trial is to prove the non-inferiority of the early conversion (at D7) versus the conversion at D90 after liver transplantation. The primary objective will be to evaluate the incidence of a first biopsy-proven acute rejection in the 6 first months, and prove the non-inferiority of the conversion at D7 + / - 3 versus the conversion at D90 + / - 5 (reference group). If non-inferiority is proved, the two strategies will be compared in terms of superiority. 250 patients will be included. Three ancillary studies will be added : a PK study in a subgroup of 40 patients (20 patients per arm), an assay of the calcineurin activity on a subgroup of 40 patients, and a medicoeconomic study in all patients
Read the detailed description
Rationale :
Conversion from Prograf (tacrolimus administered twice daily) to Advagraf (once-daily prolonged-release tacrolimus) is currently proposed in both stable and de novo liver transplant recipients. However, the early conversion (around D7 after transplantation), during hospitalization, may be difficult due to the more frequent need of dose adjustments under Advagraf than under Prograf, so that there is no consensus on the best period for the conversion. The aim of this prospective, randomized, multicenter trial is to prove the non-inferiority - in terms of efficacy - of the early conversion (at D7) versus the conversion at D90 after liver transplantation.
Primary objective :
To evaluate the incidence of biopsy-proven acute rejection in the 6 first months after liver transplantation, and prove the non-inferiority of the conversion at D7 + / - 3 versus the conversion at D90 + / - 5 (reference group).
Secondary objectives :
Compare the two strategies in terms of:
- Severity of acute rejection (criteres of Banff 97)
- Steroid-resistant acute rejection
- Number of dose adjustments to obtain the target trough level after conversion
- Patient and graft survival Analyse the PK profile of two subgroups (20 patients in each arm) under Advagraf Measure the calcineurin activity in the two groups (in the patients selected for the PK analysis) Evaluate tolerance, with a particular focus on the renal function at 6 months (glomerular filtration rate using MDRD4) and on adverse events.
Primary endpoint:
Percentage of patients with a first episode of biopsy-proven acute rejection.
Methodology :
Multicenter (13 French liver transplant centers), randomized (central randomisation), open study, of non-inferiority, comparing the efficacy at 6 months of two strategies of conversion from Prograf to Advagraf (D7 + / - 3 versus D90 + / - 5), in addition to mycophenolate mofetil and steroids, in liver transplant recipients. If non-inferiority is proved, the two strategies will be compared in terms of superiority. Inclusion of 250 patients (to analyse at least 112 patients in each arm). Calculation of the sample size is based on the following data: Incidence of acute rejection at 6 months = 20% in the 2 groups, Non-inferiority margin = 15%, alpha risk = 2.5%, power = 80%).
Treatments :
- Prograf introduced at 0,1 - 0,2 mg/kg/day
- Mycophenolate mofetil : 1g TD
- Steroids according to the current use in each center Trough blood concentration of tacrolimus will be 8 - 15 ng/mL during the first 3 months, then 5 à 12 ng/mL thereafter.
PK study: For the 40 patients included in the PK study (20 patients per arm), the PK profile (C0, Cmax and AUC) will be established on 9 points : 0 (before Advagraf administration) then at 20min, 40 min, 60 min, 2h, 3h, 4h, 6h, 8h.
- 7 days after conversion in the first group (early conversion)
- 14 + / - 5 days after conversion in the other group (conversion at D90) Calcineurin activity will be assayed on the blood samples used for the trough concentration determination at D5, D7, M1, M3 and M6 and on a baseline sample.
Medicoeconomic study : The costs induced by liver transplantation will be calculated in all the patients included and randomized according to the French recommendations.
- Being tested
- Conversion at day 7 ± 3 Prograf® to Advagraf®, Conversion at day 90±5 Prograf® to Advagraf®
- Keywords
- Liver transplantation,, Conversion (Prograf® to Advagraf®),, Prograf® ,, Advagraf® ,, acute rejection,, GFR
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Conversion at day 7 ± 3 Prograf® to Advagraf®Drug
Conversion from Prograf® (tacrolimus administered twice daily) to Advagraf® (once-daily prolonged-release tacrolimus) at day 7±3
Conversion at day 90±5 Prograf® to Advagraf®Drug
Conversion from Prograf® (tacrolimus administered twice daily) to Advagraf® (once-daily prolonged-release tacrolimus) at day 90±5
| Study group | Role | What they receive |
|---|---|---|
| Conversion at day 7 ± 3 | Experimental | Conversion from Prograf to Advagraf at D7 ± 3 Receives: Drug: Conversion at day 7 ± 3 Prograf® to Advagraf® |
| Conversion at day 90±5 | Active comparator | Conversion from Prograf to Advagraf at 90±5 Receives: Drug: Conversion at day 90±5 Prograf® to Advagraf® |
What is being measured
The primary outcome is the main question the study is designed to answer.
