The SPECTRA-HFpEF Study is a randomized, double-blind, Phase 2 clinical study designed to evaluate and compare the biological effects of vicadrostat in combination with empagliflozin, empagliflozin alone, and spironolactone in combination with empagliflozin in adults with heart failure and preserved ejection fraction. The study will enroll approximately 200 participants with chronic heart failure, New York Heart Association Class II to IV symptoms, and left ventricular ejection fraction greater than 40%. The primary objective is to determine whether treatment with vicadrostat/empagliflozin produces differential changes in circulating plasma proteins compared with spironolactone/empagliflozin, using a broad proteomic panel measured over the course of treatment. These proteomic changes may help identify biological pathways affected by each treatment strategy, including pathways related to inflammation, myocardial fibrosis and remodeling, kidney function, cardiac stress, and aldosterone-related signaling.
Participants will complete an approximately 26-week study period, including screening, treatment, and follow-up phases. After screening and any required washout of prior sodium-glucose cotransporter 2 inhibitor therapy, participants will receive open-label empagliflozin and will be randomized in a blinded manner to receive vicadrostat or placebo during the first treatment period. During the second treatment period, participants will receive either continued vicadrostat with empagliflozin or spironolactone with empagliflozin. During the third treatment period, vicadrostat or spironolactone will be discontinued while empagliflozin is continued. Blood and urine samples will be collected at specified visits to evaluate changes in proteomic markers, renin-angiotensin-aldosterone system biomarkers, collagen turnover markers, sex hormone markers, kidney function, proteinuria, inflammatory biomarkers, and cardiac stress biomarkers. Echocardiography and patient-reported health status assessments will also be performed to explore potential effects on cardiac structure, function, symptoms, and quality of life.
The study is intended to improve understanding of how aldosterone synthase inhibition with vicadrostat differs from mineralocorticoid receptor antagonism with spironolactone when each is used with empagliflozin in patients with heart failure and preserved ejection fraction. By comparing treatment-related proteomic and biomarker changes across study arms, the study may provide insight into mechanistic differences between these therapeutic approaches and help inform future development of targeted combination therapies for heart failure. Safety and tolerability will be monitored throughout the study through collection of adverse events, serious adverse events, vital signs, electrocardiograms, physical examinations, and clinical laboratory assessments, including kidney function and serum potassium monitoring.
Participant is aged ≥18 years.
Participant provides informed consent to participate in the study in accordance with ICH-GCP and local legislation prior to any study procedures taking place.
Women of childbearing potential (WOCBP) must agree to use a highly effective method of birth control per ICH M3 (R2) that results in a low failure rate of <1% per year when used consistently and correctly.
Participant has chronic HF diagnosed ≥3 months before enrollment, and in New York Heart Association (NYHA) class II-IV.
Treatment with an MRA (e.g. spironolactone, eplerenone, finerenone) within 14 days prior to enrollment and no intention to initiate MRA during the study.
Treatment with amiloride, direct renin inhibitor (e.g. aliskiren), or the combination of ACEi plus ARB.
Treatment with any other ASi.
Major contraindication to SGLT2 inhibition, including history of Type 1 diabetes or previous ketoacidosis.
Parallel
empa plus vica
DrugParticipants will be randomized to to this arm will receive empa (open-label)/vica (blinded). In treatment period 1 those randomized to empa/vica will be administered one tablet of empa 10 mg QD and one tablet of vica 10 mg QD for 8 weeks. In treatment period 2 for those randomized to empa/vica will continue to take empa 10 mg QD and vica 10 mg QD plus a placebo-matching spiro for 10 weeks. In treatment period 3, this group will receive open-label empa 10 mg QD for 4 weeks.
Comparator: empa 10 plus spironolactone
DrugFor those randomized to empa (open-label) spiro (blinded), in treatment period 1 they will be administered one tablet of empa 10 mg QD and vica matching placebo for 8 weeks. In treatment period 2 for those randomized to empa/spiro, they will take empa 10 mg QD, spiro 25 mg titrating to 50 mg QD plus a vica matching placebo tablet for 10 weeks. In treatment period 3, this group will receive open-label empa 10 mg QD for 4 weeks.
Differences in the proteomic regulation following Treatment Period 2
To evaluate the relative change in plasma concentration of a pre-specified panel of 5400 proteins measured using the Olink Explore HT panel from Study Visit 1 (baseline) through Study Visit 7 (18 weeks), compared between those treated with vica/empa versus spiro/empa.
Differences in the proteomic regulation following Treatment Period 1.
To evaluate the relative change in plasma concentration of a pre-specified panel of 5400 proteins measured using the Olink Explore HT panel from Study Visit 1 (baseline) through Study Visit 4 (8 weeks), compared between those treated with vica/empa versus empa will be evaluated.
Differences in the proteomic regulation following Treatment Period 2
To evaluate the relative change in plasma concentration of a pre-specified panel of 5400 proteins measured using the Olink Explore HT panel from Visit 4 (8 weeks) through Study 7 (18 weeks), compared between those treated with vica/empa versus empa.
Differences in proteomic regulation following Treatment Period 3.
To compare the relative change in plasma concentration of a pre-specified panel of 5400 proteins measured using the Olink Explore HT panel from Study Visit 7 (18 weeks) through Study Visit 8 (22 weeks), compared between those treated with vica/empa in Treatment Periods 1 and 3 versus empa alone in Treatment Period 3.
Differences in renin, aldosterone and aldosterone precursors across each Treatment Period.
To evaluate mean within- participant change in plasma renin activity/concentration, serum aldosterone, and 11-deoxycorticosterone from the beginning and end of each Treatment Period, compared across treatment arms.
Differences in safety and tolerability between treatment groups (vica/empa; placebo/empa; and spiro/empa)
To evaluate Incidence of TEAEs and SAEs
Differences in safety and tolerability between vica/empa and placebo/empa across Treatment Period 1
To evaluate change from baseline in clinical laboratory values (serum potassium) with the unit of measure mEq/L
Differences in safety and tolerability between vica/empa and placebo/empa across Treatment Period 1.
To evaluate change from baseline in clinical laboratory values (serum creatinine) measured in mg/dL
Differences in safety and tolerability between vica/empa and placebo/empa across Treatment Period 1.
To evaluate change from baseline in blood pressure measured in mm/Hg
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