Multicentre, Open-label, Randomised, Two-arm, Parallel-group, Superiority Trial to Assess Bioavailability and Practicability of Two Once-daily Tacrolimus Formulations, Envarsus® Compared With Advagraf™, Administered in Kidney Transplant Recipients
试验速览
- 阶段
- 4 期
- 状态
- 招募中
- 发起方
- 入组人数
- 300
- 试验地点
- 9
- 主要终点
- Dose-normalised blood trough level of tacrolimus (concentration/dose ratio)
研究概览
简要总结
The goal of this clinical trial is to compare the bioavailability and practicability of two different formulations of tacrolimus in kidney transplant recipients. The main objective is to demonstrate that Envarsus® (test drug) has superior (higher) oral bioavailability compared with Advagraf™ (comparator drug) at 12 weeks after kidney transplantation. The trial also aims to compare the practicability (handling) of the two drugs using a series of pharmacokinetic parameters and to explore the relationship between drug bioavailability and long-term clinical outcomes, with a special focus on dose-dependent adverse reactions, measured until 3 years post-transplantation. The trial incorporates a pharmacokinetic sub-study designed to profile the peak tacrolimus blood concentration up to 6 hours after drug intake on the day of the 12-week study visit.
详细描述
This clinical trial aims to compare the bioavailability and practicability of two alternative once-daily formulations of tacrolimus in patients who have received either a first or second kidney transplant and require prophylactic immunosuppressive treatment to prevent allograft rejection. Trial participants are randomised within 7 days prior to kidney transplantation surgery in a 1:1 ratio to two alternative treatment arms containing either Envarsus (test arm) or Advagraf (comparator arm) as first-line calcineurin inhibitor within a standard-of-care immunosuppressive regimen. Tacrolimus blood trough levels and drug doses are monitored at regular intervals to measure a dose-normalised trough level (concentration/dose, C/D ratio) as an estimate of tacrolimus bioavailability.
The primary objective is to demonstrate that the C/D ratio of tacrolimus measured in kidney transplant recipients treated with Envarsus® (test drug) is superior to (higher than) the C/D ratio measured in patients treated with Advagraf™ (comparator drug) at 12 weeks post-transplantation. The trial also aims to compare the practicability (handling) of these two once-daily drug formulations using a series of pharmacokinetic parameters that will measure the speed with which therapeutic blood trough levels are attained and the ease with which stable blood trough levels are maintained over time.
Secondarily, TaC:Drop aims to explore the relationship between the early C/D ratio measured at 12 weeks post-transplantation and later clinical outcomes measured until three years post-transplantation. The study aims to investigate whether a superior pharmacokinetic drug profile is associated with fewer and milder dose-dependent drug toxicities and superior kidney graft function, as measured by long-term safety and efficacy parameters.
Drug pharmacokinetics will be explored in greater detail during a sub-study designed to profile the peak blood concentration of Envarsus® and Advagraf™ at 12 weeks post-transplantation in patients who volunteer to provide three additional blood samples at two-hour intervals after drug intake on the day of the 12-week trial visit. Participation in this sub-study is voluntary and available to all trial centres and all trial patients.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Signed and dated written informed consent
- •Adult (≥18 years old) male or female
- •Renal insufficiency necessitating kidney transplantation and approved to receive a first or second kidney allograft from a living or deceased organ donor
- •ABO blood type compatible with the donor kidney
- •Able to swallow an oral formulation of tacrolimus in tablet or capsule form
排除标准
- •Multi-organ transplantation
- •Any previous solid organ transplantation (other than a first kidney allograft)
- •For recipients of a second kidney transplant: loss of first kidney transplant within 2 years after transplantation owing to immunological reasons or recurrence of the underlying renal disease
- •Patient and/or donor is positive for HCV, HBV or HIV
- •History of any malignancy that could not be curatively treated
- •Ongoing abuse of drugs or alcohol
- •Signs of advanced liver disease or any signs of liver decompensation
- •Ongoing uncontrolled systemic infection
- •Severe diarrhoea, vomiting, active peptic ulcer, previous bariatric surgery, or any other gastrointestinal disorder that may affect absorption of tacrolimus
- •Planned or foreseeable use of cyclosporine, belatacept or any tacrolimus preparation other than Envarsus® or Advagraf™
- •Known contraindication or hypersensitivity to tacrolimus, and/or to any of the excipients listed in section 6.1 of the Summary of Product Characteristics (SmPC) of both Envarsus® and Advagraf™, and/or to any other macrolides
- •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
- •Women of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant, unless using a highly-effective method of contraception
- •Participation in another interventional clinical trial in the time period starting from 4 weeks prior to randomisation and throughout the entire trial period
- •Any condition or factor which, in the judgement of the investigator, would place the subject at undue risk, invalidate communication with the investigator or study team, or hamper compliance with the trial protocol or follow-up schedule
- •Inability to freely give informed consent (e.g. individuals under legal guardianship)
研究组 & 干预措施
Envarsus
Participants take prolonged-release tacrolimus tablets (Envarsus) orally once daily and additionally receive standard-of-care immunosuppressive background therapy according to routine practice.
