Baxdrostat and Ventricular Remodeling

Official title

A Randomized, Double-blind, Placebo-controlled Study to Evaluate the Effects of Baxdrostat on Ventricular Remodeling

Overview

The goal of this trial is to learn whether adding the blood pressure medication baxdrostat (Baxfendy) to standard-of-care medical therapies will beneficially change the heart structure and function of adults who have high blood pressure, thickened left heart walls, and are at risk for heart or kidney disease. To determine if baxdrostat improves heart structure and function, the participants will: * take a baxdrostat or a placebo (a look-alike tablet that contains no drug) tablet once a day for 12 months * undergo a safe and non-invasive cardiac magnetic resonance imaging scan (to measure heart mass, stiffness and function) at the beginning of the study and 12 months later * visit the clinic for checkups and blood or urine tests 2 weeks, 1 month, 3 months, 6 months, 9 months and 12 months after taking the first tablet

Detailed description

The BaxREMODEL CardioLink-18 Research Study is a multicentre, prospective, randomized, double-blind, parallel research study of baxdrostat vs placebo in addition to standard-of-care in adults with a history of hypertension and either cardiovascular or cardiorenal risk factors plus evidence of left ventricular hypertrophy or increased left ventricular mass. A total of 286 individuals will be assigned (1:1) to receive either baxdrostat 2 mg or placebo QD for 12 months.

Interventions

• Drug Baxdrostat
  Participants will take 2mg baxdrostat (Baxfendy) once daily (orally), in addition to standard-of-care.
• Drug Placebo
  Participants will take placebo once daily (orally), in addition to standard-of-care.

Primary outcome measures

• Left Ventricular Mass indexed to baseline body surface area (LVMi) [Time frame: 12 months]

Secondary outcome measures (7)

• Left Atrial Volume indexed to baseline body surface area (LAVi) [Time frame: 12 months]
• Left Ventricular Ejection Fraction (LVEF) [Time frame: 12 months]
• Left Ventricular End-Diastolic Volume indexed to baseline body surface area (LVEDVi) [Time frame: 12 months]
• Left Ventricular End-Systolic Volume indexed to baseline body surface area (LVESVi) [Time frame: 12 months]
• Right Ventricular Ejection Fraction (RVEF) [Time frame: 12 months]
• Right Ventricular End-Diastolic Volume indexed to baseline body surface area (RVEDVi) [Time frame: 12 months]
• Right Ventricular End-Systolic Volume indexed to baseline body surface area (RVESVi) [Time frame: 12 months]

Eligibility criteria

Inclusion criteria

• Individuals ≥18 years of age who are willing and able to provide signed informed consent
• History of hypertension (Systolic BP >140 and <170 mmHg)
• Serum K+ ≥3.5 and <5.0 mmol/L at Screening
• Evidence of left ventricular (LV) hypertrophy ≤12 months prior to or at screening showing at least one (≥1) of the following:

• Interventricular septal (IVS) thickness by echocardiography: Female ≥1.2 cm or Male ≥1.3 cm
• Posterior wall (PW) thickness by echocardiography: Female ≥1.2 cm or Male ≥1.3 cm
• Left ventricular mass indexed to baseline body surface area (LVMi) by echocardiography: Female >95 g⁄m\^2 or Male >115 g⁄m\^2
• LVMi by cMRI: Female >68 g⁄m\^2 or Male >85 g⁄m\^2
• The presence of ≥1 of the following risk factors:

• Documented type 2 diabetes mellitus or a glycated hemoglobin (A1C) level ≥6.5%
• Estimated glomerular filtration rate (eGFR) 45-60 mL/min/1.73m\^2 at Screening
• Urine albumin-creatinine ratio (UACR) ≥3 mg/mmol
• IVS ≥1.4 cm
• PW ≥1.4 cm
• LVMi ≥105 g⁄m\^2 for female and ≥125 g⁄m\^2 for male individuals (by echocardiography)
• History of HFpEF (LV ejection fraction ≥50%)
• NT-proBNP ≥125 pg/mL (within past 6 months)
• Female individuals who are of childbearing age can only be considered eligible if:

• they are postmenopausal (amenorrhoeic for ≥12 months following cessation of exogenous hormonal treatment) or have had a surgical procedure (eg. hysterectomy, bilateral oophorectomy, or bilateral salpingectomy) ≥6 months at Screening that prevents them from becoming pregnant or
• the result of their pregnancy test at the baseline visit is negative, and they agree to use at least one highly effective and one effective contraception method to avoid pregnancy during the 30 days before randomization, throughout the research study, and for at least 30 days after taking the last dose of the assigned IP

