End Stage Renal Failure With Renal TransplantNCT01653847
Study in Recipients of Renal Transplant Allograft to Evaluate the Impact of Two Immunosuppressive Regimens
A study testing Tacrolimus with MMF and Group 2: Tacrolimus with Everolimus. in people with End Stage Renal Failure With Renal Transplant, run by Northwestern University at 1 site in United States.
Trial summary
The immune system is the body's defense against infection and other disease. After transplantation, the body sees the new organ as "foreign" and tries to destroy or "reject" it. Immunosuppressive medications help to prevent the immune system from attacking a transplanted organ. Read more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- End Stage Renal Failure With Renal Transplant
- What is being tested?
- Tacrolimus with MMF and Group 2: Tacrolimus with Everolimus.
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 88 participants
- Where
- 1 siteUnited States
- Study dates
- Feb 2013to May 2020
- Phase
- Interventional
- 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 to 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Subjects should be adults between 18 and 70 years of age
- Subjects can be either gender or of any ethnic background
- Subjects should be single organ recipients (kidney only)
- Subjects must be able to understand the protocol and provide informed consent.
- Recipient of living donor kidney transplants
- Panel reactive antibody (PRA) < 20%
Who cannot join
- Subjects with End Stage Renal Disease (ESRD) secondary to primary focal segmental glomerulonephritis (FSGS).
- Inability to fully understand the purpose of the study and the inability to sign the informed consent
- Subjects with a significant or active infection
- Subjects who are pregnant or nursing females
- Subjects with a history of severe hyperlipidemia not controlled with statins, patients with Cholesterol > 400mg/dl
- Subjects with a platelet count < 100,000mm3, WBC < 2,000mm3 (or clinical practice)
- Subjects, who, due to the existence of a surgical, medical or psychiatric condition, other than the current transplant, which in the opinion of the investigator, precludes enrollment into this trial.
Trial locations and contacts
1 site in 1 country.
United States1 site
Northwestern Memorial Hospital
Chicago, Illinois, 60611
About this study
Official title: Impact of Two Prednisone-free Maintenance Immunosuppressive Regimens With Reduced Dose FK506+Everolimus vs. Standard Dose Tacrolimus (FK506)+ Mycophenolate Mofetil (MMF) on Subpopulation of T and B Cells, Renal Allograft Function and Gene Expression Profiles in Renal Allograft Biopsies at 12 Months Post-transplant. Prospective Single Center Study in Recipients of Renal Transplant Allograft.
The immune system is the body's defense against infection and other disease. After transplantation, the body sees the new organ as "foreign" and tries to destroy or "reject" it. Immunosuppressive medications help to prevent the immune system from attacking a transplanted organ. The primary purpose of this study is to investigate the impact of two maintenance immunosuppressive regimens. Subjects who enroll in this study will be randomly selected to have tacrolimus and everolimus (group 1) or tacrolimus and mycophenolate mofetil (group 2) as their immunosuppression medication.
This study will enroll adult patients who are scheduled to receive a kidney transplant.
The study is designed to understand the mechanisms of Everolimus in regards to kidney function in transplant recipients. The investigators hypothesis is that decreased exposure to Tacrolimus to the immune system will then translate in better renal allograft function.
Read the detailed description
Immunosuppressive therapy with the calcineurin inhibitors (CNI) Cyclosporine (CsA) and Tacrolimus (Tac), have radically changed the field of organ transplantation. Ironically, although extensively and effectively used for kidney transplantation and other solid organ transplants, CsA and Tac cause important adverse renal side effects: acute and chronic renal dysfunction, hemolytic-uremic syndrome, hypertension, electrolyte disturbances and tubular acidosis. Chronic nephrotoxicity from CNI has been implicated as a principal cause of post-transplant renal dysfunction and it is characterized by an irreversible and progressive tubular atrophy, interstitial fibrosis, and focal hyalinosis of small renal arteries and arterioles. Furthermore, this class of medications is associated also, by blocking Interleukin-2 (IL2) production, with negative impact on regulatory T cells (T-Regs) generation (an important subpopulation of T helper cells that has been associated with positive immunomodulation and donor specific hypo responsiveness).
