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Phase 2 Randomized Study of the Efficacy and Safety of PF-07328948 in Adults with Heart Failure with Preserved or Mildly Reduced Ejection Fraction

Trial ID: 2024-518438-94-00
Protocol: C4921003
Sponsor: Pfizer Inc.

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Diseases & Conditions

Cardiac failure

Objectives

The primary objective is to evaluate the efficacy of PF-07328948 compared to a placebo in adults with heart failure with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF). This investigation focuses on the impact of daily oral administration over 36 weeks on clinical events, including cardiovascular death and worsening heart failure events, as well as physical function and symptoms. 5, 7

Secondary objectives include the following:

Assessment of safety and tolerability of PF-07328948 compared to placebo. 4, 13
Evaluation of disease-specific health status related to heart failure.
Comparison of effects on physical function.
Measurement of a biomarker utilized to assess heart failure risk. 6

Participants

This study involves 264 participants diagnosed with heart failure with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF). The study population includes both male and female individuals aged 18 to <80 years. Eligible participants must have a clinical diagnosis of chronic heart failure for at least 3 months and meet New York Heart Association Class II-IV criteria. Inclusion requires a left ventricular ejection fraction (LVEF) greater than 40% and specific structural heart abnormalities if the LVEF is ≥50%. Additionally, participants must exhibit evidence of elevated natriuretic peptide levels, elevated cardiac filling pressures, or recent clinical interventions for congestion, such as hospitalization or diuretic intensification. Selected individuals must have a body mass index (BMI) of ≥27.0 kg/m² or specific waist circumference measurements, or presence of type 2 diabetes mellitus, or specific glycated hemoglobin levels, or elevated triglycerides. All participants are required to be receiving therapy with an SGLT2 inhibitor for at least 30 days prior to randomization. The objectives of the trial are:

To compare the effect of PF-07328948 versus placebo on cardiovascular death and worsening heart failure events.
To evaluate changes in physical function and symptoms over a 36-week period.

Plans and Procedures

This Phase 2, randomized, double-blind, placebo-controlled study is designed to evaluate the efficacy and safety of PF-07328948, an oral branched-chain ketoacid dehydrogenase kinase inhibitor, in adults with heart failure. The research methodology involves comparing the effects of the test product against a placebo administered daily over a 36-week period. The study procedure begins with a screening phase to assess eligibility based on clinical diagnosis, left ventricular ejection fraction, and specific metabolic or structural criteria. Following screening, participants may undergo an SGLT2i run-in period if required. The trial includes a randomization visit, subsequent follow-up assessments to monitor clinical events, physical function, and symptoms, and concludes with an end-of-study visit. Primary endpoints include a hierarchical combination of cardiovascular death, worsening heart failure events, changes in the 6-minute walk distance, and Kansas City Cardiomyopathy Questionnaire scores. A CPET substudy is also incorporated for a subset of participants to evaluate peak oxygen uptake. Participant involvement is expected to last approximately 36 weeks of treatment, though early termination may occur if participants do not comply with the protocol or scheduled activities.

Treatment

The experimental treatment consists of PF-07328948, an oral branched-chain ketoacid dehydrogenase kinase inhibitor. The medication is administered in tablet form via the oral route on a daily basis for a duration of 36 weeks.

The control group receives a placebo, which is intended to match the PF-07328948 tablet for administration purposes.

Efficacy

The efficacy of PF-07328948 in adults with heart failure is evaluated through a hierarchical combination of primary endpoints at week 36. These endpoints include adjudicated clinical events, specifically cardiovascular death and weight-based heart failure events. The latter includes events resulting in hospitalization, intravenous diuretic administration during an urgent visit, or oral diuretic intensification in an outpatient setting. Additionally, the primary assessment incorporates the change from baseline in the six-minute walk distance and the Kansas City Cardiomyopathy Questionnaire-23 total symptom score.

Secondary efficacy assessments at week 36 include:

