Liver TransplantationPhase 3SIMCERNCT01625377
A National Multi-center Randomized, Open Label Study to Evaluate Efficacy and Safety of Everolimus With EC-MPS Compared to Standard Treatment Combination Tacrolimus and EC-MPS in de Novo Liver Transplant Recipients
A Phase 3 study testing tacrolimus, everolimus and Basiliximab in people with Liver Transplantation, run by Novartis Pharmaceuticals at 14 sites in France.
Trial summary
The aims of the study was to evaluate the safety and efficacy of early introduction one month post-transplantation of everolimus associated to EC-MPS with tacrolimus discontinuation in de novo liver transplant recipients and to evaluate if it leads to a better renal function 6 month post-transplantation compared to… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Liver Transplantation
- What is being tested?
- tacrolimus, everolimus and Basiliximab
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 188 participants
- Where
- 14 sitesFrance
- Study dates
- Dec 2012to Mar 2015
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Man or woman aged 18 years or greater, recipient of a primary liver transplant from a deceased donor with whole or split liver
Who cannot join
- Patient recipient of multiple solid organ or islet cell tissue transplants, or have previously received an organ or tissue transplant
- Recipient of a liver from a living donor or cadaveric non heart beating donor
- ABO incompatible transplant graft
- Transplantation following autoimmune liver hepatitis, primitive sclerosing cholangitis or primitive biliary cirrhosis
- Estimated glomerular filtration rate ≤ 30ml/min at selection
- History of malignancy within the 5 past years, other than non-metastatic basal or squamous cell carcinoma and hepatocellular carcinoma
- Alpha-foeto-protein > 1000 ng/ml (only in case of hepatocellular carcinoma)
Trial locations and contacts
14 sites in 1 country.
14 sites in 1 country
France14 sites
Novartis Investigative Site
Besançon, 25030
Novartis Investigative Site
Bordeaux, 33076
Novartis Investigative Site
Chambray-lès-Tours, 37044
Novartis Investigative Site
Clichy, 92110
Novartis Investigative Site
Créteil, 94010
Novartis Investigative Site
Grenoble, 38043
Novartis Investigative Site
Lille, 59037
Novartis Investigative Site
Marseille, 13385
Novartis Investigative Site
Montpellier, 34295
Novartis Investigative Site
Nice, 06202
Novartis Investigative Site
Paris, 75651
Novartis Investigative Site
Rennes, 35033
Novartis Investigative Site
Toulouse, 31054
Novartis Investigative Site
Villejuif, 94800
About this study
Official title: A National, Multi-center, Randomized, Open Label Study to Evaluate the Efficacy and Safety of Everolimus Combined With Enteric-coated Mycophenolate Sodium Compared to the Standard Treatment Combining Tacrolimus and Enteric-coated Mycophenolate Sodium in de Novo Liver Transplant Recipients
The aims of the study was to evaluate the safety and efficacy of early introduction one month post-transplantation of everolimus associated to EC-MPS with tacrolimus discontinuation in de novo liver transplant recipients and to evaluate if it leads to a better renal function 6 month post-transplantation compared to standard treatment associating tacrolimus and EC-MPS.
The renal function was estimated by glomerular filtration rate.
- Conditions
- Liver Transplantation
- Being tested
- tacrolimus, everolimus, Basiliximab, Mycophenolic Acid, Corticosteroids
- Keywords
- Everolimus,, liver transplantation,, early introduction,, renal function
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
tacrolimusDrug
Also called Prograf®
Arm 1 : tacrolimus (C0 6-10 ng/ml) from D3-D5 post-transplantation to month 6 post-transplantation. Arm 2 : tacolimus (C0 6-10 ng/ml) from D3-D5 post-transplantation to 16 weeks post-transplantation at the latest.
