A Research Study to Look at How Ziltivekimab Works Compared to Placebo in People With Heart Failure and Inflammation (HERMES)

• ClinicalTrials.gov Identifier: NCT05636176
• Recruitment Status: Recruiting
• First Posted: December 5, 2022
• Last Update Posted: April 30, 2024
• Sponsor: Novo Nordisk A/S
• Information provided by (Responsible Party): Novo Nordisk A/S

Tracking Information

• First Submitted Date: November 23, 2022
• First Posted Date: December 5, 2022
• Last Update Posted Date: April 30, 2024
• Actual Study Start Date: May 8, 2023
• Estimated Primary Completion Date: July 2, 2027 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 23, 2022)

Time to First Occurrence of a Composite Heart Failure Endpoint Consisting of: Cardiovascular (CV) Death, Heart Failure (HF) Hospitalisation or Urgent HF Visit [ Time Frame: From randomisation (month 0) to end of study (up to 48 months) ]

Measured in months.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: December 23, 2022)

• Time to First Occurrence of 4-point Expanded Composite HF Endpoint, a Composite Endpoint Consisting of: CV Death, HF Hospitalisation or Urgent HF Visit, Non-fatal Myocardial Infarction (MI), Non-fatal Stroke [ Time Frame: From randomisation (month 0) to end of study (up to 48 months) ]
  Measured in months.
• Number of CV Deaths, HF Hospitalisations or Urgent HF Visits (First and Recurrent) [ Time Frame: From randomisation (month 0) to end of study (up to 48 months) ]
  Measured as count of event.
• Time to Occurrence of CV Death [ Time Frame: From randomisation (month 0) to end of study (up to 48 months) ]
  Measured in months.
• Time to Occurrence of all-cause Death [ Time Frame: From randomisation (month 0) to end of study (up to 48 months) ]
  Measured in months.
• Time to First Occurrence of 4-point Expanded Composite HF Endpoint, a Composite Endpoint Consisting of: All-cause Death, HF Hospitalisation or Urgent HF Visit, Non-fatal MI, Non-fatal stroke [ Time Frame: From randomisation (month 0) to end of study (up to 48 months) ]
  Measured in months.
• Hierarchical Composite of: Time to All-cause Death, Number of HF Hospitalisations or Urgent HF Visits, Time to First HF Hospitalisation or Urgent HF Visit, difference of at least 5 in KCCQ clinical summary score change from baseline to 12 months [ Time Frame: From randomisation (month 0) to end of study (up to 48 months) ]
  Kansas City Cardiomyopathy Questionnaire (KCCQ) measures Health-Related Quality of Life (HRQOL) and is a disease-specific health status instrument for HF. Score ranges from 0 to 100, with 0 as the lowest score and 100 as the highest score. Higher scores indicate better health status, fewer symptoms, and greater disease-specific health related quality of life, respectively. Measured as total wins for each treatment group.
• Time to First Occurrence of HF Hospitalisation or Urgent HF Visit [ Time Frame: From randomisation (month 0) to end of study (up to 48 months) ]
  Measured in months.
• Number of Events of Atrial Fibrillation [ Time Frame: From randomisation (month 0) to end of study (up to 48 months) ]
  Measured as count of event.
• Change in KCCQ Clinical Summary Score [ Time Frame: From randomisation (month 0) to 12 months ]
  KCCQ measures Health-Related Quality of Life (HRQOL) and is a disease-specific health status instrument for HF. Score ranges from 0 to 100, with 0 as the lowest score and 100 as the highest score. Higher scores indicate better health status, fewer symptoms, and greater disease-specific health related quality of life, respectively. Measured as score.