In renal transplant recipients, complete avoidance of calcineurin inhibitors from the time of renal transplant surgery has been associated with increased incidence of acute cellular rejection, and the combination of mammalian target of rapamycin (mTOR) inhibitors with full dose CNI has been shown to be synergistically nephrotoxic and it has been associated with poor graft outcome. CNI conversion to mTOR inhibitors, at different time point post-transplant, has been tested with promising results, by different investigators and by the investigators group. The investigators have shown that in a Prednisone-free immunosuppression, conversion from Tacrolimus to mTor inhibitors at different time point post transplant is safe, it is not associated with an increased risk of acute rejection and more importantly it is associated with an a persistent increase of regulatory T cells (Data presented at the American Transplant Congress (ATC) 09 and 2010) Recently the A2309 study allowed Everolimus to be FDA approved. The A2309 was a study designed to combined reduced dose Cyclosporine+Everolimus. Interesting the reduced exposure to Cyclosporine was not associated with an increase rate of albumin-creatinine ratio (ACR) and renal allograft function was well maintained compared to the control group. The A2309 opens then an important question regarding the mechanism(s) that can explain the efficacy of a low dose CNI with an mTOR inhibitor in preventing acute allograft rejection.
The present proposal is designed to understand the mechanisms of the synergistic effect(s) of low dose CNI and mTOR inhibitors (Everolimus) in controlling allo-reactive T and B cells while expanding T-Regs.
The investigators hypothesis based in published data and from their laboratory (see preliminary data-Supportive documents), is that mTOR inhibitors allow expansion of T-Regs and low exposure of CNI is sufficient to control allo-reactive T cells. Decrease exposure to CNI and concomitant increase of T-Regs will then translate in better renal allograft function and histology.
- Being tested
- Tacrolimus with MMF, Group 2: Tacrolimus with Everolimus.
- Keywords
- transplant, kidney, renal disease
- Medical subject headings
- Kidney Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Tacrolimus with MMFDrug
Also called Tacrolimus, FK 506, mycophenolate mofetil, MMF
Standard dose Tacrolimus and MMF. This will follow standard of care procedures at Northwestern Memorial Hospital's Comprehensive Transplant Center. MMF trough or area under the concentration time curve (AUC) shall not be used to adjust dosing. In this group, Tacrolimus will be initiated according to our practice. The Tacrolimus dose will be adjusted from day 3 on to achieve a target whole blood trough concentration of 8 ng/mL to 10 ng/mL. From month 2 until Month 6, the target Tacrolimus trough level will be reduced to 6 ng/mL to 8 ng/mL. After month 6, the target level of Tacrolimus will be reduced to 4 ng/mL to 8 ng/mL.
Group 2: Tacrolimus with Everolimus.Drug
Also called Everolimus, Zortress, Tacrolimus, FK 506
From day 5 on, the starting dose of Everolimus (0.75 mg bid) will be increased if the trough level is < 3 ng/mL, or reduced if the trough level is > 8 ng/mL. Tacrolimus will be initiated according to our practice. In this treatment arm, the Tacrolimus dose will be adjusted from day 3 on, to a target whole blood trough concentration of 4 ng/mL to 7 ng/mL. From month 2 until Month 6, the target Tacrolimus trough level will be 3 ng/mL to 6 ng/mL. After month 6, the Tacrolimus dose should be adjusted in order to achieve a target trough level of 2 ng/mL to 5 ng/mL. MMF dose will be initiated as 1 g b.i.d. (2 g/day). Adjustments should be made for adverse events including but not limited to gastrointestinal intolerance and a decrease in white blood cell (WBC).
| Study group | Role | What they receive |
|---|---|---|
| Group 1: Tacrolimus with MMF. | Active comparator | This group will receive a standard dose Tacrolimus and MMF. This will follow standard of care protocol at Northwestern Memorial Hospital's Comprehensive Transplant Center. Receives: Drug: Tacrolimus with MMF |
| Group 2: Tacrolimus with Everolimus | Active comparator | This group will receive a low dose Tacrolimus with concentration controlled Everolimus Receives: Drug: Group 2: Tacrolimus with Everolimus. |
| Donors | No intervention | One time blood samples will be collected from kidney donors to recipients in this study |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in T Cell & B Cell Generation
Evaluate the change in regulatory T cell generation and review the relationship of the newly generated T cells with their function in the two maintenance immunosuppressive regimens at baseline, 3 and 12 months post-transplant.
Measured: Baseline, 3 months, and 12 months post-transplant
Change in Glomerular Filtration Rate (GFR)
Evaluate the change in graft function (as measured by GFR) at 12 months post-transplant from baseline.
Measured: 3 months, 6 months, and 12 months post-transplant
Secondary outcomes (3)
Patient Survival
The number of patients who were alive at 2 years post transplant
Measured: baseline - 24 months post transplant
Renal Allograft Survival
The number of subjects with renal allograft survival.
Measured: 12 months post-transplant
Acute Rejection
Number of subjects who experience acute rejection of the renal allograft.
Measured: 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 posted31 Jul 2012 (estimated)
- Study startFeb 2013
- Primary completionMay 2020
- Study completionMay 2020
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 End Stage Renal Failure With Renal TransplantStudies of the same condition, open and under way.