everolimusDrug
Also called Certican® / RAD001
Arm 1: no everolimus Arm 2: everolimus (C0 6-10 ng/ml) from randomization to month 6 post-transplantation
BasiliximabDrug
Also called Simulect®
Basiliximab was supplied to the participating centers as marketed, i.e. in packs containing one vial of 20-mg powder, and water for injection (WFI). 20 mg at D0 and D4
Mycophenolic AcidDrug
Also called Myfortic®
Dose of 1440 mg/day from transplantation to month 6 post- transplantation
CorticosteroidsDrug
Administration of oral corticosteroid therapy was at the discretion of the centers according to their usual practice
| Study group | Role | What they receive |
|---|---|---|
| Tacrolimus | Active comparator | From transplantation to randomization: Basiliximab (40mg) at Day 0 and Day 4 + tacrolimus (C0 6-10 ng/ml) from Day 3-Day 5 + mycophenolic acid 1440 mg/d ± oral corticosteroids. From randomization to month 6 : tacrolimus (C0 6-10 ng/ml) + mycophenolic acid 1440 mg/d ± oral corticosteroids Receives: Drug: tacrolimus; Drug: Basiliximab; Drug: Mycophenolic Acid; Drug: Corticosteroids |
| Everolimus (RAD001) | Experimental | From transplantation to randomization: Basiliximab (40mg) at Day 0 and Day 4 + tacrolimus (C0 6-10 ng/ml) from Day 3-Day 5 + mycophenolic acid 1440 mg/d ± oral corticosteroids.
From randomization to month 6 : everolimus (recommended starting dose of 2 mg/day, then adjusted to achieve the target 6 ≤ C0 ≤ 10 ng/mL, until W24) + mycophenolic acid 1440 mg/d ± oral corticosteroids. The dose of tacrolimus was reduced by 50% twice: at the introduction of everolimus and at week 8 post-transplantation. Tacrolimus had to be finally discontinued in week 12 post-transplantation (by week 16 at the latest). Receives: Drug: tacrolimus; Drug: everolimus; Drug: Basiliximab; Drug: Mycophenolic Acid; Drug: Corticosteroids |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change From Baseline (Randomization) in Renal Function
Change in renal function was measured by change in glomerular filtration rate (GFR). GFR calculated using the abbreviated modification of diet in renal disease (aMDRD) formula.
GFR in mL/min/1.73m^2 for men of non-black ethnicity: 186 * [C/88]^-1.154 * [A]^-0.023*G*R ; C = serum creatinine (in μmol/L); A = Age (in years). G = 0.742 when the patient is a women; Otherwise G=1 R= 1.21 when the patient was of black ethnicity; Otherwise R = 1 Baseline was Day 28 visit.
Measured: Baseline, Week 24
Secondary outcomes (12)
Number of Patients With Treatment Failures
Incidence of treatment failures, assessed with composite criterion including treated biopsy proven acute rejection (tBPAR) with a rejection activity index (RAI) according to Banff classification >3, graft loss or death at 6 months.
Biopsy proven acute rejection (BPAR) was defined as a clinically suspected acute rejection confirmed by biopsy. The Banff Rejection Activity Index (RAI) comprises 3 components scored from 0 to 3: venous endothelial inflammation; bile duct inflammation damage; and portal inflammation; the scores are combined to an overall score (the RAI) ranging from 0 to 9. An overall score of 0-3 is considered indeterminate, score of 4-5 is mild acute, score of 6-7 is moderate acute , and score of 8-9 is severe acute. Only the episode with the highest total RAI score for each participant was counted.
The graft was presumed to be lost on the day the patient was registered again on the waiting list, or the day he/she received a new graft.
Measured: At week 12 and week 24
Number of Patients With Treated or Not Treated Biopsy Proven Acute Rejection (BPAR)
Biopsy proven acute rejection was defined as a clinically suspected acute rejection confirmed by biopsy.
Measured: at 12 week and 24 week
Number of Patients Reported With Different Categories of Severity of BPAR According to Banff Classification
Biopsy proven acute rejection was defined as a clinically suspected acute rejection confirmed by biopsy.