First episode of acute rejection during the first 6 months
First episode of acute rejection during the first 6 months
Measured: 6 months
Secondary outcomes (3)
Renal function
Glomerular filtration rate using MDRD4
Measured: 6 months
Adverse effects
All side effects
Measured: 6 months
Severity of acute rejection
Histological severity of acute rejection using the Banff 2007 criteria
Measured: 6 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Apr 2014 (estimated)
- Study startNov 2014
- Primary completionOct 2016
- Study completion17 Oct 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Immunosuppression After Liver TransplantationStudies of the same condition, open and under way.
- More trials run by Assistance Publique - Hôpitaux de ParisThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 90 participants (actual)
Sponsor and investigators
- Lead sponsor
- Assistance Publique - Hôpitaux de Paris
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Yvon Calmus, MD, PhD, Principal investigator, Assistance Publique
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02105155
- Sponsor's protocol ID
- P 120907
- Other IDs
- HAO 2012
- Acronym
- Conversion
- Status last verified
- Nov 2017
- First submitted
- 2 Apr 2014
- Last updated
- 8 Dec 2017
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Allard M, Puszkiel A, Conti F, Chevillard L, Kamar N, Noe G, White-Koning M, Thomas-Schoemann A, Simon T, Vidal M, Calmus Y, Blanchet B. Pharmacokinetics and Pharmacodynamics of Once-daily Prolonged-release Tacrolimus in Liver Transplant Recipients. Clin Ther. 2019 May;41(5):882-896.e3. doi: 10.1016/j.clinthera.2019.03.006. Epub 2019 Apr 17.
PubMed 31003735
Study at a glance
From the registry record, last updated by the sponsor on 8 Dec 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Non-inferiority and Tolerance of Conversion From Prograf® to Advagraf® at D7 Versus D90 After Liver Transplantation
- ClinicalTrials.gov ID
- NCT02105155
- Acronym / sponsor ID
- Conversion / P 120907
- Keywords
- Liver transplantation,, Conversion (Prograf® to Advagraf®),, Prograf® ,, Advagraf® ,, acute rejection,, GFR
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 90 participants (actual)
- Lead sponsor
- Assistance Publique - Hôpitaux de ParisUniversity, hospital or other
- Study start
- Nov 2014 (actual)
- Primary completion
- Oct 2016 (actual)
- Study completion
- 17 Oct 2016 (actual)
- First posted
- 7 Apr 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The best period for the conversion from Prograf (tacrolimus administered twice daily) to Advagraf (once-daily prolonged-release tacrolimus) remains unknown. The aim of this prospective, randomized, multicenter trial is to prove the non-inferiority of the early conversion (at D7) versus the conversion at D90 after liver transplantation. The primary objective will be to evaluate the incidence of a first biopsy-proven acute rejection in the 6 first months, and prove the non-inferiority of the conversion at D7 + / - 3 versus the conversion at D90 + / - 5 (reference group). If non-inferiority is proved, the two strategies will be compared in terms of superiority. 250 patients will be included. Three ancillary studies will be added : a PK study in a subgroup of 40 patients (20 patients per arm), an assay of the calcineurin activity on a subgroup of 40 patients, and a medicoeconomic study in all patients
Detailed description
Rationale :
Conversion from Prograf (tacrolimus administered twice daily) to Advagraf (once-daily prolonged-release tacrolimus) is currently proposed in both stable and de novo liver transplant recipients. However, the early conversion (around D7 after transplantation), during hospitalization, may be difficult due to the more frequent need of dose adjustments under Advagraf than under Prograf, so that there is no consensus on the best period for the conversion. The aim of this prospective, randomized, multicenter trial is to prove the non-inferiority - in terms of efficacy - of the early conversion (at D7) versus the conversion at D90 after liver transplantation.
Primary objective :
To evaluate the incidence of biopsy-proven acute rejection in the 6 first months after liver transplantation, and prove the non-inferiority of the conversion at D7 + / - 3 versus the conversion at D90 + / - 5 (reference group).
Secondary objectives :
Compare the two strategies in terms of:
- Severity of acute rejection (criteres of Banff 97)
- Steroid-resistant acute rejection
- Number of dose adjustments to obtain the target trough level after conversion
- Patient and graft survival Analyse the PK profile of two subgroups (20 patients in each arm) under Advagraf Measure the calcineurin activity in the two groups (in the patients selected for the PK analysis) Evaluate tolerance, with a particular focus on the renal function at 6 months (glomerular filtration rate using MDRD4) and on adverse events.
Primary endpoint:
Percentage of patients with a first episode of biopsy-proven acute rejection.
Methodology :
Multicenter (13 French liver transplant centers), randomized (central randomisation), open study, of non-inferiority, comparing the efficacy at 6 months of two strategies of conversion from Prograf to Advagraf (D7 + / - 3 versus D90 + / - 5), in addition to mycophenolate mofetil and steroids, in liver transplant recipients. If non-inferiority is proved, the two strategies will be compared in terms of superiority. Inclusion of 250 patients (to analyse at least 112 patients in each arm). Calculation of the sample size is based on the following data: Incidence of acute rejection at 6 months = 20% in the 2 groups, Non-inferiority margin = 15%, alpha risk = 2.5%, power = 80%).