干预措施: Tacrolimus Pill (Drug)
Advagraf
Participants take prolonged-release tacrolimus capsules (Advagraf) orally once daily and additionally receive standard-of-care immunosuppressive background therapy according to routine practice.
干预措施: Tacrolimus capsule (Drug)
结局指标
主要结局
Dose-normalised blood trough level of tacrolimus (concentration/dose ratio)
时间窗: 12 weeks after kidney transplantation
To calculate C/D ratio, "concentration" is the blood trough level of tacrolimus measured in a blood sample collected immediately prior to drug dosing on the day of the 12-week trial visit and "dose" is the daily dose taken by the patient on the day prior to the visit. C/D ratio is measured as a surrogate for tacrolimus bioavailability (i.e. systemic exposure per mg of drug). The primary endpoint uses a blood trough level reading that is measured in a central laboratory.
次要结局
- Proportion of patients with trough levels lower, within, or higher than the target range(4 days, 14 days, 28 days and 12 weeks after kidney transplantation)
- Treatment failure rate(12 weeks and 1, 2, 3 years after kidney transplantation)
- Time to reach the first trough level in target range(Time period measured in days, assessed within the first 2 weeks after kidney transplantation)
- Mean daily dose of tacrolimus and inter-patient variability (range) of tacrolimus daily dose(4 days, 14 days, 28 days and 12 weeks after kidney transplantation)
- Incidence rate of graft failure(12 weeks and 1, 2, 3 years after kidney transplantation)
- Graft function measured by eGFR (estimated glomerular filtration rate)(4 days, 14 days, 28 days, 12 weeks and 1, 2, 3 years after kidney transplantation)
- Incidence rate of for-cause biopsies(12 weeks after kidney transplantation)
- Mean tacrolimus trough level and inter-patient variability (range) of tacrolimus trough levels(4 days, 14 days, 28 days and 12 weeks after kidney transplantation)
- Tacrolimus concentration/dose (C/D) ratio(4 days, 14 days, 28 days and 1, 2, 3 years after kidney transplantation)
- Intra-patient variability of C/D ratio and daily dose(Measured over the time points: day 4, day 14, day 28 and week 12)
- Time to treatment failure after transplantation(Measured until 3 years after kidney transplantation)
- Incidence rate, severity and time to clinically-confirmed biopsy-proven acute rejection(12 weeks and 1, 2, 3 years after kidney transplantation)
- Mortality rate(12 weeks and 1, 2, 3 years after kidney transplantation)
- Incidence rate of acute rejection episodes requiring treatment(12 weeks after kidney transplantation)
- Incidence of hepatotoxicity(12 weeks and 1, 2, 3 years after kidney transplantation)
- Blood pressure(12 weeks and 1, 2, 3 years after kidney transplantation)
- Incidence rate of primary non-function of the renal allograft(Measurable within the first 12 weeks after kidney transplantation)
- Recurrence of primary kidney disease(12 weeks and 3 years after kidney transplantation)
- Incidence of de novo DSA(Detected within the first year after kidney transplantation)
- Patient-reported health-related quality-of-life measured using the Kidney Transplant Questionnaire-34 (KTQ-34)(12 weeks and 3 years after kidney transplantation)
- Incidence rate of steroid-resistant episodes of biopsy-proven acute rejection(12 weeks and 1 year after kidney transplantation)
- Incidence of CMV and BKV infection (including organ manifestation, if relevant)(12 weeks and 1 year after kidney transplantation)
- Incidence of de novo tremor(12 weeks and 3 years after kidney transplantation)
- Incidence rate of delayed graft function(Measurable within the first 2 weeks after kidney transplantation)
- Incidence, type, severity and seriousness of adverse reactions (ARs)(12 weeks and 3 years after kidney transplantation)
- Incidence of gastrointestinal disorders requiring diagnostic investigation(12 weeks and 3 years after kidney transplantation)
- Incidence of new onset diabetes mellitus after transplantation (NODAT)(12 weeks and 1, 2, 3 years after kidney transplantation)
- Doses and duration of glucocorticosteroid treatment(12 weeks and 1, 2, 3 years after kidney transplantation)
- Dose of mycophenolate(12 weeks and 1, 2, 3 years after kidney transplantation)
- Incidence and time to study treatment discontinuation(3 years after kidney transplantation)
- Incidence, time to and reason for patient withdrawal from study(3 years after kidney transplantation)
研究者
Edward Geissler
Head of the Department of Experimental Surgery
University of Regensburg