- More trials run by Northwestern UniversityThe 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 N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 88 participants (actual)
Sponsor and investigators
- Lead sponsor
- Northwestern University
- Sponsor type
- University, hospital or other
- Collaborators
- Novartis
- Responsible party
- Principal investigator, Lorenzo Gallon, Northwestern University
- Investigators
- Lorenzo Gallon, MD, Principal investigator, Northwestern University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01653847
- Sponsor's protocol ID
- Novartis- Everolimus
- Status last verified
- Feb 2021
- First submitted
- 4 Apr 2012
- Last updated
- 2 Mar 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 2 Mar 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Impact of Two Prednisone-free Maintenance Immunosuppressive Regimens With Reduced Dose FK506+Everolimus vs. Standard Dose Tacrolimus (FK506)+ Mycophenolate Mofetil (MMF) on Subpopulation of T and B Cells, Renal Allograft Function and Gene Expression Profiles in Renal Allograft Biopsies at 12 Months Post-transplant. Prospective Single Center Study in Recipients of Renal Transplant Allograft.
- ClinicalTrials.gov ID
- NCT01653847
- Acronym / sponsor ID
- Novartis- Everolimus
- Keywords
- transplant, kidney, renal disease
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 88 participants (actual)
- Lead sponsor
- Northwestern UniversityUniversity, hospital or other
- Collaborators
- Novartis
- Study start
- Feb 2013
- Primary completion
- May 2020 (actual)
- Study completion
- May 2020 (actual)
- First posted
- 31 Jul 2012 (estimated)
- Results
- Posted 2 Mar 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The immune system is the body's defense against infection and other disease. After transplantation, the body sees the new organ as "foreign" and tries to destroy or "reject" it. Immunosuppressive medications help to prevent the immune system from attacking a transplanted organ. The primary purpose of this study is to investigate the impact of two maintenance immunosuppressive regimens. Subjects who enroll in this study will be randomly selected to have tacrolimus and everolimus (group 1) or tacrolimus and mycophenolate mofetil (group 2) as their immunosuppression medication.
This study will enroll adult patients who are scheduled to receive a kidney transplant.
The study is designed to understand the mechanisms of Everolimus in regards to kidney function in transplant recipients. The investigators hypothesis is that decreased exposure to Tacrolimus to the immune system will then translate in better renal allograft function.
Detailed description
Immunosuppressive therapy with the calcineurin inhibitors (CNI) Cyclosporine (CsA) and Tacrolimus (Tac), have radically changed the field of organ transplantation. Ironically, although extensively and effectively used for kidney transplantation and other solid organ transplants, CsA and Tac cause important adverse renal side effects: acute and chronic renal dysfunction, hemolytic-uremic syndrome, hypertension, electrolyte disturbances and tubular acidosis. Chronic nephrotoxicity from CNI has been implicated as a principal cause of post-transplant renal dysfunction and it is characterized by an irreversible and progressive tubular atrophy, interstitial fibrosis, and focal hyalinosis of small renal arteries and arterioles. Furthermore, this class of medications is associated also, by blocking Interleukin-2 (IL2) production, with negative impact on regulatory T cells (T-Regs) generation (an important subpopulation of T helper cells that has been associated with positive immunomodulation and donor specific hypo responsiveness).
In renal transplant recipients, complete avoidance of calcineurin inhibitors from the time of renal transplant surgery has been associated with increased incidence of acute cellular rejection, and the combination of mammalian target of rapamycin (mTOR) inhibitors with full dose CNI has been shown to be synergistically nephrotoxic and it has been associated with poor graft outcome. CNI conversion to mTOR inhibitors, at different time point post-transplant, has been tested with promising results, by different investigators and by the investigators group. The investigators have shown that in a Prednisone-free immunosuppression, conversion from Tacrolimus to mTor inhibitors at different time point post transplant is safe, it is not associated with an increased risk of acute rejection and more importantly it is associated with an a persistent increase of regulatory T cells (Data presented at the American Transplant Congress (ATC) 09 and 2010) Recently the A2309 study allowed Everolimus to be FDA approved. The A2309 was a study designed to combined reduced dose Cyclosporine+Everolimus. Interesting the reduced exposure to Cyclosporine was not associated with an increase rate of albumin-creatinine ratio (ACR) and renal allograft function was well maintained compared to the control group. The A2309 opens then an important question regarding the mechanism(s) that can explain the efficacy of a low dose CNI with an mTOR inhibitor in preventing acute allograft rejection.
The present proposal is designed to understand the mechanisms of the synergistic effect(s) of low dose CNI and mTOR inhibitors (Everolimus) in controlling allo-reactive T and B cells while expanding T-Regs.
