Liver TransplantationPhase 3REFLECTNCT02115113
REnal Function in Liver Transplantation: Everolimus With Calcineurin Inhibitor (CNI)-Sparing sTrategy
A Phase 3 study testing Everolimus and Tacrolimus in people with Liver Transplantation, run by Novartis Pharmaceuticals at 14 sites in Italy.
Trial summary
The purpose of this study was, starting from the Italian clinical practice in liver transplantation, to optimize the immunosuppressive therapy, considering specific patient characteristics as alcoholic cirrhosis, hepatitis C virus (HCV), hepatocellular carcinoma (HCC), and short/long-term implications. 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?
- Everolimus and Tacrolimus
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 78 participants
- Where
- 14 sitesItaly
- Study dates
- 28 Mar 2014to 30 Sep 2016
- 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
- Male and female liver transplant recipients who are ≥ 18 years of age, treated with a tacrolimus-based immunosuppressive regimen, who have received an induction therapy or i.v. steroids as per local clinical practice.
- Recipients of a full-size or technically modified liver allograft will be eligible at 4 weeks (± 7 days) after liver transplantation.
- Allograft is functioning at an acceptable level by the time of Baseline as defined by the AST, ALT, total bilirubin levels ≤ 3 times ULN and INR < 1.5 times ULN.
- Abbreviated MDRD-4 eGFR ≥ 30 mL/min/1.73m2. Serum creatinine results obtained within 5 days prior to Baseline are acceptable.
- Effective tacrolimus minimization, confirmed by stable blood trough levels in the two months prior to randomization, i.e. verification of last two tacrolimus blood trough level ≤ 5 ng/mL in the two months prior to randomization. Investigators should make adjustments in tacrolimus dosing to continue to target trough levels ≤ 5 ng/mL prior to randomization.
- Abbreviated MDRD-4 eGFR ≥ 30 mL/min/1.73m2. Serum creatinine results obtained within 5 days prior to Visit 5 are acceptable.
Who cannot join
- Patients who are recipients of multiple solid organ transplants, (e.g., multivisceral or combined liver-kidney transplants), or have previously received an organ or tissue transplanted, or who received an AB0 incompatible transplant.
- Patients who experienced more than one episode of treated biopsy proven acute rejection (BANFF ≥ 3 or RAI ≥ 7) or one steroid-resistant acute rejection.
- Patients who require renal replacement therapy.
- Patients with a confirmed spot urine protein/creatinine ratio that indicates ≥1.0 g/24 hrs of proteinuria.
- History of malignancy of any organ system within the past 5 years whether or not there is evidence of local recurrence or metastases, other than non-metastatic basal or squamous cell carcinoma of the skin or HCC.
- Patients who experienced more than two episodes of treated biopsy proven acute rejection (BANFF ≥ 3 or RAI ≥ 7) since transplantation or one steroid-resistant acute rejection during the run-in period.
- Patients with a confirmed spot urine protein/creatinine ratio that indicates ≥ 3.0 g/24 hrs of proteinuria.
Trial locations and contacts
14 sites in 1 country.
14 sites in 1 country
Italy14 sites
Novartis Investigative Site
Ancona, AN, 60126
Novartis Investigative Site
Bari, BA, 70124
Novartis Investigative Site
Bergamo, BG, 24127
Novartis Investigative Site
Bologna, BO, 40138
Novartis Investigative Site
Milan, MI, 20122
Novartis Investigative Site
Modena, MO, 41124
Novartis Investigative Site
Naples, 80132
Novartis Investigative Site
Padova, PD, 35128
Novartis Investigative Site
Pisa, PI, 56124
Novartis Investigative Site
Roma, RM, 00144
Novartis Investigative Site
Roma, RM, 00168
Novartis Investigative Site
Torino, TO, 10126
Novartis Investigative Site
Udine, UD, 33100
Novartis Investigative Site
Verona, VR, 37126
About this study
Official title: Multicenter, Prospective, Open-label, Controlled, Randomized, Parallel Groups Study to Evaluate the Renal Function of Adult Liver Transplant Recipients Treated With Two Everolimus-based Immunosuppressive Regimens (Tacrolimus Withdrawal vs. Minimization) Until 12 Months Post-transplant, With a 6-months Follow-up
The purpose of this study was, starting from the Italian clinical practice in liver transplantation, to optimize the immunosuppressive therapy, considering specific patient characteristics as alcoholic cirrhosis, hepatitis C virus (HCV), hepatocellular carcinoma (HCC), and short/long-term implications. Then efficacy and safety of a calcineurin inhibitor (CNI)-withdrawal regimen was evaluated in comparison with a CNI-minimization regimen.
- Conditions
- Liver Transplantation
- Being tested
- Everolimus, Tacrolimus
- Keywords
- Liver transplantation, everolimus, CNI-minimization, CNI-elimination, renal function
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
EverolimusDrug
Commercial product labeled according to local requirements will be provided as 0.25 mg and 0.75 mg tablets for oral administration.
