Purpose:
An estimated 843.6 million people worldwide live with chronic kidney disease (CKD), and CKD was number 10 of the most common global causes of death in 2019, with predictions suggesting that it will become the fifth highest cause of years of life lost globally by 2040. In the United States, approximately one in three adults aged 65 years and older has CKD, defined as an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m², which is a measure of kidney function. Estimates of global incidence, prevalence, and mortality of CKD have all increased dramatically since 1990; an effect driven by population growth, ageing, and increased prevalence of hypertension and diabetes. Patients with CKD are not only at risk for progressing to lifelong dialysis, but also six times more likely to experience cardiovascular-related death. The presence of a lower eGFR and/or higher levels of albumin in the urine (UACR) generally portends higher risk of progression to dialysis and cardiovascular mortality. Patients who reach kidney failure are dependent on long-term dialysis or kidney transplantation for survival. Patients on dialysis remain at high risk for death with five-year survival in the United States less than 50%.
Hypertension is one of the strongest cardiovascular risk factors worldwide and is also closely associated with the development and progression of CKD. Hypertension affects 67% to 92% of patients with CKD and is associated with more rapid progression to end-stage kidney disease and dialysis. Hypertension, known as the “silent killer,” is defined as a resting blood pressure in a seated position of > 130/80 and is associated not only with chronic kidney disease but also with stroke, heart failure, and dementia. Nearly half of adults in the United States have hypertension, with only 1 in 4 adults with hypertension having their blood pressure under control. Reasons for this include the patient not being appropriately diagnosed with the condition, an unhealthy sedentary lifestyle, obesity, and high salt intake. Compliance with hypertensive treatments is relatively poor. Optimal blood pressure control to pressures less than 130/80 can slow the progression of chronic kidney disease.
Aldosterone is a hormone secreted by the adrenal gland. It plays an important role in maintaining blood pressure and electrolyte balance by binding to the mineralocorticoid receptor. Aldosterone also plays a significant role in the progression of CKD and cardiovascular disease. Elevated aldosterone levels, particularly in individuals with CKD, are associated with increased risk of disease progression.
Baxdrostat is a highly selective aldosterone synthase inhibitor that can significantly reduce aldosterone levels, offering the potential to improve blood pressure in CKD patients and ameliorate the negative impacts of aldosterone on kidney function. Baxdrostat, by blocking the enzyme responsible for the synthesis of aldosterone, is expected to be more effective than currently available mineralocorticoid receptor antagonists such as spironolactone. The addition of baxdrostat on top of the SGLT2 inhibitor, dapagliflozin, is expected to improve renal outcomes in hypertensive patients with CKD. Dapagliflozin has been found to have renal protective effects in its own right. The study is designed to assess the efficacy, safety, and tolerability of baxdrostat in combination with dapagliflozin compared with dapagliflozin alone on renal outcomes and cardiovascular mortality in participants with CKD and high blood pressure.
As baxdrostat and dapagliflozin have different and complementary mechanisms of action, their combination is anticipated to provide additive benefits in preserving renal function and slowing the progression of CKD. Combination therapy is expected to improve CKD outcomes also via blood pressure reduction and by counteracting the pro-inflammatory and profibrotic effects of aldosterone. Combining baxdrostat with dapagliflozin is also expected to provide additional benefit by reducing the risk of hyperkalemia.
Description:
This is a Phase III, multicenter, randomized, double-blind, active-controlled trial to evaluate the effect of baxdrostat in combination with dapagliflozin versus dapagliflozin alone on the measure of kidney function referred to as eGFR change over time in participants with CKD and hypertension. Patients will be in the trial for approximately 24 months.
Key Eligibility Requirements:
(Please note: Additional eligibility requirements may be assessed at the time of study screening evaluation.)
Participants with:
- eGFR ≥ 30 and < 60 mL/min/1.73 m², and UACR ≥ 30 mg/g and < 500 mg/g (56.5 mg/mmol)
- eGFR ≥ 30 and ≤ 75 mL/min/1.73 m² and UACR ≥ 500 mg/g and ≤ 5000 mg/g
- A history of hypertension and a systolic blood pressure ≥ 130 mmHg
- On a stable and maximum tolerated dose of an ACEi or an ARB
Patients May Be Excluded From Trial Participation If They Have:
- Systolic blood pressure > 180 mmHg, or diastolic BP > 110 mmHg
- Known hyperkalemia
- Uncontrolled T2DM with HbA1c > 10.5%
- A documented history of adrenal insufficiency
- Any use of mineralocorticoid receptor antagonists (spironolactone, eplerenone, or finerenone) or potassium-sparing diuretics (such as triamterene or amiloride) within 4 weeks prior to screening
PARTICIPATION IN THIS TRIAL CAN BE UP TO 21 MONTHS
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