The EFfect of FinErenone in Kidney TransplantiOn Recipients: The EFFEKTOR Study
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 100
- 试验地点
- 2
- 主要终点
- Feasibility of recruitment to the main clinical trial: Total number of participants who were eligible and enrolled in the main clinical trial
研究概览
简要总结
EFFEKTOR is a vanguard, multicenter, phase 2 randomized, double blinded, placebo controlled clinical trial to determine the feasibility, tolerability, safety, and efficacy of finerenone in kidney transplant recipients (KTRs). One hundred fifty (150) KTRs will be randomized in a 2:1 ratio of finerenone to placebo, with two embedded substudies: (i) a kidney biopsy substudy in 50 participants who undergo a research kidney biopsy prior to randomization and at the end of active treatment; and (ii) a functional MRI (fMRI) substudy in 50 participants who undergo fMRI prior to randomization and at the end of active treatment.
详细描述
Kidney transplantation yields significant improvements in morbidity, mortality, and quality of life for patients with end-stage kidney disease (ESKD), however, the burden from progressive chronic kidney disease (CKD), cardiovascular (CV) events and death remain high. CKD is the result of several pathologic processes, including diabetic and hypertensive sclerosis, calcineurin inhibitor toxicity (CNIT), chronic inflammation and fibrosis that ensues post-acute rejection episodes and other nonspecific insults that can result in CKD mediators. Currently, mean allograft survival is currently 8 years and 12 years for deceased and living donor kidney transplants, respectively. More than 80% of KTRs are under 65 years and 60% under age 55 years, indicating most KTRs will either require a second transplant or eventually transition to maintenance dialysis which portends a poor prognosis and decreased quality of life. CV disease is also highly prevalent, with KTRs having 50 times the annual rate of fatal or nonfatal cardiovascular events and up to 10 times the rate of cardiac death as the general population. Specifically, heart failure is common, with 19% of KTRs sustaining a new diagnosis of heart failure just 3 years post-transplant, and a mean 5.7-7.1 Congestive heart failure (CHF) acute care utilization episodes per 100 person-years. Moreover, kidney and cardiovascular health are tightly intertwined, with kidney disease inciting and exacerbating cardiovascular pathology and vice versa. Thus, there is a critical need for improvements in post kidney transplantation cardiovascular morbidity, mortality, and allograft survival.
Finerenone, a potent, selective, nonsteroidal mineralocorticoid receptor antagonist (MRA), has been shown to significantly reduce the risk of incident worsening CKD and ESKD, as well as preventing major adverse CV events and death in persons with diabetes and native CKD. The pathogenetic mechanisms through which finerenone acts are incompletely understood, but involve reduction of inflammation and fibrosis, key factors in the pathogenesis of CKD and CV disease in KTRs. Moreover, there are preliminary data to suggest that any renin-angiotensin aldosterone system (RAAS blockade), but particularly MRAs and finerenone, could be important to mitigating the effects of CNIT, a significant contributor to graft loss. While current, published clinical trials have been in people with type 2 diabetes and CKD, there is compelling evidence to suggest that these benefits will extend to people with CKD in the absence of diabetes.
Given the high cardiovascular and kidney disease burden in KTRs, and compelling evidence for finerenone in kidney and cardiac protection in patients with native CKD, a vanguard clinical trial of finerenone in 150 KTRs will be undertaken using a randomized, double blind, placebo-controlled study design over the course of 13 months.
Objective 1: To determine the feasibility of recruitment of KTRs to a clinical trial of finerenone with embedded kidney biopsy study. Finerenone is postulated to decrease the risk of kidney and cardiovascular events in KTRs, unrelated to the immunologic inciting factors or mediators of acute rejection episodes. In essence, it is hypothesized that the mechanisms by which finerenone decreases kidney and cardiovascular endpoints in people with type 2 diabetes (T2D) and native CKD, will be similarly effective in patients (regardless of diabetes status) living with a kidney transplant. It is unknown to what extent KTRs and their treating transplant physicians would be willing to participate in a clinical trial of a drug that is targeted at 'general' reduction of CKD and cardiovascular outcomes. In particular, this trial could help provide strategies for successful recruitment of KTRs into such trials.
