de Novo Kidney Transplant RecipientsPhase 3EVIDENCENCT01023815
Once-a-day Regimen With Everolimus, Low Dose Cyclosporine and Steroids in Comparison With Steroid Withdrawal or Twice a Day Regimen With Everolimus, Low Dose Cyclosporine and Steroids.
A Phase 3 study testing everolimus, cyclosporine and Prednison (continuous steroids) in people with de Novo Kidney Transplant Recipients and Renal Transplantation, run by Novartis at 28 sites in Italy.
Trial summary
This study will compare the following immunosuppressive regimens in recipients of kidney transplantation: A) everolimus, cyclosporine and steroids given once-a-day; B) everolimus and cyclosporine given twice a day with steroid withdrawal; C) everolimus, cyclosporine given twice a day and continuous steroids. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- de Novo Kidney Transplant Recipients, Renal Transplantation
- What is being tested?
- everolimus, cyclosporine and Prednison (continuous steroids)
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 330 participants
- Where
- 28 sitesItaly
- Study dates
- Apr 2009to Jul 2012
- 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
- recipients of 1st or 2nd single kidney transplant
- donor age >14 years
- females capable of becoming pregnant must have a negative serum pregnancy test within 7 days prior to or at Baseline (Visit 2), and are required to practice an approved method of birth control for the duration of the study and for a period of 2 months following discontinuation of study medication
- patientswho are willing and able to participate in the study and from whom written informed consent has been obtained
Who cannot join
- Exclusion criteria at screening (pre-transplantation, Visit 1):
- recipients of kidney-pancreas transplant, double kidney or any other transplant
- recipients of a 2nd kidney transplant who lost the 1st for immunological reasons
- focal segmental glomerulosclerosis (FSGS), primary oxaluria or other diseases (as cause of end stage renal failure - ESRF) at high risk of rapid recurrence or requiring continuous corticosteroid treatment
- recipients of A-B-O incompatible transplants
- historical or current peak PRA of >25% (current = 3 months)
Show all 32Show fewer
- patients with already existing antibodies against the donor
- thrombocytopenia (platelets <75,000/mm³), absolute neutrophil count of <1,500/mm³, leucopenia (leucocytes <2,500/mm³), or hemoglobin <6 g/dL
- symptoms of significant somatic or mental illness. Inability to cooperate or communicate with the investigator, or to comply with the study requirements, or to give informed consent
- history of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases
- patients who are HIV positive or Hepatitis B surface antigen positive (HbsAg); HCV positive patients receiving interferon and/or ribavirin
- evidence of severe liver disease (incl. abnormal liver enzyme profile, i.e. AST, ALT or total bilirubin >3 times UNL)
- evidence of drug or alcohol abuse
- body mass index (BMI) >35
- patients who need to be treated with drugs known to strongly interact with CsA and/or everolimus (as detailed in Appendix 2 of the protocol) should be excluded, if according the investigator this interferes with the objectives of the study
- women of child-bearing potential, UNLESS they are using two birth control methods. The two methods can be a double barrier method or a barrier method plus a hormonal method
- pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (>5 mIU/mL)
- use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of enrollment, whichever is longer
- history of hypersensitivity to any of the study drugs or to drugs of similar chemical classes
- patients with severe active infections or any other medical condition(s) that in the view of the investigator prohibits participation in the study (specify as required)
- Additional exclusion criteria post-transplantation (Visit 2):
- graft not perfused or with thrombosis of the main vessels, according to angioscintigraphy or echocolordoppler within 48 hours after the end of surgical procedure
- To avoid any possible influence of the confounding factors on the results of this study additional exclusion criteria at randomization were (Visit 5, Month 3):
- unsatisfactory renal function (CrCl according Cockcroft and Gault<40 mL/min)
- proteinuria ≥0.8 g/24 hrs
- steroid-resistant, humoral, moderate/severe (BANFF grade ≥II) biopsy proven acute rejections
- multiple (2 or more) biopsy proven or treated acute rejections or acute rejections leading to relevant loss of renal function
- acute rejection or impairment of renal function (increase of serum creatinine>30%) in the month preceding randomization
- severe/uncontrollable adverse events with suspected relationship to everolimus (e.g. anemia, oral aphtosis, arthralgia) for the control of which the investigator has planned the withdrawal of everolimus
- severe infections requiring hospitalization in the two weeks preceding randomization
- poor compliance to prescribed treatments
- Other protocol-defined inclusion/exclusion criteria may apply
Trial locations and contacts
28 sites in 1 country.