EXCLUSION

• Considered unsuitable by the investigator for any reason that may either place the participant at increased risk during participation or interfere with the interpretation of the study outcomes
• Female individuals who are pregnant, or can get pregnant, are breast-feeding or are planning to breastfeed and are/will not be using at least one highly effective contraception method (see Inclusion Criteria section for definitions) during the 30 days before Randomization, throughout the research study, and for at least 30 days after taking the last dose of the assigned IP
• Upper arm circumference <18 cm or >43 cm at Screening
• Body mass index >40 kg/m\^2 (Image quality and accurate assessment of cardiac function degrades with obesity across all imaging modalities. Although CMR-derived images are the least compromised by high body mass indexes, MRI bore sizes and table weight limits, greater safety risks \[eg. thermal burns\] as well as increased frequencies of claustrophobia remain major challenges.
• Contraindication or inability to undergo CMR scan
• Serum Na+ level <135 mmol/L at Screening
• A1C >10% if living with T2DM during the 30 days before Randomization
• At Screening

• Systolic BP ≤120 mmHg
• Heart rate >110 or <45 bpm per electrocardiogram (ECG) performed at Screening
• eGFR <45 mL/min/1.73m\^2 at Screening
• New York Heart Association (NYHA) functional HF class IV
• At Screening or first IP intake

• White blood cell (WBC) count >15 X 10\^9/L or absolute neutrophil count <1 X 10\^9/L
• Hemoglobin (Hb) <100 g/L and/or anticipated initiation of erythropoietin-stimulating agents and/or planned transfusion within 60 days after screening
• Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >3X upper limits of normal (ULN) with a corresponding bilirubin >34 μmol/L unless the potential participant has a history of Gilbert syndrome
• Medical history

• Planned dialysis or kidney transplant during this research study
• Adrenal insufficiency
• Primary pulmonary hypertension, chronic pulmonary embolism, severe pulmonary disease including chronic obstructive pulmonary disease
• Secondary causes of hypertension eg. Cushing's syndrome, aortic coarctation, renal artery stenosis, uncontrolled hyperthyroidism, untreated hyperthyroidism, hypothyroidism or pheochromocytoma
• HF due to infiltrative cardiomyopathy (eg. sarcoid, amyloid), arrhythmogenic right ventricular (RV) cardiomyopathy, Takutsubo cardiomyopathy, genetic hypertrophic cardiomyopathy or obstructive cardiomyopathy, active myocarditis, constrictive pericarditis, cardiac tamponade, uncorrected more than moderate primary valve disease
• Acute coronary syndrome, myocardial infarction, stroke, unstable angina pectoris, hypertensive encephalopathy, transient ischemic attack, or hospitalization for HF, during the 30 days before Screening
• Persistent atrial fibrillation, left bundle branch block or any cardiac arrhythmia requiring treatment
• Severe hepatic impairment, defined as Child-Pugh Class C, based on records that confirm documented medical history
• Clinical evidence of, or suspicion of, active infection (at the discretion of the Site Investigator)
• Surgical history

• Undergone a major cardiovascular surgical procedure (eg. percutaneous coronary intervention/coronary artery bypass grafting or percutaneous coronary
• Intervention/coronary artery bypass grafting) or major endoscopic procedure (thoracoscopic or laparoscopic) during the 60 days before Randomization
• Previous or planned coronary, carotid, or peripheral artery revascularization during the 45 days before Screening
• Prior solid organ transplant and/or cell transplants
• Previous cardiac device implant (eg. implantable cardioverter defibrillator/cardiac resynchronization therapy/pacemaker) or planned device implant ≤90 days after screening
• Prior treatment (within 30 days before Screening) with or currently on an angiotensin-receptor blocker (ARB) in combination with an angiotensin converting enzyme inhibitor (ACEi)
• Prior treatment (within 30 days before Screening) with or currently on a mineralocorticoid receptor antagonist (MRA) or a K+-sparing diuretic, or anticipated initiation of either of these agents during the study period
• Unwilling to discontinue taking K+ supplements
• On K+ binders within 30 days prior to Screening
• On or expected to initiate a strong cytochrome P450 3A (CYP3A) inducer (eg. carbamazepine, enzalutamide, mitotane, phenytoin, rifabutin, rifampin and St. John's wort)
• Prior treatment within 6 months prior to Screening with a cytotoxic therapy (eg. cisplatin, doxorubicin, etoposide, misoprostol, trastuzumab)
• Known hypersensitivity to baxdrostat or drugs of the same class or any of its excipients
• Participation in another clinical study involving the investigational drug within 30 days prior to Screening or has plans to participate in another clinical study within 30 days of discontinuing the investigational drug

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Canada · 2 centers

• North York Diagnostic and Cardiac Centre — North York
• Diagnostic Assessment Centre — Toronto

Identifiers

NCT: NCT07655362 · CL-0018

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