The severity of BPAR was categorized as :
Mild (Banff grade I, RAI = 4 and 5) Moderate (Banff grade II, RAI = 6 and 7) Severe (Banff grade III, RAI = 8 and 9) Banff Rejection Activity Index (RAI) comprises 3 components scored from 0 to 3: venous endothelial inflammation; bile duct inflammation damage; and portal inflammation; the scores are combined to an overall score (the RAI) ranging from 0 to 9. An overall score of 0-3 is considered indeterminate, score of 4-5 is mild acute, score of 6-7 is moderate acute , and score of 8-9 is severe acute. Only the episode with the highest total RAI score for each participant was counted.
Measured: at 12 week and 24 week
Number of Patients With Treated or Untreated BPAR With RAI Score Greater Than 3
Biopsy proven acute rejection (BPAR) was defined as a clinically suspected acute rejection confirmed by biopsy. The Banff Rejection Activity Index (RAI) comprises 3 components scored from 0 to 3: venous endothelial inflammation; bile duct inflammation damage; and portal inflammation; the scores are combined to an overall score (the RAI) ranging from 0 to 9. An overall score of 0-3 is considered indeterminate, score of 4-5 is mild acute, score of 6-7 is moderate acute , and score of 8-9 is severe acute. Only the episode with the highest total RAI score for each participant was counted.
The patients with treated or untreated BPAR having RAI score > 3 were reported in this end point.
Measured: At 24 weeks
Number of Patients With Death or Graft Loss
The graft was presumed to be lost on the day the patient was registered again on the waiting list, or the day he/she received a new graft.
Measured: at week 24
Change From Baseline (Randomization) in Serum Creatinine
Change in serum creatinine concentrations from baseline (randomization) to week 24 post-randomization was one of the efficacy assessments of renal function.
Baseline was Day 28 visit.
Measured: Baseline, Week 24
Change From Baseline (Randomization) in Urine Protein/Creatinine Ratio
Change in urine protein/creatinine ratio from baseline (randomization) to week 24 post-randomization was one of the efficacy assessments of renal function. Baseline was Day 28 visit.
Measured: Baseline, week 24
Change From Baseline (Randomization) in Creatinine Clearance Estimated Using the Adjusted Cockcroft-Gault Formula
Creatinine clearance by the Cockcroft-Gault formula is computed in mL/min/1.73m^2 from the creatinine clearance in mL/min by multiplying it by 1.73 and dividing it by the body surface area Baseline was Day 28 visit.
Measured: Baseline, Week 24
Change From Baseline (Randomization) in Glomerular Filtration Rate Estimated by Abbreviated Modification of Diet in Renal Disease (MDRD) Formula
Change in glomerular filtration rate was calculated using the MDRD abbreviated formula.
GFR in mL/min/1.73m^2 for men of non-black ethnicity: 186 * [C/88]^-1.154 * [A]^-0.023*G*R ; C = serum creatinine (in μmol/L); A = Age (in years). G = 0.742 when the patient is a women; Otherwise G=1 R= 1.21 when the patient was of black ethnicity; Otherwise R = 1 Baseline was Day 28 visit.
Measured: Baseline, Week 24
Change From Baseline (Randomization) in Glomerular Filtration Rate Estimated by CKD-EPI Formula
GFR estimated by using the Chronic kidney disease- epidemiology (CKD-EPI) formula:
eGFR (mL/min/1.73m^2) = 141 * min(C/K,1)^ α * max(C/K,1)^-1.209 * 0.993^A * 1.1018 (if male) * 1.159 (if black) where C = serum creatinine (in mg/dL) ; A = Age (in years); K = 0.7 for women and 0.9 for men; α = -0.329 for women and -0.411 for men. Baseline was Day 28 visit.
Measured: Baseline, Week 24
Number of Patients in Different Stages of Chronic Kidney Diseases According to the K/DOQI Classification System
Kidney disease outcomes quality initiative (K/DOQI) classification is based on glomerular filtration rate (GFR), abbreviated MDRD formula (mL/min/1.73m^2) :
Stage 1 : GFR >= 90; Stage 2 = GFR was between 60-89; Stage 3 = GFR was between 30-59 ; Stage 4 = GFR was between 15-29; Stage 5 = GFR was < 15 (or dialysis)
Measured: At Week 24
Number of Patients With Any Adverse Events, Serious Adverse Events, Death and Premature Discontinuation
Baseline was Day 28 visit. This endpoint reports patients with total adverse events (any), serious adverse events, death and premature discontinuation.
