Clinical trial NCT03672110: Slow and Low Start of a Tacrolimus Once Daily Immunosuppressive Regimen
Official title: Slow and Low Start of a Tacrolimus Once Daily Immunosuppressive Regimen: A Multicentre Prospective Randomized Controlled Study
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Renal Failure
Renal Insufficiency
Renal Disease
Renal Insufficiency, Chronic
Lead sponsor: Technische Universität Dresden
Sponsor class: OTHER
First posted: 2018-09-14
Enrollment: 400
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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. 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.

Eligibility criteria: Inclusion Criteria:

* 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

Exclusion Criteria:

* 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
* 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

Primary outcomes:
measure: Combined endpoint: defined as biopsy-proven acute rejection, graft loss or death between the groups at month 6 post-transplantation in renal transplantation)
timeFrame: 6 months after transplantation
Secondary outcomes:
measure: Rate of necessary dose modifications to achieve Advagraf target levels in early post-op period
timeFrame: 6 months after transplantation
measure: Improved renal transplant function in the early postoperative period and 6 months post-op
timeFrame: 6 months after transplantation
measure: Lower incidence of delayed graft function (DGF)
timeFrame: 6 months after transplantation
measure: Reduced incidence of new onset diabetes after renal Transplantation (NODAT)
timeFrame: 6 months after transplantation
measure: Reduced rates of infection
timeFrame: 6 months after transplantation
measure: Incidence of malignancies
timeFrame: 6 months after transplantation
measure: Incidence of fractures
timeFrame: 6 months after transplantation
measure: Incidence of heart failure
timeFrame: 6 months after transplantation
measure: Incidence of myocardial infarction
timeFrame: 6 months after transplantation
measure: Incidence of venous thrombosis
timeFrame: 6 months after transplantation
measure: Incidence of peripheral vascular disease
timeFrame: 6 months after transplantation
measure: Incidence of cerebrovascular disease
timeFrame: 6 months after transplantation
measure: Incidence of hypercholesterolemia
timeFrame: 6 months after transplantation
measure: Incidence of hypertriglyceridemia
timeFrame: 6 months after transplantation
measure: Incidence of hyperlipoproteinemia
timeFrame: 6 months after transplantation
measure: Incidence of hypolipoproteinemia
timeFrame: 6 months after transplantation
measure: Incidence of dyslipidemia
timeFrame: 6 months after transplantation
measure: Incidence of arterial hypertension
timeFrame: 6 months after transplantation
measure: Incidence of anemia
timeFrame: 6 months after transplantation
measure: Incidence of cardiovascular mortality
timeFrame: 6 months after transplantation
measure: Chronic humoral rejection
timeFrame: 6 months after transplantation
measure: Interstitial fibrosis and tubular atrophy as histological changes in renal transplant biopsies
timeFrame: 6 months after transplantation
measure: Incidence of polyomavirus nephropathy
timeFrame: 6 months after transplantation
measure: Recurrence rate of the underlying kidney disease requiring renal transplantation
timeFrame: 6 months after transplantation
measure: Rate of donor-specific antibodies
timeFrame: 6 months after transplantation
Other outcomes:
Locations:
city: Dresden
country: Germany
facility: Universitätsklinikum Carl Gustav Carus
Study officials:
affiliation: TU Dresden
name: Christian Hugo, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: