Renal FailurePhase 3S&LNCT03672110
Slow and Low Start of a Tacrolimus Once Daily Immunosuppressive Regimen
A Phase 3 study testing Advagraf in people with Renal Failure and Renal Insufficiency, run by Technische Universität Dresden at 1 site in Germany.
Trial summary
The purpose of this study is to demonstrate non-inferiority of an advagraf based immunosuppressive regimen with slower dose tapering and lower starting dose of Advagraf compared with a standard Advagraf-based immunosuppressive regimen in de novo renal transplantation. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Renal Failure, Renal Insufficiency, Renal Disease
- What is being tested?
- Advagraf
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 400 participants
- Where
- 1 siteGermany
- Study dates
- Sep 2014to Dec 2025
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- male or female allograft recipients at least 18 years old
- primary or secondary kidney transplantation
- deceased or living donor
- normal immunological risk profile (PRA level > 20%, AB0-compatible donation, negative crossmatch)
- informed consent of the patient
Who cannot join
- graft loss due to severe rejection within the first year after transplantation (in case of secondary transplantation)
- multi-organ recipient
- patients receiving a kidney from a non-beating donor
- complete human leukocyte antigen (HLA)-identical living donor (twins)
- patients with a history of malignancy during the last five years (except squamous or basal cell carcinoma of the skin after successful treatment)
- patients with uncontrolled infectious disease, particularly patients who are HIV-positive or suffer from chronic hepatitis B or C or tuberculosis
Show all 16Show fewer
- patients with severe gastroenteric disorder, particularly severe diarrhea and symptoms of enteric malabsorption
- patients suffering from liver cirrhosis CHILD B or C or other severe liver disease (aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), GammaGT ≥ 3-fold increased)
- thrombopenia < 70,000/mm3
- leukopenia < 2,500/mm3
- participation in another clinical trial within the last 4 weeks prior to inclusion
- estimated addiction or other disorders that do not allow the person concerned, the nature and scope and possible consequences of the clinical trial
- pregnant or breast-feeding women
- women of childbearing age, except women who meet any of the following criteria: post-menopausal (12 months natural amenorrhea or 6 months amenorrhea with serum > 40 U/ml, postoperatively (6 weeks after bilateral oophorectomy with or without hysterectomy), regular and correct use of a contraceptive method with error rate < 1 % per year (e. g. implants, depot injections, oral contraceptives, intrauterine device IUD), sexual abstinence, vasectomy of the partner
- evidence that the patient is likely to fail to comply with the protocol (e. g. lack of cooperation)
- hypersensitivity to Advagraf or a product listed in the prescribing information other component as well as to other macrolides
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Slow and Low Start of a Tacrolimus Once Daily Immunosuppressive Regimen: A Multicentre Prospective Randomized Controlled Study
The purpose of this study is to demonstrate non-inferiority of an advagraf based immunosuppressive regimen with slower dose tapering and lower starting dose of Advagraf compared with a standard Advagraf-based immunosuppressive regimen in de novo renal transplantation. Non inferiority will be assessed by a combined study endpoint consisting of the development of biopsy-proven rejection of BANFF class Ia or higher and/or graft loss and/or patient death within the first six months after renal transplantation.
Read the detailed description
The most widely used immunosuppressive regimen, in adult kidney transplant recipients, consists of an induction therapy accompanied by maintenance with tacrolimus, mycophenolate and steroids. In the long term, tacrolimus is the single most effective immunosuppressive agent. For adult kidney transplant recipients maintenance of therapeutic levels remains crucial regarding the prevention of allograft rejections. Greater blood levels variability is associated with inferior graft survival as well as non-adherence. Lower variability of tacrolimus blood levels after conversion to extended release tacrolimus formulations has been shown. In addition, once-daily administration promotes patient adherence. The latter is one of the major causes for allograft loss.
In the first week after kidney transplantation stable tacrolimus blood levels are hardly achievable. Especially extended release tacrolimus formulations often yield high tacrolimus blood levels. High blood levels are a known risk factor for delayed graft function, which leads to a prolonged hospitalization and a reduced graft survival. Additionally high blood levels are associated with polyomavirus infections and may increase the incidence of new-onset diabetes after renal transplantation.