Measured: Baseline to 24 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Jun 2012 (estimated)
- Study startDec 2012
- Primary completionMar 2015
- Study completionMar 2015
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Liver TransplantationStudies of the same condition, open and under way.
- More trials run by Novartis PharmaceuticalsThe 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 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 188 participants (actual)
Sponsor and investigators
- Lead sponsor
- Novartis Pharmaceuticals
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Novartis Pharmaceuticals, Study director, Novartis Pharmaceuticals
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01625377
- Sponsor's protocol ID
- CRAD001HFR02
- Other IDs
- 2012-000137-39
- Acronym
- SIMCER
- Status last verified
- Mar 2016
- First submitted
- 19 Jun 2012
- Last updated
- 27 Apr 2016
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 27 Apr 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A National, Multi-center, Randomized, Open Label Study to Evaluate the Efficacy and Safety of Everolimus Combined With Enteric-coated Mycophenolate Sodium Compared to the Standard Treatment Combining Tacrolimus and Enteric-coated Mycophenolate Sodium in de Novo Liver Transplant Recipients
- ClinicalTrials.gov ID
- NCT01625377
- Acronym / sponsor ID
- SIMCER / CRAD001HFR02
- Conditions
- Liver Transplantation
- Keywords
- Everolimus,, liver transplantation,, early introduction,, renal function
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 188 participants (actual)
- Lead sponsor
- Novartis PharmaceuticalsIndustry (pharma, biotech, devices)
- Study start
- Dec 2012
- Primary completion
- Mar 2015 (actual)
- Study completion
- Mar 2015 (actual)
- First posted
- 21 Jun 2012 (estimated)
- Results
- Posted 27 Apr 2016
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The aims of the study was to evaluate the safety and efficacy of early introduction one month post-transplantation of everolimus associated to EC-MPS with tacrolimus discontinuation in de novo liver transplant recipients and to evaluate if it leads to a better renal function 6 month post-transplantation compared to standard treatment associating tacrolimus and EC-MPS.
The renal function was estimated by glomerular filtration rate.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Tacrolimus | Active comparator | Drug: tacrolimus, Drug: Basiliximab, Drug: Mycophenolic Acid, Drug: CorticosteroidsFrom transplantation to randomization: Basiliximab (40mg) at Day 0 and Day 4 + tacrolimus (C0 6-10 ng/ml) from Day 3-Day 5 + mycophenolic acid 1440 mg/d ± oral corticosteroids. From randomization to month 6 : tacrolimus (C0 6-10 ng/ml) + mycophenolic acid 1440 mg/d ± oral corticosteroids |
| Everolimus (RAD001) | Experimental | Drug: tacrolimus, Drug: everolimus, Drug: Basiliximab, Drug: Mycophenolic Acid, Drug: CorticosteroidsFrom transplantation to randomization: Basiliximab (40mg) at Day 0 and Day 4 + tacrolimus (C0 6-10 ng/ml) from Day 3-Day 5 + mycophenolic acid 1440 mg/d ± oral corticosteroids. From randomization to month 6 : everolimus (recommended starting dose of 2 mg/day, then adjusted to achieve the target 6 ≤ C0 ≤ 10 ng/mL, until W24) + mycophenolic acid 1440 mg/d ± oral corticosteroids. The dose of tacrolimus was reduced by 50% twice: at the introduction of everolimus and at week 8 post-transplantation. Tacrolimus had to be finally discontinued in week 12 post-transplantation (by week 16 at the latest). |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (1 listed)
- Man or woman aged 18 years or greater, recipient of a primary liver transplant from a deceased donor with whole or split liver
Key exclusion criteria (7 listed)
- Patient recipient of multiple solid organ or islet cell tissue transplants, or have previously received an organ or tissue transplant
- Recipient of a liver from a living donor or cadaveric non heart beating donor
- ABO incompatible transplant graft
- Transplantation following autoimmune liver hepatitis, primitive sclerosing cholangitis or primitive biliary cirrhosis