Kidney tissue is a particularly valuable tool for identifying mechanisms through which finerenone may decrease progression of interstitial fibrosis and CNIT in KTRs. Such information is deemed critical in helping to determine whether future, larger trials of KTRs are indicated, and whether kidney biopsy could be useful for stratifying participants (eg. based on the presence or degree of interstitial fibrosis). Kidney biopsy also yields valuable information helpful to clinical decisions in caring for KTRs but does come with some risks. Thus, the feasibility of enrolling KTRs to a 'not for cause' kidney biopsies in the context of a clinical trial targeting CKD and Cardiovascular Disease (CVD) is unknown.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
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
- •Clinical Trial Inclusion Criteria:
- •Adult kidney transplant recipients ≥ 18 years
- •1 to 10 years post kidney transplantation from a deceased or living donor
- •Stable kidney allograft function (within 20% baseline eGFR) and based on the clinical judgement of the investigator
- •Preserved kidney allograft function defined as an eGFR ≥ 25 mL/min/1.73 m
- •Urine albumin:creatinine ratio (UACR) ≥30 ug/mg
- •Ability of the participant, or their legally authorized representative, to provide informed consent
- •Contraceptive requirements:
- •Women of non-childbearing potential do not need to undergo pregnancy testing or agree to use adequate contraception. Non-childbearing potential is defined as documented hysterectomy, bilateral salpingectomy, oophorectomy or postmenopausal females (amenorrhea for 12 months without an alternative medical cause). A single high follicle stimulating hormone level in the postmenopausal range may be used to confirm a postmenopausal state.
- •Women of childbearing potential can only be included if a pregnancy test is negative at the screening visit and if they agree to use adequate contraception during the study and until 8 weeks after the last study intervention dose. Adequate contraception is defined as an intrauterine device, implant or combined oral contraceptive with a physical barrier (e,g., condom).
- •Additional Inclusion Criteria for Kidney Biopsy Sub-study:
- •Willingness to undergo research study biopsies at screening and following the 12 month treatment period
- •Ability to safely discontinue antiplatelet or anticoagulant treatments
- •No known intrinsic bleeding diathesis
- •Hemoglobin >9.0 g/dL; Platelets > 100,000; International Normalised Ratio (INR) <1.4 on the day of kidney biopsy
- •Body mass index <40
- •Blood pressure controlled on the day of biopsy to <160/90
- •Medical Condition
排除标准
- •Documented recurrent lupus nephritis, ANtineutrophilic Cytoplasmic Antibody (ANCA) vasculitis, membranoproliferative glomerulonephritis (including C3 glomerulopathy)
- •History of solid organ transplantation other than kidney
- •Acute kidney injury requiring dialysis within 6 months prior to screening
- •Uncontrolled hypertension with a sitting Systolic Blood Pressure (SBP) ≥180 mmHg or Diastolic Blood Pressure (DBP) ≥100 mmHg
- •Any indication for treatment with a steroidal MRA
- •UACR >3500 mg/g at screening. This may be reassessed if one of the three first morning urine samples is >3500 mg/g at the screening visit
- •CV event within 3 months prior to screening (heart failure requiring acute care, myocardial infarction, stroke, transient ischemic attack, pulmonary embolism, elective coronary artery bypass grafting)
- •Elective percutaneous coronary intervention within 1 month prior to screening
- •Known hypersensitivity to the study treatment
- •Addison's disease
- •Hepatic insufficiency classified as Child-Pugh C
- •Pregnancy, breast feeding or intention to become pregnant
- •Concomitant Therapies Exclusion Criteria:
- •Concomitant therapy with spironolactone, eplerenone, sacubitril/valsartan combination, or potassium-sparing diuretic which cannot be discontinued at least 2 weeks prior to screening
- •Simultaneous use of Angiotensin-Converting Enzyme Inhibitors (ACEI) and Angiotensin Receptor Blockers (ARB), without being able to discontinue one of these at least 2 weeks prior to screening
- •Use of potent CYP3A4 inhibitors or inducers (to be stopped at least 7 days before randomization).