Taking this into consideration, authors demand for calcineurin inhibitor (CNI)-free immunosuppression or the delayed onset of CNI therapy after a stable graft function is reached. This would inevitably lead to a higher rate of acute allograft rejections in the early phase after kidney transplantation. Avoiding high tacrolimus levels, especially early after transplantation, to minimize delayed graft function as well as long term undesirable side effects, seems particularly necessary.
For early dose adjustments of extended release tacrolimus formulations, more medical experience is needed compared to immediate release formulations. More stable tacrolimus blood levels can be seen after the first week of administration.
To avoid high blood levels of tacrolimus, especially early after transplantation, the investigators aim to demonstrate in this study a non-inferiority of a low dose extended release tacrolimus regimen compared to a standard extended release tacrolimus-based immunosuppressive regimen in de novo renal transplantation. Given inclusion criteria and excluding the exclusion criteria, participants will be randomized into two groups, a standard tacrolimus administration group with daily dose adjustments within the first week after transplantation and a fixed dose tacrolimus administration group, without dose adjustments within the first week after transplantation. In the first 6 months after renal transplantation different blood levels of tacrolimus shall be reached. In the case of the standard tacrolimus administration group the investigators aim at tacrolimus blood levels of 7-9 ng/ml in the first 2 months after transplantation and 6-8 ng/ml for days 61 to 180. In the fixed dose tacrolimus administration group, the low extended release tacrolimus dose of 5mg per day well no be changed in the first week after transplantation. For safety reasons blinded measurements will take place in the first week and study officials will be alerted in case of repeated tacrolimus levels > 20 ng/ml. On days 7 to 60 the investigators aim at tacrolimus blood levels of 5-7 ng/ml and from days 61 to 180 4-6 ng/ml. Non inferiority will be assessed by a combined study endpoint consisting of the development of biopsy-proven rejection of BANFF class Ia or higher and/or graft loss and/or patient death within the first six months after renal transplantation.
- Being tested
- Advagraf
- Medical subject headings
- Renal Insufficiency, Kidney Diseases, Renal Insufficiency, Chronic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AdvagrafDrug
Also called no other intervention name
intervention: different advagraf dosing in the study compared to the control arm, see above
| Study group | Role | What they receive |
|---|---|---|
| Standard tacrolimus group | Active comparator | Control group: Advagraf will be administered as usual (0.2mg/kg bodyweight), trough levels will be measured every day in the first week after kidney transplantation (TX) and Advagraf dose will be adjusted accordingly. Receives: Drug: Advagraf |
| Fixed dose tacrolimus group | Experimental | Study group: Advagraf will be administered per fix dose 5mg/day, trough levels will be blinded during the first week, there will be no adjustments in the first week after TX. Receives: Drug: Advagraf |
What is being measured
The primary outcome is the main question the study is designed to answer.