Change from baseline in the Kansas City Cardiomyopathy Questionnaire-23 total symptom score, clinical symptom score, and physical limitation.
Change from baseline in the six-minute walk distance.
Change from baseline in N-terminal pro-brain natriuretic peptide.
In a specific cardiopulmonary exercise testing substudy, the change from baseline in peak oxygen uptake.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Male or female participants aged 18 years to < 80 years, at screening. a. Women of child-bearing potential can only be enrolled if a pregnancy test is negative at screening and randomization, and if they agree not to become pregnant or breastfeed while participating in this study. All fertile female participants must agree to use a highly effective method of contraception (permitted by protocol). b. Reproductive criteria for male and female participants are detailed in the main protocol.
Receiving therapy with an SGLT2i for at least 30 days prior to randomization (V4). An SGLT2i run-in period is required for participants who are confirmed eligible for this study based on all other criteria but who are not currently prescribed an SGLT2i despite no history of prior intolerance/hypersensitivity or contraindication to an SGLT2i.
CPET substudy requirement: pVO2 less than 80% of the predicted normal value with RER ≥1.05 on Day 1 (V4). If a participant does not meet this pVO2 requirement on Day 1, that participant can continue with randomization as planned, but will not be included in the CPET substudy and will not undergo CPET during Week 36/V14 visit or ET visit.
Signed and dated informed consent form before any trial-related activities.
Willing and able to comply with all study visits and procedures detailed in the Schedule of Activities for the duration of the trial.
Clinical diagnosis of chronic heart failure for at least 3 months prior to screening visit (V1), with each of the following criteria: • New York Heart Association (NYHA) Class II-IV at V1. • Left ventricular ejection fraction (LVEF) > 40% based on most recent assessment available in medical records.
Evidence of the following on screening echocardiogram performed during V2, based on analysis by central reader: a. LVEF >40% b. If LVEF ≥50%, then one or more of the following structural heart abnormalities must be present: • Average E/e’ ≥11; • Left atrial (LA) volume index >34 mL/m2 • Left ventricular (LV) mass index ≥115 g/m2 for males and ≥95 g/m2 for females.
Have at least one of the following: a. An elevated natriuretic peptide at screening (V1), analyzed by central laboratory, and defined as a NT-proBNP: • ≥300 ng/L for patients with body mass index (BMI) <30.0 kg/m2 in sinus rhythm; • ≥150 ng/L for patients with BMI ≥30.0 kg/m2 in sinus rhythm; • ≥600 ng/L for patients with BMI <30.0 kg/m2 in persistent or permanent atrial fibrillation; • ≥300 ng/L for patients with BMI ≥30.0 kg/m2 in persistent or permanent atrial fibrillation. b. Evidence for elevated cardiac filling pressures within 12 months of screening (V1) as defined by either: • Mean pulmonary capillary wedge pressure or LV end diastolic pressure (LVEDP) ≥15 mm Hg during catheterization at rest, or • Mean pulmonary capillary wedge pressure or LVEDP ≥25 mm Hg during catheterization performed during exercise, or • Pulmonary artery diastolic pressure measured by implantable monitor of ≥15 mm Hg c. Hospitalization with a primary diagnosis of decompensated HF requiring IV loop diuretic treatment within 12 months of screening (V1; but not within 1 month immediately prior to V1 or during the screening period). d. Urgent outpatient visit for worsening HF requiring IV loop diuretic treatment within 6 months of screening (V1, but not within 1 month immediately prior to V1 or during screening period). e. Oral diuretic intensification within 6 months of screening, defined as either a doubling of loop diuretic dose and/or new initiation of combination diuretic therapy to relieve congestion. Combination diuretic therapy could include: 1) new initiation of a thiazide-type diuretic (e.g., hydrochlorothiazide, metolazone, or chlorothiazide) plus a loop diuretic; or 2) new initiation of a mineralocorticoid receptor antagonist (e.g., spironolactone or eplerenone) OR SGLT2 inhibitor OR tolvaptan plus a loop diuretic.
Able to perform the 6-minute walk test at screening (V1) with a minimum distance of 75 meters.
KCCQ-23 TSS <85 at screening (V1).
Have at least one of the following: a. BMI: ≥27.0 and <50.0 kg/m2 at screening (V1) b. Waist circumference >94 cm (37 inches) for males or >80 cm (31 inches) for females. c. Type 2 diabetes mellitus. d. Glycated hemoglobin (HbA1c) ≥5.7% (and < 10.0%) at screening (V1), analyzed by central laboratory e. Fasting serum triglyceride level ≥ 150 mg/dL (or ≥ 1.7 mmol/L) at screening (V2), analyzed by central laboratory