28 sites in 1 country
Italy28 sites
Novartis Investigative Site
Ancona, 60100
Novartis Investigative Site
Bologna
Novartis Investigative Site
Brescia
Novartis Investigative Site
Cagliari
Novartis Investigative Site
Catania
Novartis Investigative Site
Coppito
Novartis Investigative Site
Florence
Novartis Investigative Site
Genova, 16132
Novartis Investigative Site
Milan, 20122
Novartis Investigative Site
Modena, 41100
Novartis Investigative Site
Naples
Novartis Investigative Site
Novara, 28100
Novartis Investigative Site
Padova
Novartis Investigative Site
Palermo
Novartis Investigative Site
Parma
Novartis Investigative Site
Perugia, Perugia, 06070
Novarits Investigative Site
Pisa
Novartis Investigative Site
Roma
Novartis Investigative Site
Rome
Novartis Investigative Site
Salerno
Novartis Investigative Site
Sassari, Sassari, 07100
Novartis Investigative Site
Siena, 53100
Novartis Investigative Site
Torino, 10126
Novartis Investigative Site
Treviso
Novartis InvestigativeSite
Udine
Novartis Investigative Site
Varese
Novartis Investigative Site
Verona
Novartis Investigative Site
Vicenza
About this study
Official title: Once-a-day Regimen or Steroid Withdrawal in de Novo Kidney Transplant Recipients Treated With Everolimus, Cyclosporine and Steroids: a 12-month, Prospective, Randomized, Multicenter, Open-label Study. The EVIDENCE Study (EVerolImus Once-a-Day rEgimen With Neoral Versus Corticosteroid Elimination).
This study will compare the following immunosuppressive regimens in recipients of kidney transplantation: A) everolimus, cyclosporine and steroids given once-a-day; B) everolimus and cyclosporine given twice a day with steroid withdrawal; C) everolimus, cyclosporine given twice a day and continuous steroids. The purpose of this study is to evaluate regimens A and B in comparison with the control group (group C) for efficacy, using as main endpoint the treatment failure rate, a composite endpoint including death, graft loss, BPAR and lost to follow-up between randomization and Month 12.
- Being tested
- everolimus, cyclosporine, Prednison (continuous steroids)
- Keywords
- Immunosuppression, renal transplantation, once-a-day regimen, steroid withdrawal, drug minimization, immunosuppression for prevention of acute rejections
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
everolimusDrug
Also called Certican®)
Everolimus (Certican®) was provided in blisters containing tablets of 0.25 mg and 0.75 mg. Everolimus was initiated within 48 hours after graft reperfusion and it was administered orally.
cyclosporineDrug
Also called CsA, Sandimmun® Neoral®
Cyclosporine for microemulsion (CsA, Sandimmun® Neoral®) was coadministered with everolimus at the same time of the day. CsA was available in alu-alu blisters containing soft gelatine capsules of 100 mg, 50 mg, 25 mg and 10 mg. Oral solution, as bottles containing 50 mL of solution (100 mg/mL) has been provided and used in case the drug had been administered to patients by nasogastric tube immediately after transplant.
Prednison (continuous steroids)Drug
continuous steroids
| Study group | Role | What they receive |
|---|---|---|
| Group A -Once-a-day regimen | Experimental | Everolimus: in patients randomized to Group A before Amendment 1 approval, from the day following randomization, the whole daily dose of everolimus was taken in the morning, at the same time of the CsA and steroid dosing. At the Rand+1W visit, the everolimus dose was adjusted to reach and maintain everolimus blood levels between 5 and 8 ng/mL until end of Month 12.