- •Other Exclusion Criteria:
- •Participation in the MRI Study is excluded for certain pacemakers, electronic implants, shrapnel of the eye and certain types of aneurysm clips.
- •Any other history, condition, or therapy which could, in the opinion of the investigator, affect compliance with the study treatment and procedures
- •Close affiliation with the investigational site, investigators or staff
- •Simultaneous participation in another interventional trial within 30 days prior to randomization
研究组 & 干预措施
Finerenone
Participants in this study arm will receive the study drug Finerenone.
Initial Dosing: Dosing regimen of 10 mg or 20 mg once daily (QD), based upon screening eGFR. For eGFR < 60 mL/min/1.73m^2, participants will start at 10 mg QD. For eGFR ≥ 60 mL/min/1.73m^2, participants will start at 20 mg QD.
Dose Titration: Dose will be titrated according to potassium levels. For participants initiated at 10mg, the dose will be up titrated to 20 mg if the potassium level measured after 2 weeks is ≤4.8 meq/L and eGFR has not decreased by >30 percent of the screening visit value. Study drug dosing may be titrated up or down per the below.
Potassium level: ≤ 4.8
- If on lower dose, up-titrate to higher dose
- If on higher dose, continue on the same dose
Potassium level: 4.9-5.5 = continue same dose
Potassium level: >5.5 = withhold study drug and recheck potassium within 3 days. Re-initiate study drug at the 10 mg dose once potassium is ≤4.8 meq/L.
干预措施: Finerenone Oral Tablet (Drug)
Placebo
Participants in this study arm will receive the placebo comparator.
Initial Dosing: Dosing regimen of 10 mg or 20 mg once daily (QD), based upon screening eGFR. For eGFR < 60 ml/min/1.73m^2, participants will start at 10mg QD. For eGFR ≥ 60ml/min/1.73m^2, participants will start at 20 mg QD.
Dose Titration: Dose will be titrated according to potassium levels. For participants initiated at 10 mg, the dose will be up titrated to 20 mg if the potassium level measured after 2 weeks is ≤4.8 meq/L and eGFR has not decreased by >30 percent of the screening visit value. Study drug dosing may be titrated up or down per the table below.
Potassium level: ≤ 4.8
- If on lower dose, up-titrate to higher dose
- If on higher dose, continue on the same dose
Potassium level: 4.9-5.5 = continue same dose
Potassium level: >5.5 = withhold study drug and recheck potassium within 3 days. Re-initiate study drug at the 10 mg dose once potassium is ≤4.8 meq/L.
干预措施: Placebo (Drug)
结局指标
主要结局
Feasibility of recruitment to the main clinical trial: Total number of participants who were eligible and enrolled in the main clinical trial
时间窗: Up to 3 months after launching the full study protocol
Signed consent by 30 participants for the main clinical trial within 3 months of launching the full study protocol (date of first person randomized).
Feasibility of recruitment to the kidney biopsy substudy: Total number of participants who were eligible and enrolled in the kidney biopsy substudy
时间窗: Up to 3 months after launching the full study protocol
Signed consent by 10 participants for the biopsy substudy within 3 months of launching the full study protocol (date of first person randomized).
次要结局
- Overall safety of finerenone(From randomization to last on study drug visit, approximately 12 months)
- Relative tolerability of finerenone(From randomization to last on study drug visit, approximately 12 months)
- Risk for discontinuation of finerenone(From randomization to last on study drug visit, approximately 12 months)
- Adverse Event (AE) related to acute kidney injury(From randomization to last on study drug visit, approximately 12 months)
- Efficacy for albuminuria reduction(From randomization to last on study drug visit, approximately 12 months)
- Efficacy for prevention of congestive heart failure (CHF)(From randomization to last on study drug visit, approximately 12 months)
- Adverse Event (AE) related to hyperkalemia(From randomization to last on study drug visit, approximately 12 months)