• Improvement of 5 Points or More in KCCQ Clinical Summary Score (Yes/No) [ Time Frame: From randomisation (month 0) to 12 months ]
  Kansas City Cardiomyopathy Questionnaire (KCCQ) measures Health-Related Quality of Life (HRQOL) and is a disease-specific health status instrument for HF. Score ranges from 0 to 100, with 0 as the lowest score and 100 as the highest score. Higher scores indicate better health status, fewer symptoms, and greater disease-specific health related quality of life, respectively. Measured as count of participant.
• Improvement of 10 Points or More in KCCQ Clinical Summary Score (Yes/No) [ Time Frame: From randomisation (month 0) to 12 months ]
  Kansas City Cardiomyopathy Questionnaire (KCCQ) measures Health-Related Quality of Life (HRQOL) and is a disease-specific health status instrument for HF. Score ranges from 0 to 100, with 0 as the lowest score and 100 as the highest score. Higher scores indicate better health status, fewer symptoms, and greater disease-specific health related quality of life, respectively. Measured as count of participant.
• Improvement in New York Heart Association (Classification) [NYHA Class] (Yes/No) [ Time Frame: From randomisation (month 0) to 12 months ]
  NEW YORK HEART ASSOCIATION CLASSIFICATION (NYHA) Class I: Participant with cardiac disease but without resulting limitations of physical activity. Class II: Participants with cardiac disease resulting in slight limitation of physical activity. Class III: Participants with cardiac disease resulting in marked limitation of physical activity. Class IV: Participants with cardiac disease resulting in inability to carry on any physical activity without discomfort. Measured as count of participant.
• Time to First Occurrence of a Composite Chronic Kidney Disease (CKD) Endpoint Consisting of: CV death, Onset of Persistent Greater Than Equal To 40 Percentage Reduction in eGFR (CKD- EPI) compared with baseline; Kidney failure [ Time Frame: From randomisation (month 0) to end of study (up to 48 months) ]
  eGFR = estimated glomerular filtration rate; CKD-EPI = chronic kidney disease - epidemiology collaboration. Kidney failure defined as: death from kidney failure, onset of persistent eGFR less than 15 milliliters per minute (mL/min)/1.73 meter square (m^2) (CKD-EPI), initiation of chronic kidney replacement therapy (maintenance dialysis or kidney transplantation). Measured in months.
• Change in Estimated Glomerular Filtration Rate (eGFR) (Chronic Kidney Disease - Epidemiology Collaboration [CKD-EPI]) [ Time Frame: From randomisation (month 0) to 12 months ]
  Measured as mL/min/1.73 m^2.
• Annual Rate of Change in eGFR (CKD-EPI) (Total eGFR Slope) [ Time Frame: From randomisation (month 0) to end of study (up to 48 months) ]
  Measured as mL/min/1.73 m^2/year.
• Number of Hospitalisations With Infection as Primary Cause or Death Due to Infection [ Time Frame: From randomisation (month 0) to end of study (up to 48 months) ]
  Measured as count of event.
• Change in High-sensitivity C-reactive Protein (hs-CRP) [ Time Frame: From randomisation (month 0) to 12 months ]
  Measured as ratio to baseline.
• Change in N-terminal-pro-brain Natriuretic Peptide (NT-proBNP) [ Time Frame: From randomisation (month 0) to 12 months ]
  Measured as ratio to baseline.