Cyclosporine: in patients randomized to Group A before Amendment 1 approval, from the day following randomization, the whole cyclosporine daily dose was taken in the morning. The dose was then adjusted to maintain C2 levels between 350 and 700 ng/mL.
Prednisone: In patients randomized to Group A before Amendment 1 approval, the dose of prednisone was kept stable at 5 mg/day in the morning. Receives: Drug: everolimus; Drug: cyclosporine; Drug: Prednison (continuous steroids) |
| Group B - Steroid Withdrawal group | Experimental | Everolimus: after randomization the everolimus dose was adjusted, if necessary, to maintain a C0 within 6-10 ng/mL until M12.
Cyclosporine:after randomization the cyclosporine dose was adjusted to maintain CsA C2 levels within 300-500 ng/mL until M12.
Prednisone: starting from Visit 5 (day 90 ± 28 days), oral prednisone was tapered until complete stop. It was recommended to taper prednisone by 1 mg/week until complete stop in 5 to 6 weeks. Receives: Drug: everolimus; Drug: cyclosporine; Drug: Prednison (continuous steroids) |
| Group C - Standard twice-a-day group | Active comparator | Everolimus: after randomization the everolimus dose was adjusted, if necessary, in order to maintain a C0 within 6-10 ng/mL until M12.
Cyclosporine: after randomization the cyclosporine dose was gradually adjusted to reach and maintain C2 blood levels of 200-450 ng/mL between Month 6 and Month 12.
Prednisone: the dose of prednisone was kept stable at 5 mg/day in the morning. Receives: Drug: everolimus; Drug: cyclosporine; Drug: Prednison (continuous steroids) |
| Not Randomized Population (NRP) | Experimental | NRP defined in whom a renal transplantation was performed, received at least one dose of study drug (everolimus) but who did not qualify for randomization at Visit 5, Day 90. This group was addressed as "not randomized patients" (NRP) and described with respect to baseline characteristics, treatment and outcome variables. Receives: Drug: everolimus |
What is being measured
The primary outcome is the main question the study is designed to answer.
Treatment Failure Rate
Occurrence or not of treatment failure in each patient. Treatment failure was defined as a composite endpoint of biopsy-proven acute rejection (a biopsy graded IA, IB, IIA, IIB or III according to Banff '97 grading with 2007 update), graft loss, death or lost to follow-up occurring after randomization (V5) and within M12 (V9).
Measured: Between randomization (Month 3) and Month 12
Secondary outcomes (5)
Changes in the Estimated Glomerular Filtration Rate (eGFR) Between Randomization (Month 3) and Month 12
eGFR by Nankivell, in terms of descriptive statistics and change vs randomization visit - to compare the changes in the estimated GFR (Nankivell) between randomization and Month 12 in the steroid withdrawal group (Group B) to the change observed in the standard twice-a-day group (Group C), for non-inferiority
Measured: Month 3 to Month 12
Biopsy Proven Acute Rejection (BPAR) Rate Between Randomization and Month 12
Occurrence of BPAR (after randomization) between arm B (steroid withdrawal group) and arm c (standard twice-a-day group).
BPAR was defined as a biopsy graded IA, IB, IIA, IIB, or III according to Banff 1997 grading with 2007 update.
Measured: Month 3 to Month 12
Number of Participants With Graft and Patient Survival After Randomization
Graft Survival, calculated from the date of transplantation to the date of irreversible graft failure signified by return to long-term retransplantation or the date of the last follow-up during the period when the transplant was still functioning or to the date of death.
Patient survival, calculated from the date of transplantation to the date of death or the date of the last follow-up.
Measured: Month 3 to Month 12
Change in Estimated Creatine Clearance
At each visit, estimated creatinine clearance was measured in the local laboratory to analyze the evolution of the renal function. The following indirect measures of renal function were computed: estimated creatinine clearance according to Cockcroft and Gault formula and MDRD formula.
Measured: M3, M12
Change in Serum Creatinine
Serum creatinine (a blood measurement) is an important indicator of renal health because it is an easily-measured by-product of muscle metabolism. Measuring serum creatinine is a simple test and it is the most commonly used indicator of renal function.