- Estimated glomerular filtration rate ≤ 30ml/min at selection
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 |
|---|---|---|
| tacrolimusAlso: Prograf®Arm 1 : tacrolimus (C0 6-10 ng/ml) from D3-D5 post-transplantation to month 6 post-transplantation. Arm 2 : tacolimus (C0 6-10 ng/ml) from D3-D5 post-transplantation to 16 weeks post-transplantation at the latest. | Drug | Everolimus (RAD001), Tacrolimus |
| everolimusAlso: Certican® / RAD001Arm 1: no everolimus Arm 2: everolimus (C0 6-10 ng/ml) from randomization to month 6 post-transplantation | Drug | Everolimus (RAD001) |
| BasiliximabAlso: Simulect®Basiliximab was supplied to the participating centers as marketed, i.e. in packs containing one vial of 20-mg powder, and water for injection (WFI). 20 mg at D0 and D4 | Drug | Everolimus (RAD001), Tacrolimus |
| Mycophenolic AcidAlso: Myfortic®Dose of 1440 mg/day from transplantation to month 6 post- transplantation | Drug | Everolimus (RAD001), Tacrolimus |
| CorticosteroidsAdministration of oral corticosteroid therapy was at the discretion of the centers according to their usual practice | Drug | Everolimus (RAD001), Tacrolimus |
Primary outcome
Change From Baseline (Randomization) in Renal Function
Time frame: Baseline, Week 24
Change in renal function was measured by change in glomerular filtration rate (GFR). GFR calculated using the abbreviated modification of diet in renal disease (aMDRD) formula. GFR in mL/min/1.73m^2 for men of non-black ethnicity: 186 * [C/88]^-1.154 * [A]^-0.023*G*R ; C = serum creatinine (in μmol/L); A = Age (in years). G = 0.742 when the patient is a women; Otherwise G=1 R= 1.21 when the patient was of black ethnicity; Otherwise R = 1 Baseline was Day 28 visit.
12 secondary outcomes
Number of Patients With Treatment Failures
Time frame: At week 12 and week 24
Number of Patients With Treated or Not Treated Biopsy Proven Acute Rejection (BPAR)
Time frame: at 12 week and 24 week
Number of Patients Reported With Different Categories of Severity of BPAR According to Banff Classification
Time frame: at 12 week and 24 week
Number of Patients With Treated or Untreated BPAR With RAI Score Greater Than 3
Time frame: At 24 weeks
Number of Patients With Death or Graft Loss
Time frame: at week 24
Change From Baseline (Randomization) in Serum Creatinine
Time frame: Baseline, Week 24
Change From Baseline (Randomization) in Urine Protein/Creatinine Ratio
Time frame: Baseline, week 24
Change From Baseline (Randomization) in Creatinine Clearance Estimated Using the Adjusted Cockcroft-Gault Formula
Time frame: Baseline, Week 24
Change From Baseline (Randomization) in Glomerular Filtration Rate Estimated by Abbreviated Modification of Diet in Renal Disease (MDRD) Formula
Time frame: Baseline, Week 24
Change From Baseline (Randomization) in Glomerular Filtration Rate Estimated by CKD-EPI Formula
Time frame: Baseline, Week 24
Number of Patients in Different Stages of Chronic Kidney Diseases According to the K/DOQI Classification System
Time frame: At Week 24
Number of Patients With Any Adverse Events, Serious Adverse Events, Death and Premature Discontinuation
Time frame: Baseline to 24 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Apr 2016.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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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.
Novartis Pharmaceuticals study director
Novartis Pharmaceuticals
14 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing tacrolimus, everolimus and Basiliximab in people with Liver Transplantation, run by Novartis Pharmaceuticals at 14 sites 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 1 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 27 Apr 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 14 sites 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 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 27 Apr 2016). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
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?
Change From Baseline (Randomization) in Renal Function (time frame: Baseline, Week 24). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 27 Apr 2016.