Combined endpoint: defined as biopsy-proven acute rejection, graft loss or death between the groups at month 6 post-transplantation in renal transplantation)
combined endpoint: defined as biopsy-proven acute rejection, graft loss or death between the groups at month 6 post-transplantation in renal transplantation
Measured: 6 months after transplantation
Secondary outcomes (25)
Rate of necessary dose modifications to achieve Advagraf target levels in early post-op period
rate of necessary dose modifications in order to achieve Advagraf target levels in the early postoperative period
Measured: 6 months after transplantation
Improved renal transplant function in the early postoperative period and 6 months post-op
renal function defined by need for renal replacement therapy as well as by means of glomerular filtration rate
Measured: 6 months after transplantation
Lower incidence of delayed graft function (DGF)
rate of DGF defined as need for at least one postoperative hemodialysis
Measured: 6 months after transplantation
Reduced incidence of new onset diabetes after renal Transplantation (NODAT)
incidence of NODAT. Diabetes mellitus defined by American Diabetes Association - Guidelines 2016
Measured: 6 months after transplantation
Reduced rates of infection
incidence of viral or other infections
Measured: 6 months after transplantation
Incidence of malignancies
incidence rate of biopsy proven malignancies
Measured: 6 months after transplantation
Incidence of fractures
incidence rate of radiography or clinically proven fractures
Measured: 6 months after transplantation
Incidence of heart failure
incidence rate of heart failure
Measured: 6 months after transplantation
Incidence of myocardial infarction
incidence rate of myocardial infarction
Measured: 6 months after transplantation
Incidence of venous thrombosis
incidence rate of venous thrombosis proven by color-coded duplex sonography or radiography
Measured: 6 months after transplantation
Incidence of peripheral vascular disease
incidence rate of peripheral vascular disease, sonography or radiography proven
Measured: 6 months after transplantation
Incidence of cerebrovascular disease
incidence rate of cerebrovascular disease, sonography or radiography proven
Measured: 6 months after transplantation
Incidence of hypercholesterolemia
hypercholesterolemia is defined as > upper limit of normal and measured in mmol/L
Measured: 6 months after transplantation
Incidence of hypertriglyceridemia
hypertriglyceridemia is defined as > upper limit of normal and measured in mmol/L
Measured: 6 months after transplantation
Incidence of hyperlipoproteinemia
hyperlipoproteinemia is defined as low density lipoproteins cholesterol > upper limit of normal and measured in mmol/L
Measured: 6 months after transplantation
Incidence of hypolipoproteinemia
hypolipoproteinemia is defined as high density lipoproteins cholesterol < lower limit of normal and measured in mmol/L
Measured: 6 months after transplantation
Incidence of dyslipidemia
dyslipidemia is defined as low density lipoproteins cholesterol > upper limit of normal and high density lipoproteins cholesterol < lower limit of normal and each measured in mmol/L
Measured: 6 months after transplantation
Incidence of arterial hypertension
blood pressure is measured in mm of mercury (mmHg) and arterial hypertension is defined according to the American College of Cardiology 2017 Guideline for High Blood Pressure in Adults
Measured: 6 months after transplantation
Incidence of anemia
anemia is defined as hemoglobin level or erythrocyte count < lower limit of normal and measured in mmol/L or Tpt/L respective
Measured: 6 months after transplantation
Incidence of cardiovascular mortality
cardiovascular mortality is defined as death attributable to myocardial ischemia and infarction, heart failure, cardiac arrest because of other or unknown cause, or cerebrovascular accident
Measured: 6 months after transplantation
Chronic humoral rejection
Rate of biopsy proven chronic humoral rejections
Measured: 6 months after transplantation
Interstitial fibrosis and tubular atrophy as histological changes in renal transplant biopsies
interstitial fibrosis and tubular atrophy are expressed as percentage in biopsy reports
Measured: 6 months after transplantation
Incidence of polyomavirus nephropathy
polyomavirus nephropathy is defined by simian virus 40 (SV40) positive histological staining in renal transplant biopsies
Measured: 6 months after transplantation
Recurrence rate of the underlying kidney disease requiring renal transplantation
Biopsy proven recurrence of the underlying disease
Measured: 6 months after transplantation
Rate of donor-specific antibodies
rate of donor-specific antibodies
Measured: 6 months after transplantation
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Sep 2018
- Study startSep 2014
- Primary completionFeb 2020
- Study completionDec 2025 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Renal FailureStudies of the same condition, open and under way.
