The EFfect of FinErenone in Kidney TransplantiOn Recipients: The EFFEKTOR Study

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.

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.

Objective 2: To measure the tolerability and safety of finerenone in KTRs. Finerenone has not been administered in KTRs and it is unclear whether tolerability will be similar to that of people with diabetes (and perhaps those without) and CKD. The primary concerns include risks for hyperkalemia and creatinine fluctuations which may necessitate temporary or permanent withdrawal of finerenone and also result in downstream interventions specific to kidney transplantation. Immunosuppression for KTRs most often includes a calcineurin inhibitor (CNI) which increases the risk for hyperkalemia, as does finerenone. Moreover, many KTRs are also treated with renin angiotensin system (RAS) blockers, which only further increases this risk. This study will help determine the magnitude of this risk, optimal approaches to managing hyperkalemia specifically in KTRs, and which subpopulations are less likely to tolerate finerenone (eg. those on CNI and RAS blockers), in order to inform potential future clinical trials. The other concern for tolerability of finerenone in KTRs, is the tendency in clinical practice to discontinue medications with the potential to reduce eGFR in KTRs when creatinine levels rise, in order to assess whether rejection is in progress. Ultimately, if KTRs are not able to be maintained on finerenone for a reasonable period, it is unlikely that they would experience potential benefits either. Tolerability will be measured by the relative time on study drug in the two comparator groups.

Safety analyses will build further upon the outcomes of tolerability and will include: hyperkalemia (\>5.5m Eq/L), other hyperkalemia-associated events designated by the investigator as requiring holding/discontinuing study drug or RAS blocker, and acute kidney injury episodes defined by Kidney Disease Improving Global Outcomes (KDIGO) criteria, infections requiring acute care (emergency room visits or hospitalization).

Objective 3: To determine the effect of finerenone on clinical, radiologic and pathologic kidney markers in KTRs. Finerenone decreases the risk for progression of CKD and CV events in people with T2D and CKD. It is likely that the effect is similar, regardless of diabetes status, and trials are underway to determine this. KTRs have several potential confounding factors relating to the pathogenesis of worsening kidney disease, namely use of CNIs, donor derived disease, BK virus associated nephropathy and other urinary tract infections, and both acute and chronic T cell or antibody mediated rejection, which may override any potential benefit from finerenone. Alternatively, the anti-inflammatory and antifibrotic effects of finerenone may be particularly beneficial in KTRs with chronic kidney dysfunction secondary to any of the above processes as the final common pathway that results in allograft dysfunction and failure in all of the above is inflammation and fibrosis.

CV disease is a major burden in KTRs, with event rates higher than in the general population, which may partly be related to the fact that most KTRs spend several years on dialysis prior to transplantation. KTRs are at also at high risk of other complicating/competing factors linked to CV events, including the vascular impact of immunosuppressive agents, infection and malignancy. It is unknown whether the complex health status and treatments of KTRs will alter the potential benefit of finerenone on CV events and death.

This relatively short-term trial will include multiple exploratory clinical, radiologic and pathologic endpoints. Exploratory clinical kidney and CV endpoints will focus on relative changes in albuminuria, eGFR slope and the relative difference in the need for acute care for congestive heart failure. Exploratory radiologic endpoints include kidney cortical perfusion, oxygenation and fibrosis as measured by fMRI, and pathologic parameters are to include changes in Banff classification, percent change in interstitial fibrosis using sirius red staining. Blood, urine and kidney specific cytokines and fibrotic markers will also be measured at baseline and at the end of active treatment.

Eligibility Criteria:
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 Exclusion Criteria:

* 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