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Exclusion Criteria

Any medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator’s judgment, make the participant inappropriate for the study.
Investigator site staff directly involved in the conduct of the study and their family members, site staff otherwise supervised by the investigator, and sponsor and sponsor delegate employees directly involved in the conduct of the study and their family members.
Any condition possibly affecting drug absorption (eg, prior or planned bariatric surgery, gastrectomy, or any area of intestinal resection, active inflammatory bowel disease or pancreatic insufficiency).
Any other condition judged by the investigator to be the primary cause of dyspnea, including heart failure due to restrictive cardiomyopathy or infiltrative conditions (eg, amyloidosis, sarcoidosis), hypertrophic cardiomyopathy, complex congenital heart disease, primary pulmonary arterial hypertension, severe chronic obstructive pulmonary disease (eg, requiring long term supplemental oxygen), or right sided heart failure due to pulmonary disease.
Any major surgery scheduled for the duration of the trial, affecting walking ability in the opinion of the investigator (eg, knee replacement).
Any of the following cardiovascular conditions: a. Acute coronary syndrome (including myocardial infarction), acute myocarditis, coronary artery bypass graft surgery, other major CV surgery, urgent percutaneous coronary intervention, cardiac resynchronization therapy, stroke, or transient ischemic attack within 3 months prior to screening (V1). b. Elective percutaneous coronary intervention within 30 days prior to screening (V1). c. Planned coronary, carotid or peripheral artery revascularization. d. Hospitalization for heart failure, or urgent outpatient visit for worsening HF requiring IV loop diuretic treatment, within 30 days prior to screening (V1) or during the screening period.
History of heart transplantation, currently listed for heart transplant, current/planned mechanical circulatory support, or current/planned use of intravenous vasodilators and/or inotropes (eg, dobutamine, milrinone).
Life-threatening or uncontrolled tachyarrhythmias at screening and/or randomization (V1-V4) including but not limited to sustained ventricular tachycardia and atrial fibrillation or atrial flutter with resting ventricular rate >110 bpm. -Applicable to EU only: Life-threating or uncontrolled tachyarrhythmias at screening and/or randomization (V1-V4) including but not limited to sustained ventricular tachycardia and atrial fibrillation or atrial flutter with resting ventricular rate >110 bpm.
Type 1 diabetes mellitus.
Prior intolerance/known hypersensitivity to an SGLT2i or contraindication to an SGLT2i. However, participants who demonstrate an intolerance/hypersensitivity to SGLT2i that prompts discontinuation during the protocol-specified run-in period may still proceed to randomization, following discussion with medical monitor.
Active, untreated human immunodeficiency virus (HIV) or hepatitis infection, including hepatitis B and C.
Previous administration of an investigational product (drug or vaccine) within 30 days or 5 half-lives preceding screening (whichever is longer). Note: local regulations or other factors may require a washout period of more than 30 days.
Liver cirrhosis.
Renal disease requiring ongoing dialysis.
Active malignancy requiring treatment (except for basal cell or squamous cell carcinomas of the skin).
Any condition that would limit projected life-expectancy to less than 2 years in the clinical judgement of the investigator.
Current use of any prohibited concomitant medication(s) or unwillingness or inability to use a required concomitant medication(s). The list of prohibited concomitant medications is provided in the main protocol.
Current use of dietary supplements specifically intended to supplement BCAAs.
Life-Threatening uncontrolled bradyarrhythmia including but not limited to a resting heart rate < 40 bpm, in the absence of a functioning pacemaker or implantable cardioverter defibrillator
Presence of hemodynamically significant valvular heart disease (eg, moderate or severe valvular disease) in the opinion of the investigator.
Prior participation in a trial involving PF-07328948.
Systolic blood pressure >160 mm Hg, on two consecutive measurements performed at least 10 minutes apart, at screening (V1). [Note: a participant may be rescreened once if blood pressure control is subsequently established].
Symptomatic hypotension with mean systolic blood pressure <90 mm Hg at screening (V1). [Note: a participant may be rescreened once if blood pressure control is subsequently established].
Participants with ANY of the following abnormalities in clinical laboratory tests at Screening (V1, unless otherwise stated), as assessed by the central laboratory and confirmed by a single repeat test, if deemed necessary: • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level ≥2 × upper limit of normal (ULN), or total bilirubin level ≥ 2 × ULN (unless in the setting of presumed Gilbert’s syndrome when total bilirubin level of ≥ 3 × ULN would be applied) • Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2, calculated using the CKD-EPI recommended serum creatinine-based formula • Fasting plasma glucose (FPG)>270 mg/dL (15 mmol/L) at V2 • Hemoglobin ≤9 g/dL • Urine albumin/creatinine ratio (UACR) ≥2200 mg/g • HbA1c ≥ 10.0%.
A positive urine drug test at screening (V1). • Note: Participants who have been medically prescribed opiates/opioids, amphetamines or benzodiazepines and report the use of these drugs to the investigator at screening may be allowed to participate if approved by the sponsor.
History of non-compliance to medical regimens or hospital visits.
BMI >50.0 kg/m2 at screening (V1)
Initiation and titration of a glucagon-like peptide-1 receptor agonist (GLP1-RA) within 24 weeks of enrollment with the express goal of obesity treatment. Change in GLP1-RA type or dose in a stable, pre-existing prescription does not represent an exclusion criterion.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Bulgaria	Recruiting	19 Nov 2025	50
Czechia	Recruiting	19 Nov 2025	73
France	Recruiting	19 Nov 2025	30
Hungary	Recruiting	19 Nov 2025	50
Poland	Recruiting	19 Nov 2025	50
Spain	Recruiting	19 Nov 2025	103

Sites & Investigators

Research sites

Kardiologicka ambulance Brno s.r.o.EFERTUS healthcare s.r.o.AGEL Stredomoravska nemocnicni a.s.Central Hospital Of Northern Pest Military Hospital

Investigators

Jozsef L.Muriel S.Borislav K.Marta C. M.

Investigational Products

Details about the medicinal products being studied in this clinical trial.

Product Name	Role in Trial	Formulation	Administration	Max Daily Dose	Treatment Duration	EU MP Number
Placebo for pf-07328948 tablet (CCI) mg	Placebo	N/A	—	—	—	N/A
Placebo for pf-07328948 tablet (CCI) mg	Placebo	N/A	—	—	—	N/A