- More trials run by Technische Universität DresdenThe 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
- 400 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Technische Universität Dresden
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Christian Hugo, MD, PhD, Principal investigator, TU Dresden
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03672110
- Sponsor's protocol ID
- TUD-SplusL-061
- Acronym
- S&L
- Status last verified
- Aug 2022
- First submitted
- 8 Oct 2014
- Last updated
- 3 Aug 2022
- Results posted
- No
Study at a glance
From the registry record, last updated by the sponsor on 3 Aug 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Slow and Low Start of a Tacrolimus Once Daily Immunosuppressive Regimen: A Multicentre Prospective Randomized Controlled Study
- ClinicalTrials.gov ID
- NCT03672110
- Acronym / sponsor ID
- S&L / TUD-SplusL-061
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 400 participants (estimated)
- Lead sponsor
- Technische Universität DresdenUniversity, hospital or other
- Study start
- Sep 2014
- Primary completion
- Feb 2020 (actual)
- Study completion
- Dec 2025 (estimated)
- First posted
- 14 Sep 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of this study is to demonstrate non-inferiority of an advagraf based immunosuppressive regimen with slower dose tapering and lower starting dose of Advagraf compared with a standard Advagraf-based immunosuppressive regimen in de novo renal transplantation. Non inferiority will be assessed by a combined study endpoint consisting of the development of biopsy-proven rejection of BANFF class Ia or higher and/or graft loss and/or patient death within the first six months after renal transplantation.
Detailed description
The most widely used immunosuppressive regimen, in adult kidney transplant recipients, consists of an induction therapy accompanied by maintenance with tacrolimus, mycophenolate and steroids. In the long term, tacrolimus is the single most effective immunosuppressive agent. For adult kidney transplant recipients maintenance of therapeutic levels remains crucial regarding the prevention of allograft rejections. Greater blood levels variability is associated with inferior graft survival as well as non-adherence. Lower variability of tacrolimus blood levels after conversion to extended release tacrolimus formulations has been shown. In addition, once-daily administration promotes patient adherence. The latter is one of the major causes for allograft loss.
In the first week after kidney transplantation stable tacrolimus blood levels are hardly achievable. Especially extended release tacrolimus formulations often yield high tacrolimus blood levels. High blood levels are a known risk factor for delayed graft function, which leads to a prolonged hospitalization and a reduced graft survival. Additionally high blood levels are associated with polyomavirus infections and may increase the incidence of new-onset diabetes after renal transplantation.
Taking this into consideration, authors demand for calcineurin inhibitor (CNI)-free immunosuppression or the delayed onset of CNI therapy after a stable graft function is reached. This would inevitably lead to a higher rate of acute allograft rejections in the early phase after kidney transplantation. Avoiding high tacrolimus levels, especially early after transplantation, to minimize delayed graft function as well as long term undesirable side effects, seems particularly necessary.
For early dose adjustments of extended release tacrolimus formulations, more medical experience is needed compared to immediate release formulations. More stable tacrolimus blood levels can be seen after the first week of administration.
To avoid high blood levels of tacrolimus, especially early after transplantation, the investigators aim to demonstrate in this study a non-inferiority of a low dose extended release tacrolimus regimen compared to a standard extended release tacrolimus-based immunosuppressive regimen in de novo renal transplantation. Given inclusion criteria and excluding the exclusion criteria, participants will be randomized into two groups, a standard tacrolimus administration group with daily dose adjustments within the first week after transplantation and a fixed dose tacrolimus administration group, without dose adjustments within the first week after transplantation. In the first 6 months after renal transplantation different blood levels of tacrolimus shall be reached. In the case of the standard tacrolimus administration group the investigators aim at tacrolimus blood levels of 7-9 ng/ml in the first 2 months after transplantation and 6-8 ng/ml for days 61 to 180. In the fixed dose tacrolimus administration group, the low extended release tacrolimus dose of 5mg per day well no be changed in the first week after transplantation. For safety reasons blinded measurements will take place in the first week and study officials will be alerted in case of repeated tacrolimus levels > 20 ng/ml. On days 7 to 60 the investigators aim at tacrolimus blood levels of 5-7 ng/ml and from days 61 to 180 4-6 ng/ml. Non inferiority will be assessed by a combined study endpoint consisting of the development of biopsy-proven rejection of BANFF class Ia or higher and/or graft loss and/or patient death within the first six months after renal transplantation.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Standard tacrolimus group | Active comparator | Drug: AdvagrafControl group: Advagraf will be administered as usual (0.2mg/kg bodyweight), trough levels will be measured every day in the first week after kidney transplantation (TX) and Advagraf dose will be adjusted accordingly. |
