1.4-Trial_Design

FINE-ONE: A pioneering phase 3 clinical trial evaluating
KERENDIA in patients with T1D and CKD

In FINE-ONE, a randomized, double-blind, placebo-controlled trial, KERENDIA was evaluated when added to a maximum-tolerated dose of an ACEi or ARB in adults with CKD associated with T1D

Primary outcome: efficacy

Change in UACR from baseline over 6 months

Secondary outcomes: safety

TEAEs or serious TEAEs from baseline to 7 months
Hyperkalemia (an AE of special interest) from baseline to 7 months

Criteria and characteristics

*On top of a maximum-tolerated dose of either an ACEi or ARB. ^†For participants with an eGFR ≥25 to <60 mL/min/1.73 m², starting dose is 10 mg od. For participants with an eGFR ≥60 mL/min/1.73 m², starting dose is 20 mg od. Up-titration and down-titration of study intervention will be based on local serum [K+] and kidney function (eGFR) values.

AE=adverse event; CKD=chronic kidney disease; CV=cardiovascular; eGFR=estimated glomerular filtration rate; HF=heart failure; MI=myocardial infarction; TEAE=treatment-emergent adverse event; T1D=type 1 diabetes; T2D=type 2 diabetes; UACR=urine albumin-to-creatinine ratio.

Trial Design UACR Safety

IMPORTANT SAFETY INFORMATION AND INDICATIONS

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS:

Hypersensitivity to any component of this product
Concomitant use with strong CYP3A4 inhibitors
Patients with adrenal insufficiency

WARNINGS AND PRECAUTIONS:

Hyperkalemia: KERENDIA can cause hyperkalemia. The risk for developing hyperkalemia increases with decreasing kidney function and is greater in patients with higher baseline potassium levels or other risk factors for hyperkalemia

Measure serum potassium and eGFR in all patients before initiation of treatment with KERENDIA and dose accordingly. Do not initiate KERENDIA if serum potassium is >5 mEq/L. Measure serum potassium periodically during treatment with KERENDIA and adjust dose accordingly. More frequent monitoring may be necessary for patients at risk for hyperkalemia, including those on concomitant medications that impair potassium excretion or increase serum potassium.
Worsening of Renal Function in Patients with Heart Failure: KERENDIA can cause worsening of renal function in patients with heart failure. Rarely, severe events associated with worsening renal function, including events requiring hospitalization, have been observed

Measure eGFR in all patients before initiation of treatment or with dose titration of KERENDIA and dose accordingly. Initiation of KERENDIA in patients with heart failure and an eGFR <25 mL/min/1.73 m² is not recommended. Measure eGFR periodically during maintenance treatment with KERENDIA in patients with heart failure. Consider delaying up-titration or interrupting treatment with KERENDIA in patients who develop clinically significant worsening of renal function

MOST COMMON ADVERSE REACTIONS:

CKD associated with T2D: From the pooled data of FIDELIO-DKD and FIGARO-DKD, the adverse reactions reported in ≥1% of patients on KERENDIA and more frequently than placebo were hyperkalemia (14% vs 6.9%), hypotension (4.6% vs 3%), and hyponatremia (1.3% vs 0.7%).
HF LVEF ≥40%: From FINEARTS-HF, the adverse reactions reported in ≥1% of patients on KERENDIA and more frequently than placebo were hyperkalemia (9.7% vs 4.2%), hypotension (7.6% vs 4.7%), and hyponatremia (1.9% vs 0.9%). Events related to worsening renal function were reported more frequently in the KERENDIA group (18%) compared with placebo (12%).

DRUG INTERACTIONS:

Strong CYP3A4 Inhibitors: Concomitant use of KERENDIA with strong CYP3A4 inhibitors is contraindicated. Avoid concomitant intake of grapefruit or grapefruit juice.
Moderate and Weak CYP3A4 Inhibitors: Monitor serum potassium during drug initiation or dosage adjustment of either KERENDIA or the moderate or weak CYP3A4 inhibitor, and adjust KERENDIA dosage as appropriate.
Strong and Moderate CYP3A4 Inducers: Avoid concomitant use of KERENDIA with strong or moderate CYP3A4 inducers.
Sensitive CYP2C8 Substrates at KERENDIA 40mg: Monitor patients more frequently for adverse reactions caused by sensitive CYP2C8 substrates if KERENDIA 40mg is co-administered with such substrates, since minimal concentration changes may lead to serious adverse reactions.

USE IN SPECIFIC POPULATIONS:

Lactation: Avoid breastfeeding during treatment with KERENDIA and for 1 day after treatment.
Hepatic Impairment: Avoid use of KERENDIA in patients with severe hepatic impairment (Child Pugh C) and consider additional serum potassium monitoring with moderate hepatic impairment (Child Pugh B).