Measured: M3, M12
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Dec 2009 (estimated)
- Study startApr 2009
- Primary completionJul 2012
- Study completionJul 2012
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 de Novo Kidney Transplant RecipientsStudies of the same condition, open and under way.
- 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
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 330 participants (actual)
Sponsor and investigators
- Lead sponsor
- Novartis
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Novartis Pharmaceuticals, Study director, Novartis Pharmaceuticals
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01023815
- Sponsor's protocol ID
- CRAD001AIT12
- Acronym
- EVIDENCE
- Status last verified
- Jun 2016
- First submitted
- 1 Dec 2009
- Last updated
- 19 Jul 2016
- Results posted
- Yes, on ClinicalTrials.gov
Study at a glance
From the registry record, last updated by the sponsor on 19 Jul 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Once-a-day Regimen or Steroid Withdrawal in de Novo Kidney Transplant Recipients Treated With Everolimus, Cyclosporine and Steroids: a 12-month, Prospective, Randomized, Multicenter, Open-label Study. The EVIDENCE Study (EVerolImus Once-a-Day rEgimen With Neoral Versus Corticosteroid Elimination).
- ClinicalTrials.gov ID
- NCT01023815
- Acronym / sponsor ID
- EVIDENCE / CRAD001AIT12
- Keywords
- Immunosuppression, renal transplantation, once-a-day regimen, steroid withdrawal, drug minimization, immunosuppression for prevention of acute rejections
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 330 participants (actual)
- Lead sponsor
- NovartisIndustry (pharma, biotech, devices)
- Study start
- Apr 2009
- Primary completion
- Jul 2012 (actual)
- Study completion
- Jul 2012 (actual)
- First posted
- 2 Dec 2009 (estimated)
- Results
- Posted 14 Nov 2013
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This study will compare the following immunosuppressive regimens in recipients of kidney transplantation: A) everolimus, cyclosporine and steroids given once-a-day; B) everolimus and cyclosporine given twice a day with steroid withdrawal; C) everolimus, cyclosporine given twice a day and continuous steroids. The purpose of this study is to evaluate regimens A and B in comparison with the control group (group C) for efficacy, using as main endpoint the treatment failure rate, a composite endpoint including death, graft loss, BPAR and lost to follow-up between randomization and Month 12.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Group A -Once-a-day regimen | Experimental | Drug: everolimus, Drug: cyclosporine, Drug: Prednison (continuous steroids)Everolimus: in patients randomized to Group A before Amendment 1 approval, from the day following randomization, the whole daily dose of everolimus was taken in the morning, at the same time of the CsA and steroid dosing. At the Rand+1W visit, the everolimus dose was adjusted to reach and maintain everolimus blood levels between 5 and 8 ng/mL until end of Month 12. Cyclosporine: in patients randomized to Group A before Amendment 1 approval, from the day following randomization, the whole cyclosporine daily dose was taken in the morning. The dose was then adjusted to maintain C2 levels between 350 and 700 ng/mL. Prednisone: In patients randomized to Group A before Amendment 1 approval, the dose of prednisone was kept stable at 5 mg/day in the morning. |
| Group B - Steroid Withdrawal group | Experimental | Drug: everolimus, Drug: cyclosporine, Drug: Prednison (continuous steroids)Everolimus: after randomization the everolimus dose was adjusted, if necessary, to maintain a C0 within 6-10 ng/mL until M12. Cyclosporine:after randomization the cyclosporine dose was adjusted to maintain CsA C2 levels within 300-500 ng/mL until M12. Prednisone: starting from Visit 5 (day 90 ± 28 days), oral prednisone was tapered until complete stop. It was recommended to taper prednisone by 1 mg/week until complete stop in 5 to 6 weeks. |
| Group C - Standard twice-a-day group | Active comparator | Drug: everolimus, Drug: cyclosporine, Drug: Prednison (continuous steroids)Everolimus: after randomization the everolimus dose was adjusted, if necessary, in order to maintain a C0 within 6-10 ng/mL until M12. Cyclosporine: after randomization the cyclosporine dose was gradually adjusted to reach and maintain C2 blood levels of 200-450 ng/mL between Month 6 and Month 12. Prednisone: the dose of prednisone was kept stable at 5 mg/day in the morning. |