TacrolimusDrug
Commercial product labeled according to local requirements will be provided as 0.5 mg, 1.0 mg and 5.0 mg capsules for oral administration.
| Study group | Role | What they receive |
|---|---|---|
| Group A (Tacrolimus Elimination Arm) | Experimental | At study start, participants received an Everolimus starting dose of 1.0 mg twice daily in combination with Tacrolimus. Tacrolimus was administered as per center practice. Thereafter, Everolimus doses were adjusted to achieve Everolimus C-0h blood trough levels between 3-8 ng/mL by week 1 after drug initiation until 5 months after transplant. At 5 months after transplant, Everolimus doses were adjusted to achieve C-0h blood trough level target ranges 6-10 ng/mL. Tacrolimus withdrawal was completed by 6 months after transplant. Receives: Drug: Everolimus; Drug: Tacrolimus |
| Group B (Tacrolimus Minimization Arm) | Active comparator | At study start, participants received an Everolimus starting dose of 1.0 mg twice daily in combination with Tacrolimus. Tacrolimus was administered as per center practice. Thereafter, Everolimus doses were adjusted to achieve Everolimus C-0h blood trough levels between 3-8 ng/mL by week 1 after drug initiation until 5 months after transplant. At 5 months after transplant, Everolimus doses continued to be adjusted to achieve C-0h blood trough level target ranges 3-8 ng/mL and Tacorlimus doses were adjusted to achieve C-0h blood trough level target ranges 3-5 ng/mL. Receives: Drug: Everolimus; Drug: Tacrolimus |
What is being measured
The primary outcome is the main question the study is designed to answer.
Renal Function Assessed by Estimated Glomerular Filtartion Rate (eGFR)
Renal function was assessed by eGFR using the MDRD-4 formula at 12 months after transplant:
eGFR = 186.3 * (serum creatinine)-1.154 * age-0.203 * (0.742 for women) * (1.21 if African American) where serum creatinine was in mg/dL and age in years.
Measured: At 12 months post-transplant
Secondary outcomes (2)
Percentage of Participants With Treated Biopsy Proven Acute Rejection (tBPAR) Acute Rejection (AR), Graft Loss (GL) or Death (D)
Participants were assessed for tBPAR, AR, GL or death. For all suspected rejection episodes, regardless of initiation of anti-rejection treatment, a liver biopsy was to be performed preferably within 24 hours, latest within 48 hours whenever clinically possible. A treated biopsy proven acute rejection was considered an episode of acute rejection when demonstrated by local pathology reading with a rejection activity index of at least 3 or greater of acute rejection index and when treated with anti-rejection therapy. The allograft was considered lost on the day the subject was re-transplanted or died due to liver failure.
Measured: At 12 and 18 months post-transplant
Change From Baseline (Randomization) in Serum Creatinine at 12 Months Post-transplant
Blood samples were collected to assess serum creatinine.
Measured: baseline, 12 months post-transplant
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Apr 2014 (estimated)
- Study start28 Mar 2014
- Primary completion30 Sep 2016
- Study completion30 Sep 2016
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
- 78 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
- NCT02115113
- Sponsor's protocol ID
- CRAD001HIT34
- Other IDs
- 2013-004325-91
- Acronym
- REFLECT
- Status last verified
- Oct 2018
- First submitted
- 20 Mar 2014
- Last updated
- 28 Feb 2019
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- Undecided: Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com
Study at a glance
From the registry record, last updated by the sponsor on 28 Feb 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Multicenter, Prospective, Open-label, Controlled, Randomized, Parallel Groups Study to Evaluate the Renal Function of Adult Liver Transplant Recipients Treated With Two Everolimus-based Immunosuppressive Regimens (Tacrolimus Withdrawal vs. Minimization) Until 12 Months Post-transplant, With a 6-months Follow-up
- ClinicalTrials.gov ID
- NCT02115113
- Acronym / sponsor ID
- REFLECT / CRAD001HIT34
- Conditions
- Liver Transplantation
- Keywords
- Liver transplantation, everolimus, CNI-minimization, CNI-elimination, renal function
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 78 participants (actual)
- Lead sponsor
- Novartis PharmaceuticalsIndustry (pharma, biotech, devices)
- Study start
- 28 Mar 2014 (actual)
- Primary completion
- 30 Sep 2016 (actual)
- Study completion
- 30 Sep 2016 (actual)
- First posted
- 15 Apr 2014 (estimated)
- Results
- Posted 28 Feb 2019
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of this study was, starting from the Italian clinical practice in liver transplantation, to optimize the immunosuppressive therapy, considering specific patient characteristics as alcoholic cirrhosis, hepatitis C virus (HCV), hepatocellular carcinoma (HCC), and short/long-term implications. Then efficacy and safety of a calcineurin inhibitor (CNI)-withdrawal regimen was evaluated in comparison with a CNI-minimization regimen.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Group A (Tacrolimus Elimination Arm) | Experimental | Drug: Everolimus, Drug: TacrolimusAt study start, participants received an Everolimus starting dose of 1.0 mg twice daily in combination with Tacrolimus. Tacrolimus was administered as per center practice. Thereafter, Everolimus doses were adjusted to achieve Everolimus C-0h blood trough levels between 3-8 ng/mL by week 1 after drug initiation until 5 months after transplant. At 5 months after transplant, Everolimus doses were adjusted to achieve C-0h blood trough level target ranges 6-10 ng/mL. Tacrolimus withdrawal was completed by 6 months after transplant. |