Original Secondary Outcome Measures (submitted: November 23, 2022)

• Number of CV Deaths, HF Hospitalisations or Urgent HF Visits (First and Recurrent) [ Time Frame: From randomisation (month 0) to end of study (up to 48 months) ]
  Measured as count of event.
• Time to First Occurrence of 4-point Expanded Composite HF Endpoint, a Composite Endpoint Consisting of: CV Death, HF Hospitalisation or Urgent HF Visit, Non-fatal Myocardial Infarction (MI), Non-fatal Stroke [ Time Frame: From randomisation (month 0) to end of study (up to 48 months) ]
  Measured in months.
• Time to First Occurrence of 4-point Expanded Composite HF Endpoint, a Composite Endpoint Consisting of: All-cause Death, HF Hospitalisation or Urgent HF Visit, Non-fatal MI, Non-fatal stroke [ Time Frame: From randomisation (month 0) to end of study (up to 48 months) ]
  Measured in months.
• Time to Occurrence of CV Death [ Time Frame: From randomisation (month 0) to end of study (up to 48 months) ]
  Measured in months.
• Time to Occurrence of All-cause Death [ Time Frame: From randomisation (month 0) to end of study (up to 48 months) ]
  Measured in months.
• Hierarchical Composite of: Time to All-cause Death, Number of HF Hospitalisations or Urgent HF Visits, Time to First HF Hospitalisation or Urgent HF Visit, KCCQ Clinical Summary Score [ Time Frame: From randomisation (month 0) to end of study (up to 48 months) ]
  Kansas City Cardiomyopathy Questionnaire (KCCQ) measures Health-Related Quality of Life (HRQOL) and is a disease-specific health status instrument for HF. Score ranges from 0 to 100, with 0 as the lowest score and 100 as the highest score. Higher scores indicate better health status, fewer symptoms, and greater disease-specific health related quality of life, respectively. Measured as total wins for each treatment group.
• Time to First Occurrence of HF Hospitalisation or Urgent HF Visit [ Time Frame: From randomisation (month 0) to end of study (up to 48 months) ]
  Measured in months.
• Number of Events of Atrial Fibrillation [ Time Frame: From randomisation (month 0) to end of study (up to 48 months) ]
  Measured as count of event.
• Change in KCCQ Clinical Summary Score [ Time Frame: From randomisation (month 0) to 12 months ]
  KCCQ measures Health-Related Quality of Life (HRQOL) and is a disease-specific health status instrument for HF. Score ranges from 0 to 100, with 0 as the lowest score and 100 as the highest score. Higher scores indicate better health status, fewer symptoms, and greater disease-specific health related quality of life, respectively. Measured as score.
• Improvement of 5 Points or More in KCCQ Clinical Summary Score (Yes/No) [ Time Frame: From randomisation (month 0) to 12 months ]
  Kansas City Cardiomyopathy Questionnaire (KCCQ) measures Health-Related Quality of Life (HRQOL) and is a disease-specific health status instrument for HF. Score ranges from 0 to 100, with 0 as the lowest score and 100 as the highest score. Higher scores indicate better health status, fewer symptoms, and greater disease-specific health related quality of life, respectively. Measured as count of participant.
• Improvement of 10 Points or More in KCCQ Clinical Summary Score (Yes/No) [ Time Frame: From randomisation (month 0) to 12 months ]
  Kansas City Cardiomyopathy Questionnaire (KCCQ) measures Health-Related Quality of Life (HRQOL) and is a disease-specific health status instrument for HF. Score ranges from 0 to 100, with 0 as the lowest score and 100 as the highest score. Higher scores indicate better health status, fewer symptoms, and greater disease-specific health related quality of life, respectively. Measured as count of participant.
• Improvement in New York Heart Association (Classification) [NYHA Class] (Yes/No) [ Time Frame: From randomisation (month 0) to 12 months ]
  NEW YORK HEART ASSOCIATION CLASSIFICATION (NYHA) Class I: Participant with cardiac disease but without resulting limitations of physical activity. Class II: Participants with cardiac disease resulting in slight limitation of physical activity. Class III: Participants with cardiac disease resulting in marked limitation of physical activity. Class IV: Participants with cardiac disease resulting in inability to carry on any physical activity without discomfort. Measured as count of participant.
• Time to First Occurrence of a Composite Chronic Kidney Disease (CKD) Endpoint Consisting of: CV death, Onset of Persistent Greater Than Equal To 40 Percentage Reduction in eGFR (CKD- EPI); Kidney failure [ Time Frame: From randomisation (month 0) to end of study (up to 48 months) ]
  eGFR = estimated glomerular filtration rate; CKD-EPI = chronic kidney disease - epidemiology collaboration. Kidney failure defined as: death from kidney failure, onset of persistent eGFR less than 15 milliliters per minute (mL/min)/1.73 meter square (m^2) (CKD-EPI), initiation of chronic kidney replacement therapy (maintenance dialysis or kidney transplantation). Measured in months.
• Change in Estimated Glomerular Filtration Rate (eGFR) (Chronic Kidney Disease - Epidemiology Collaboration [CKD-EPI]) [ Time Frame: From randomisation (month 0) to 12 months ]
  Measured as mL/min/1.73 m^2.
• Annual Rate of Change in eGFR (CKD-EPI) (Total eGFR Slope) [ Time Frame: From randomisation (month 0) to end of study (up to 48 months) ]
  Measured as mL/min/1.73 m^2/year.
• Number of Hospitalisations With Infection as Primary Cause or Death Due to Infection [ Time Frame: From randomisation (month 0) to end of study (up to 48 months) ]
  Measured as count of event.
• Change in High-sensitivity C-reactive Protein (hs-CRP) [ Time Frame: From randomisation (month 0) to 12 months ]
  Measured as ratio to baseline.
• Change in N-terminal-pro-brain Natriuretic Peptide (NT-proBNP) [ Time Frame: From randomisation (month 0) to 12 months ]
  Measured as ratio to baseline.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Research Study to Look at How Ziltivekimab Works Compared to Placebo in People With Heart Failure and Inflammation
• Official Title: HERMES: Effects of Ziltivekimab Versus Placebo on Morbidity and Mortality in Patients With Heart Failure With Mildly Reduced or Preserved Ejection Fraction and Systemic Inflammation
• Brief Summary: This study will be done to see if ziltivekimab can be used to treat people living with heart failure and inflammation. Participants will either get ziltivekimab or placebo. Participants will get study medicine for once-monthly injections either in a pre-filled syringe to inject the study medicine into a skinfold or a pen-injector to inject the study medicine into flat skin. The study is expected to last for up to 4 years. Participants will have up to 20 clinic visits. Participants will have to use a study app on their phone to record and share information about all their injections of study medicine and to fill in questionnaires.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Heart Failure