| Not Randomized Population (NRP) | Experimental | Drug: everolimusNRP defined in whom a renal transplantation was performed, received at least one dose of study drug (everolimus) but who did not qualify for randomization at Visit 5, Day 90. This group was addressed as "not randomized patients" (NRP) and described with respect to baseline characteristics, treatment and outcome variables. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- recipients of 1st or 2nd single kidney transplant
- donor age >14 years
- females capable of becoming pregnant must have a negative serum pregnancy test within 7 days prior to or at Baseline (Visit 2), and are required to practice an approved method of birth control for the duration of the study and for a period of 2 months following discontinuation of study medication
- patientswho are willing and able to participate in the study and from whom written informed consent has been obtained
Key exclusion criteria (32 listed)
- recipients of kidney-pancreas transplant, double kidney or any other transplant
- recipients of a 2nd kidney transplant who lost the 1st for immunological reasons
- focal segmental glomerulosclerosis (FSGS), primary oxaluria or other diseases (as cause of end stage renal failure - ESRF) at high risk of rapid recurrence or requiring continuous corticosteroid treatment
- recipients of A-B-O incompatible transplants
- historical or current peak PRA of >25% (current = 3 months)
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 |
|---|---|---|
| everolimusAlso: Certican®)Everolimus (Certican®) was provided in blisters containing tablets of 0.25 mg and 0.75 mg. Everolimus was initiated within 48 hours after graft reperfusion and it was administered orally. | Drug | Group A -Once-a-day regimen, Group B - Steroid Withdrawal group, Group C - Standard twice-a-day group, Not Randomized Population (NRP) |
| cyclosporineAlso: CsA, Sandimmun® Neoral®Cyclosporine for microemulsion (CsA, Sandimmun® Neoral®) was coadministered with everolimus at the same time of the day. CsA was available in alu-alu blisters containing soft gelatine capsules of 100 mg, 50 mg, 25 mg and 10 mg. Oral solution, as bottles containing 50 mL of solution (100 mg/mL) has been provided and used in case the drug had been administered to patients by nasogastric tube immediately after transplant. | Drug | Group A -Once-a-day regimen, Group B - Steroid Withdrawal group, Group C - Standard twice-a-day group |
| Prednison (continuous steroids)continuous steroids | Drug | Group A -Once-a-day regimen, Group B - Steroid Withdrawal group, Group C - Standard twice-a-day group |
Primary outcome
Treatment Failure Rate
Time frame: Between randomization (Month 3) and Month 12
Occurrence or not of treatment failure in each patient. Treatment failure was defined as a composite endpoint of biopsy-proven acute rejection (a biopsy graded IA, IB, IIA, IIB or III according to Banff '97 grading with 2007 update), graft loss, death or lost to follow-up occurring after randomization (V5) and within M12 (V9).
5 secondary outcomes
Changes in the Estimated Glomerular Filtration Rate (eGFR) Between Randomization (Month 3) and Month 12
Time frame: Month 3 to Month 12
Biopsy Proven Acute Rejection (BPAR) Rate Between Randomization and Month 12
Time frame: Month 3 to Month 12
Number of Participants With Graft and Patient Survival After Randomization
Time frame: Month 3 to Month 12
Change in Estimated Creatine Clearance
Time frame: M3, M12
Change in Serum Creatinine
Time frame: M3, M12
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Jul 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
28 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, cyclosporine and Prednison (continuous steroids) in people with de Novo Kidney Transplant Recipients and Renal Transplantation, run by Novartis at 28 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 4 inclusion and 32 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 19 Jul 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 28 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 14 Nov 2013). 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?
Treatment Failure Rate (time frame: Between randomization (Month 3) and Month 12). 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 19 Jul 2016.