| Fixed dose tacrolimus group | Experimental | Drug: AdvagrafStudy group: Advagraf will be administered per fix dose 5mg/day, trough levels will be blinded during the first week, there will be no adjustments in the first week after TX. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- male or female allograft recipients at least 18 years old
- primary or secondary kidney transplantation
- deceased or living donor
- normal immunological risk profile (PRA level > 20%, AB0-compatible donation, negative crossmatch)
- informed consent of the patient
Key exclusion criteria (16 listed)
- graft loss due to severe rejection within the first year after transplantation (in case of secondary transplantation)
- multi-organ recipient
- patients receiving a kidney from a non-beating donor
- complete human leukocyte antigen (HLA)-identical living donor (twins)
- patients with a history of malignancy during the last five years (except squamous or basal cell carcinoma of the skin after successful treatment)
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 |
|---|---|---|
| AdvagrafAlso: no other intervention nameintervention: different advagraf dosing in the study compared to the control arm, see above | Drug | Fixed dose tacrolimus group, Standard tacrolimus group |
Primary outcome
Combined endpoint: defined as biopsy-proven acute rejection, graft loss or death between the groups at month 6 post-transplantation in renal transplantation)
Time frame: 6 months after transplantation
combined endpoint: defined as biopsy-proven acute rejection, graft loss or death between the groups at month 6 post-transplantation in renal transplantation
25 secondary outcomes
Rate of necessary dose modifications to achieve Advagraf target levels in early post-op period
Time frame: 6 months after transplantation
Improved renal transplant function in the early postoperative period and 6 months post-op
Time frame: 6 months after transplantation
Lower incidence of delayed graft function (DGF)
Time frame: 6 months after transplantation
Reduced incidence of new onset diabetes after renal Transplantation (NODAT)
Time frame: 6 months after transplantation
Reduced rates of infection
Time frame: 6 months after transplantation
Incidence of malignancies
Time frame: 6 months after transplantation
Incidence of fractures
Time frame: 6 months after transplantation
Incidence of heart failure
Time frame: 6 months after transplantation
Incidence of myocardial infarction
Time frame: 6 months after transplantation
Incidence of venous thrombosis
Time frame: 6 months after transplantation
Incidence of peripheral vascular disease
Time frame: 6 months after transplantation
Incidence of cerebrovascular disease
Time frame: 6 months after transplantation
Incidence of hypercholesterolemia
Time frame: 6 months after transplantation
Incidence of hypertriglyceridemia
Time frame: 6 months after transplantation
Incidence of hyperlipoproteinemia
Time frame: 6 months after transplantation
Incidence of hypolipoproteinemia
Time frame: 6 months after transplantation
Incidence of dyslipidemia
Time frame: 6 months after transplantation
Incidence of arterial hypertension
Time frame: 6 months after transplantation
Incidence of anemia
Time frame: 6 months after transplantation
Incidence of cardiovascular mortality
Time frame: 6 months after transplantation
Chronic humoral rejection
Time frame: 6 months after transplantation
Interstitial fibrosis and tubular atrophy as histological changes in renal transplant biopsies
Time frame: 6 months after transplantation
Incidence of polyomavirus nephropathy
Time frame: 6 months after transplantation
Recurrence rate of the underlying kidney disease requiring renal transplantation
Time frame: 6 months after transplantation
Rate of donor-specific antibodies
Time frame: 6 months after transplantation
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 Aug 2022.
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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.
Christian Hugo, MD, PhD principal investigator
TU Dresden
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Advagraf in people with Renal Failure and Renal Insufficiency, run by Technische Universität Dresden at 1 site in Germany.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 16 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: status not confirmed, as of the sponsor's last update on 3 Aug 2022. 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 Germany. 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?
Results are not available in the source record.
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?
Combined endpoint: defined as biopsy-proven acute rejection, graft loss or death between the groups at month 6 post-transplantation in renal transplantation) (time frame: 6 months after transplantation). 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 3 Aug 2022; AzTrials last refreshed its copy on 8 Nov 2026.