The investigators hypothesis based in published data and from their laboratory (see preliminary data-Supportive documents), is that mTOR inhibitors allow expansion of T-Regs and low exposure of CNI is sufficient to control allo-reactive T cells. Decrease exposure to CNI and concomitant increase of T-Regs will then translate in better renal allograft function and histology.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Group 1: Tacrolimus with MMF. | Active comparator | Drug: Tacrolimus with MMFThis group will receive a standard dose Tacrolimus and MMF. This will follow standard of care protocol at Northwestern Memorial Hospital's Comprehensive Transplant Center. |
| Group 2: Tacrolimus with Everolimus | Active comparator | Drug: Group 2: Tacrolimus with Everolimus.This group will receive a low dose Tacrolimus with concentration controlled Everolimus |
| Donors | No intervention | –One time blood samples will be collected from kidney donors to recipients in this study |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- Subjects should be adults between 18 and 70 years of age
- Subjects can be either gender or of any ethnic background
- Subjects should be single organ recipients (kidney only)
- Subjects must be able to understand the protocol and provide informed consent.
- Recipient of living donor kidney transplants
Key exclusion criteria (7 listed)
- Subjects with End Stage Renal Disease (ESRD) secondary to primary focal segmental glomerulonephritis (FSGS).
- Inability to fully understand the purpose of the study and the inability to sign the informed consent
- Subjects with a significant or active infection
- Subjects who are pregnant or nursing females
- Subjects with a history of severe hyperlipidemia not controlled with statins, patients with Cholesterol > 400mg/dl
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 |
|---|---|---|
| Tacrolimus with MMFAlso: Tacrolimus, FK 506, mycophenolate mofetil, MMFStandard dose Tacrolimus and MMF. This will follow standard of care procedures at Northwestern Memorial Hospital's Comprehensive Transplant Center. MMF trough or area under the concentration time curve (AUC) shall not be used to adjust dosing. In this group, Tacrolimus will be initiated according to our practice. The Tacrolimus dose will be adjusted from day 3 on to achieve a target whole blood trough concentration of 8 ng/mL to 10 ng/mL. From month 2 until Month 6, the target Tacrolimus trough level will be reduced to 6 ng/mL to 8 ng/mL. After month 6, the target level of Tacrolimus will be reduced to 4 ng/mL to 8 ng/mL. | Drug | Group 1: Tacrolimus with MMF. |
| Group 2: Tacrolimus with Everolimus.Also: Everolimus, Zortress, Tacrolimus, FK 506From day 5 on, the starting dose of Everolimus (0.75 mg bid) will be increased if the trough level is < 3 ng/mL, or reduced if the trough level is > 8 ng/mL. Tacrolimus will be initiated according to our practice. In this treatment arm, the Tacrolimus dose will be adjusted from day 3 on, to a target whole blood trough concentration of 4 ng/mL to 7 ng/mL. From month 2 until Month 6, the target Tacrolimus trough level will be 3 ng/mL to 6 ng/mL. After month 6, the Tacrolimus dose should be adjusted in order to achieve a target trough level of 2 ng/mL to 5 ng/mL. MMF dose will be initiated as 1 g b.i.d. (2 g/day). Adjustments should be made for adverse events including but not limited to gastrointestinal intolerance and a decrease in white blood cell (WBC). | Drug | Group 2: Tacrolimus with Everolimus |
Primary outcome
Change in T Cell & B Cell Generation
Time frame: Baseline, 3 months, and 12 months post-transplant
Evaluate the change in regulatory T cell generation and review the relationship of the newly generated T cells with their function in the two maintenance immunosuppressive regimens at baseline, 3 and 12 months post-transplant.
Change in Glomerular Filtration Rate (GFR)
Time frame: 3 months, 6 months, and 12 months post-transplant
Evaluate the change in graft function (as measured by GFR) at 12 months post-transplant from baseline.
3 secondary outcomes
Patient Survival
Time frame: baseline - 24 months post transplant
Renal Allograft Survival
Time frame: 12 months post-transplant
Acute Rejection
Time frame: 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 2 Mar 2021.
- 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.
Lorenzo Gallon, MD principal investigator
Northwestern University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Tacrolimus with MMF and Group 2: Tacrolimus with Everolimus. in people with End Stage Renal Failure With Renal Transplant, run by Northwestern University at 1 site in United States.
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 2 Mar 2021. 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 United States. 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.
Are results available for this study?
Yes. Results are posted in the registry (first posted 2 Mar 2021). 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 in T Cell & B Cell Generation (time frame: Baseline, 3 months, and 12 months post-transplant). The study lists 2 primary outcomes in all. 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 2 Mar 2021.