| Group B (Tacrolimus Minimization Arm) | Active comparator | Drug: Everolimus, Drug: TacrolimusAt study start, participants received an Everolimus starting dose of 1.0 mg twice daily in combination with Tacrolimus. Tacrolimus was administered as per center practice. Thereafter, Everolimus doses were adjusted to achieve Everolimus C-0h blood trough levels between 3-8 ng/mL by week 1 after drug initiation until 5 months after transplant. At 5 months after transplant, Everolimus doses continued to be adjusted to achieve C-0h blood trough level target ranges 3-8 ng/mL and Tacorlimus doses were adjusted to achieve C-0h blood trough level target ranges 3-5 ng/mL. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- Male and female liver transplant recipients who are ≥ 18 years of age, treated with a tacrolimus-based immunosuppressive regimen, who have received an induction therapy or i.v. steroids as per local clinical practice.
- Recipients of a full-size or technically modified liver allograft will be eligible at 4 weeks (± 7 days) after liver transplantation.
- Allograft is functioning at an acceptable level by the time of Baseline as defined by the AST, ALT, total bilirubin levels ≤ 3 times ULN and INR < 1.5 times ULN.
- Abbreviated MDRD-4 eGFR ≥ 30 mL/min/1.73m2. Serum creatinine results obtained within 5 days prior to Baseline are acceptable.
- Effective tacrolimus minimization, confirmed by stable blood trough levels in the two months prior to randomization, i.e. verification of last two tacrolimus blood trough level ≤ 5 ng/mL in the two months prior to randomization. Investigators should make adjustments in tacrolimus dosing to continue to target trough levels ≤ 5 ng/mL prior to randomization.
Key exclusion criteria (7 listed)
- Patients who are recipients of multiple solid organ transplants, (e.g., multivisceral or combined liver-kidney transplants), or have previously received an organ or tissue transplanted, or who received an AB0 incompatible transplant.
- Patients who experienced more than one episode of treated biopsy proven acute rejection (BANFF ≥ 3 or RAI ≥ 7) or one steroid-resistant acute rejection.
- Patients who require renal replacement therapy.
- Patients with a confirmed spot urine protein/creatinine ratio that indicates ≥1.0 g/24 hrs of proteinuria.
- History of malignancy of any organ system within the past 5 years whether or not there is evidence of local recurrence or metastases, other than non-metastatic basal or squamous cell carcinoma of the skin or HCC.
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 |
|---|---|---|
| EverolimusCommercial product labeled according to local requirements will be provided as 0.25 mg and 0.75 mg tablets for oral administration. | Drug | Group A (Tacrolimus Elimination Arm), Group B (Tacrolimus Minimization Arm) |
| TacrolimusCommercial product labeled according to local requirements will be provided as 0.5 mg, 1.0 mg and 5.0 mg capsules for oral administration. | Drug | Group A (Tacrolimus Elimination Arm), Group B (Tacrolimus Minimization Arm) |
Primary outcome
Renal Function Assessed by Estimated Glomerular Filtartion Rate (eGFR)
Time frame: At 12 months post-transplant
Renal function was assessed by eGFR using the MDRD-4 formula at 12 months after transplant: eGFR = 186.3 * (serum creatinine)-1.154 * age-0.203 * (0.742 for women) * (1.21 if African American) where serum creatinine was in mg/dL and age in years.
2 secondary outcomes
Percentage of Participants With Treated Biopsy Proven Acute Rejection (tBPAR) Acute Rejection (AR), Graft Loss (GL) or Death (D)
Time frame: At 12 and 18 months post-transplant
Change From Baseline (Randomization) in Serum Creatinine at 12 Months Post-transplant
Time frame: baseline, 12 months post-transplant
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Feb 2019.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: Undecided. Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com
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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 Everolimus and Tacrolimus in people with Liver Transplantation, run by Novartis Pharmaceuticals at 14 sites in Italy.
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 6 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 28 Feb 2019. 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 Italy. 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 28 Feb 2019). 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?
Renal Function Assessed by Estimated Glomerular Filtartion Rate (eGFR) (time frame: At 12 months post-transplant). 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 28 Feb 2019.