Treatments :
- Prograf introduced at 0,1 - 0,2 mg/kg/day
- Mycophenolate mofetil : 1g TD
- Steroids according to the current use in each center Trough blood concentration of tacrolimus will be 8 - 15 ng/mL during the first 3 months, then 5 à 12 ng/mL thereafter.
PK study: For the 40 patients included in the PK study (20 patients per arm), the PK profile (C0, Cmax and AUC) will be established on 9 points : 0 (before Advagraf administration) then at 20min, 40 min, 60 min, 2h, 3h, 4h, 6h, 8h.
- 7 days after conversion in the first group (early conversion)
- 14 + / - 5 days after conversion in the other group (conversion at D90) Calcineurin activity will be assayed on the blood samples used for the trough concentration determination at D5, D7, M1, M3 and M6 and on a baseline sample.
Medicoeconomic study : The costs induced by liver transplantation will be calculated in all the patients included and randomized according to the French recommendations.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Conversion at day 7 ± 3 | Experimental | Drug: Conversion at day 7 ± 3 Prograf® to Advagraf®Conversion from Prograf to Advagraf at D7 ± 3 |
| Conversion at day 90±5 | Active comparator | Drug: Conversion at day 90±5 Prograf® to Advagraf®Conversion from Prograf to Advagraf at 90±5 |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- 18 to 75 years
- First liver transplantation
- No contra-indication to tacrolimus, mycophenolate mofetil or steroids
- Informed consent signed
- French Health Assurance
Key exclusion criteria (7 listed)
- Combined transplantation
- Severe uncontrolled infection
- Hypersensitivity to tacrolimus or its excipients, to other macrolides, to mycophenolate mofetil or its excipients
- Pregnant or lactating woman, or women of childbearing potential without adequate method of contraception
- Cancer or pasthistory of cancer other than basal or squamous cell carcinoma or hepatocellular carcinoma suitable for liver transplantation
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Conversion at day 7 ± 3 Prograf® to Advagraf®Conversion from Prograf® (tacrolimus administered twice daily) to Advagraf® (once-daily prolonged-release tacrolimus) at day 7±3 | Drug | Conversion at day 7 ± 3 |
| Conversion at day 90±5 Prograf® to Advagraf®Conversion from Prograf® (tacrolimus administered twice daily) to Advagraf® (once-daily prolonged-release tacrolimus) at day 90±5 | Drug | Conversion at day 90±5 |
Primary outcome
First episode of acute rejection during the first 6 months
Time frame: 6 months
First episode of acute rejection during the first 6 months
3 secondary outcomes
Renal function
Time frame: 6 months
Adverse effects
Time frame: 6 months
Severity of acute rejection
Time frame: 6 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 8 Dec 2017.
- Derived from this study: PubMed 31003735Allard M, Puszkiel A, Conti F, Chevillard L, Kamar N, Noe G, White-Koning M, Thomas-Schoemann A, Simon T, Vidal M, Calmus Y, Blanchet B. Pharmacokinetics and Pharmacodynamics of Once-daily Prolonged-release Tacrolimus in Liver Transplant Recipients. Clin Ther. 2019 May;41(5):882-896.e3. doi: 10.1016/j.clinthera.2019.03.006. Epub 2019 Apr 17.
Related trials for Immunosuppression After Liver Transplantation
RecruitingObservational study
Immune Biomarkers for Predicting Complications After Liver Transplantation
Liver Transplantation (LT), Immuno-suppression
RecruitingPhase 3
Everolimus bAsed caLcineurin inhibiTor frEe immunosuppRession oNe Year AfTer lIver transplantatiON (ALTERNATION)
Liver Allograft, Liver Diseases
RecruitingPhase 4
Evaluation of the Benefits of Administering Immunosuppressive Drugs as Single Daily Doses Over the First Year After Liver Transplantation (EASY)
Liver Transplantation, Immunosuppression
RecruitingPhase 1/2
Immune Tolerance Induction After Liver Transplantation
Liver Transplantation, Immune Tolerance
Active, not recruitingObservational study
Using Transcriptional Assessment of Immune Response to Assess Immunosuppression After Liver Transplantation
Transplant Complication
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Yvon Calmus, MD, PhD principal investigator
Assistance Publique
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Conversion at day 7 ± 3 Prograf® to Advagraf® and Conversion at day 90±5 Prograf® to Advagraf® in people with Immunosuppression After Liver Transplantation, run by Assistance Publique - Hôpitaux de Paris at 1 site in France.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 8 Dec 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
First episode of acute rejection during the first 6 months (time frame: 6 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02105155, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Dec 2017.