INDICATIONS:

KERENDIA (finerenone) is indicated to reduce the risk of:

sustained estimated glomerular filtration rate (eGFR) decline, end-stage kidney disease, cardiovascular death, non-fatal myocardial infarction, and hospitalization for heart failure in adult patients with chronic kidney disease (CKD) associated with type 2 diabetes (T2D) (10mg, 20mg tablets)
cardiovascular death, hospitalization for heart failure, and urgent heart failure visits in adult patients with heart failure with left ventricular ejection fraction (HF LVEF) ≥40% (10mg, 20mg, 40mg tablets)

Please see the full Prescribing Information for KERENDIA.

*On top of maximum-tolerated dose of either ACEi or ARB.^2,28 ^†Up-titration of study drug was encouraged after visit 2, provided potassium value was ≤4.8 mEq/L and eGFR was stable; down-titration was allowed any time after treatment initiation for safety reasons.^29,30 ^‡The purpose of the mandatory run-in period was to allow for optimization of participant standard-of-care medical therapies. This included ensuring that a patient was pretreated with a maximum-tolerated labeled dose of either an ACEi or an ARB (preferably without dose adjustments or switching to a different ACEi or ARB) for >4 weeks prior to the screening visit.^29,30 ^§Visits at month 1, month 4, and every 4 months thereafter.^2,28 ^II4 weeks and 5 days after last dose.^29,30

ACEi=angiotensin-converting enzyme inhibitor; ARB=angiotensin receptor blocker; CKD=chronic kidney disease; CV=cardiovascular; eGFR=estimated glomerular filtration rate; T2D=type 2 diabetes.

*Data were missing for one participant in each group. ^†Race or ethnic group was reported by the participants. Two participants in the finerenone group were Native American or Native Alaskan, and race or ethnic group was not reported for one participant in each group. ^‡Data were missing for two participants in the placebo group. ^§A history of cardiovascular disease was determined by the presence of one of the following in the medical history: myocardial infarction, coronary-artery stenosis, stroke, transient ischemic attack, peripheral arterial occlusive disease, or cardiac failure. ^IIUse of sodium–glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists was not permitted in the trial. Note: Percentages may not total 100 because of rounding.

ACEi=angiotensin-converting enzyme inhibitor; ARB=angiotensin receptor blocker; BP=blood pressure; CKD=chronic kidney disease; CV=cardiovascular; CVD=cardiovascular disease; eGFR=estimated glomerular filtration rate; GLP-1RA=glucagon-like peptide-1 receptor agonist; HbA1c=glycated hemoglobin; IQR=interquartile range; [K+]=potassium concentration; MRA=mineralocorticoid receptor antagonist; SBP=systolic blood pressure; SD=standard deviation; SGLT-2/1i=sodium-glucose cotransporter-2/1 inhibitor; T1D=type 1 diabetes; UACR=urine albumin-to-creatinine ratio.

CI=confidence interval; CKD=chronic kidney disease; CV=cardiovascular; eGFR=estimated glomerular filtration rate; HR=hazard ratio; RR=relative reduction; RRR=relative risk reduction; T2D=type 2 diabetes; UACR=urine albumin-to-creatinine ratio.

REFERENCES

FINE-ONE: A pioneering phase 3 clinical trial evaluating
KERENDIA in patients with T1D and CKD

Primary outcome: efficacy

Secondary outcomes: safety

Primary CV composite endpoint^1,2

Exploratory analysis¹

Primary renal composite endpoint¹

Exploratory analysis¹

Secondary CV composite endpoint¹

REFERENCES

FINE-ONE: A pioneering phase 3 clinical trial evaluating KERENDIA in patients with T1D and CKD

Primary outcome: efficacy

Secondary outcomes: safety

FIGARO-DKD and FIDELIO-DKD shared similar designs1,2,19,28,29

Key criteria and baseline characteristics

KERENDIA for CKD associated with T2D:efficacy and safety overview

Primary CV composite endpoint1,2

Exploratory analysis1

Secondary renal composite endpoint1,2

Primary renal composite endpoint1

Exploratory analysis1

Secondary CV composite endpoint1

Safety: pooled data FIGARO-DKD and FIDELIO-DKD1

FINE-ONE: A pioneering phase 3 clinical trial evaluating
KERENDIA in patients with T1D and CKD

FIGARO-DKD and FIDELIO-DKD shared similar designs^1,2,19,28,29

KERENDIA for CKD associated with T2D:
efficacy and safety overview

Primary CV composite endpoint^1,2

Exploratory analysis¹

Secondary renal composite endpoint^1,2

Primary renal composite endpoint¹

Exploratory analysis¹

Secondary CV composite endpoint¹

Safety: pooled data FIGARO-DKD and FIDELIO-DKD¹