Intervention

• Drug: Ziltivekimab
  Ziltivekimab 15 milligrams (mg) subcutaneous (s.c.) injection in a pre-filled syringe or a pen-injector once-monthly for up to 4 years.
• Drug: Placebo
  Ziltivekimab placebo s.c. injection in a pre-filled syringe or a pen-injector once-monthly for up to 4 years.

Study Arms

• Experimental: Ziltivekimab 15 mg
  Participants will receive ziltivekimab 15 milligrams (mg) subcutaneous (s.c.) injection once-monthly and added standard of care for up to 4 years.
  Intervention: Drug: Ziltivekimab
• Placebo Comparator: Placebo
  Participants will receive ziltivekimab placebo s.c. injection once-monthly and added standard of care for up to 4 years.
  Intervention: Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: November 23, 2022): 5600
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: July 2, 2027
• Estimated Primary Completion Date: July 2, 2027 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Serum high-sensitivity C-reactive protein (hs-CRP) greater than equal to 2 milligrams per liter (mg/L) at screening (visit 1) Disease specific - cardiovascular

• At least one of the following:

  1. N-terminal-pro-brain natriuretic peptide (NT-proBNP) greater than equal to 300 picograms per milliliter (pg/mL) at screening (Visit 1) for patients without ongoing atrial fibrillation/flutter. If ongoing atrial fibrillation/flutter at screening (visit 1), NTproBNP must be greater than equal to 600 pg/mL. Note that the screening electrocardiogram (ECG) must be obtained the same day as sampling for NT-proBNP.
  2. Hospitalisation or urgent/unplanned visit with a primary diagnosis of decompensated heart failure which required intravenous loop diuretic treatment, within the last 9 months prior to screening (visit 1) in combination with NT-proBNP greater than equal to 200 pg/mL at screening (Visit 1) for patients without ongoing atrial fibrillation/flutter. If ongoing atrial fibrillation/flutter at screening (visit 1), NT-proBNP must be greater than equal to 600 pg/mL.
• Diagnosis of heart failure (New York Heart Association [classification] [NYHA] Class II-IV).
• Left ventricular ejection fraction (LVEF) greater than 40 percentage (%) documented by echocardiography within 12 months prior to or at screening (visit 1). The LVEF must be documented in medical records and the most recent measurement must be used to determine eligibility with no interim event signalling potential deterioration in ejection fraction (e.g., myocardial infarction [MI] or heart failure [HF] hospitalisation).
• Structural heart disease and/or functional heart disease documented by echocardiography within 12 months prior to or at screening (visit 1) showing at least one of the following:
• Left atrial (LA) volume index greater than 34 milliliter per meter square (mL/m^2).
• LA diameter greater than equal to 3.8 centimeter (cm).
• LA length greater than equal to 5.0 cm.
• LA area greater than equal to 20 cm square.
• LA volume greater than equal to 55 milliters (mL).
• Intraventricular septal thickness greater than equal to 1.1 cm.
• Posterior wall thickness greater than equal to 1.1 cm.
• Left ventricular (LV) mass index greater than equal to 115 grams per meter square (g⁄m^2 ) in men or greater than equal to 95 g⁄m^2 in women.
• E/e' (mean septal and lateral) greater than equal to 10.
• e' (mean septal and lateral) less than 9 centimeter per second (cm/s).
• No heart failure hospitalisations or urgent heart failure visits between screening (visit 1) and randomisation (visit 2).

