This study will look into how CDR132L (a potential new medicine) works on the structure and function of the heart in people living with heart failure. Participants will either get CDR132L or placebo (a medicine which has no effect on the body), which treatment the participants get is decided by chance. The study will last for about 60 weeks.

Inclusion Criteria:

• Age 40-84 years (both inclusive) at the time of signing the informed consent

• Documented symptomatic chronic heart failure (HF) diagnosed greater than or equal to (≥) 90 days prior to screening with at least weekly need for oral diuretic treatment, and New York Heart Association class II-III at screening

• Clinically stable and on optimised doses and unchanged drug classes of guideline-directed HF therapy ≥45 days prior to randomisation

• Left ventricular ejection fraction ≥50% as assessed by echocardiography at screening, measured by central laboratory

• Left ventricular hypertrophy assessed by echocardiography at screening measured by central laboratory with any of the following:

  1. LVMi (greater than) >88 gram per square meter (g/m^2) for female participants and >102 g/m^2 for male participants, using the truncated ellipsoid method measured by central laboratory
  2. LVMi >95 g/m2 for female participants and >115 g/m2 for male participants using the linear method (cube formula).
  3. Interventricular septum diameter measured in diastole (IVSd) in the parasternal long axis view ≥1.1 cm for female participants and ≥1.2 cm for male participants.

• Body mass index 18.5-40 kilogram per square meter (kg/m^2) (both inclusive) and body weight less than or equal to (≤) 140 kilogram (kg). Body mass index is calculated in the electronic case report form based on height and body weight at the screening visit (visit 1)

• NT-proBNP ≥300 picograms per milliliter (pg/mL); NT-proBNP ≥600 pg/mL if atrial fibrillation/flutter is present at time of screening, measured by central laboratory

Exclusion Criteria:

• Estimated glomerular filtration rate lesser than (<) 30 milliliter per minute (mL/min)/1.73 square meter (m^2) at time of screening, measured by central laboratory
• Participants with an episode of acute kidney failure or acute kidney injury, at the discretion of the investigator, within 90 days prior to randomisation
• Myocardial infarction, unstable angina pectoris or HF hospitalisation within 30 days prior to screening
• Participants receiving intravenous HF medications within 45 days prior to randomisation
• Participants with CRT, pacemaker or implantable cardioverter-defibrillator
• Planned coronary revascularisation, pacemaker/cardioverter-defibrillator/CRT implantation, ablation of cardiac arrythmias and valve repair/replacement at the time of randomisation
• Stroke or transient ischemic attack within 12 months prior to randomisation
• Participants with potential disruption of the blood-brain barrier (e.g., multiple sclerosis), in the opinion of the investigator
• Known history of severe liver disease and/or alanine aminotransferase or aspartate aminotransferase >2.5 x upper limit of normal at screening, measured by central laboratory
• Known genetic (or highly suspected due to family history) cause of increased cardiac mass (including dilated cardiomyopathy, Fabry disease and likely pathogenic or pathogenic variants within hypertrophic cardiomyopathy [HCM]).
• Participants with suspected or diagnosed cardiac amyloidosis or sarcoidosis.

According to the Novo Nordisk disclosure commitment on novonordisk-trials.com.

Sponsor staff involved in the clinical trial is masked according to company standard procedures.