Exclusion Criteria:

Medical conditions - cardiovascular

• Myocardial infarction, stroke, unstable angina pectoris, transient ischaemic attack, or heart failure hospitalisation, within 30 days prior to screening (visit 1).
• Systolic blood pressure greater than equal to 180 millimeters of mercury (mmHg) at screening (visit 1). If the systolic blood pressure is 160-179 mmHg, the patient should be receiving greater than equal to 3 antihypertensive drugs. (Note: Potential participants may be retested for this criterion within the visit window and without rescreening, at the discretion of the investigator).
• Heart rate above 110 or below 40 beats per minute as evaluated on the electrocardiogram (ECG) performed at screening (visit 1) (Note: Potential participants may be retested for this criterion within the visit window and without rescreening, at the discretion of the investigator).
• Planned coronary, carotid or peripheral artery revascularisation known during the screening period (visit 1). (Note: Planned coronary angiogram is not exclusionary).
• Planned cardiac device or atrial flutter/atrial fibrillation ablation procedure known during the screening period (visit 1).
• Major cardiac surgical, non-cardiac surgical, or major endoscopic procedure (thoracoscopic or laparoscopic) within the past 60 days prior to randomisation (visit 2) or any major surgical procedure planned at the time of randomisation (visit 2).
• Heart failure due to infiltrative cardiomyopathy (e.g., sarcoid, amyloid), arrhythmogenic right ventricular cardiomyopathy, Takutsubo cardiomyopathy, genetic hypertrophic cardiomyopathy or obstructive cardiomyopathy, active myocarditis, constrictive pericarditis, cardiac tamponade, uncorrected more than moderate primary valve disease.
• Primary pulmonary hypertension, chronic pulmonary embolism, severe pulmonary disease including COPD.
• Any other condition judged by the investigator that could account for heart failure symptoms and signs (e.g., anaemia, hypothyroidism).

Medical conditions - infections/immunosuppression

- Clinical evidence of, or suspicion of, active infection at the discretion of the investigator.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Novo Nordisk; (+1) 866-867-7178; clinicaltrials@novonordisk.com

• Listed Location Countries: Argentina, Australia, Austria, Belgium, Bosnia and Herzegovina, Brazil, Bulgaria, Canada, China, Colombia, Croatia, Czechia, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, India, Ireland, Israel, Italy, Japan, Korea, Republic of, Latvia, Lithuania, Malaysia, Mexico, Netherlands, North Macedonia, Norway, Poland, Portugal, Romania, Serbia, Singapore, Slovakia, Slovenia, South Africa, Spain, Taiwan, Thailand, Turkey, United Kingdom, United States

Administrative Information

• NCT Number: NCT05636176
• Other Study ID Numbers: EX6018-4915; U1111-1280-0810 ( Other Identifier: World Health Organization (WHO) ); 2022-501939-16-00 ( Other Identifier: European Medicines Agency (EMA) ); jRCT2031230085 ( Registry Identifier: jRCT (Japan) )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: According to the Novo Nordisk disclosure commitment on novonordisk-trials.com
• URL: http://novonordisk-trials.com

• Current Responsible Party: Novo Nordisk A/S
• Original Responsible Party: Same as current
• Current Study Sponsor: Novo Nordisk A/S
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Transparency (dept. 2834); Novo Nordisk A/S

• PRS Account: Novo Nordisk A/S
• Verification Date: April 2024