To Evaluate the Safety, Tolerability and Efficacy of R2R01 Combined With SOC as Compared to SOC Alone in Outpatients With Worsening Heart Failure (WHF)

Inclusion Criteria: 1. Able and willing to give written informed consent, and able to follow instructions and comply with follow-up procedures. 2. History of symptomatic HF (heart failure). 3. Male or female ≥ 18 years of age at screening. 4. Previous hospitalization for HF within the last 12 months prior to screening. 5. Patients on optimal background therapy as per local practice for at least 30 days prior to screening and tolerating this well. 6. Patients must present with at least 2 of the following signs / symptoms of WHF congestion: 1. Dyspnea 2. Orthopnea 3. Fatigue 4. Jugular venous distension 5. Rales 6. Edema 7. Patient requires intensification (doubling the dose, adding another diuretic targeting another tubular segment) of oral diuretics, or IV diuresis for WHF as per Investigator at screening and treated as an outpatient patient. 8. Estimated Glomerular Filtration Rate (eGFR) between 20 and 75 mL/ min/1.73 m2 (calculated using the CKD-EPI equation) at screening. 9. NT-pro-BNP levels at screening: 1. ≥ 1000 pg/mL for patients with LVEF ≤ 40% 2. ≥ 700 pg/mL for patients with LVEF \> 40% 3. ≥ 1500 pg/mL for patients with current atrial fibrillation, regardless of LVEF. For patients with BMI ≥ 30 kg/m2 the NT-pro-BNP values are lowered by 20%. The values are as follows: <!-- --> 1. ≥ 800 pg/mL for patients with LVEF ≤ 40% 2. ≥ 560 pg/mL for patients with LVEF \> 40% 3. ≥ 1200 pg/mL for patients with current atrial fibrillation, regardless of LVEF. The most recent LVEF value assessed in the 12 months prior to screening should be used. 10. Systolic Blood Pressure (SBP) ≥ 105 mmHg at screening. 11. Willing and able to stay in the clinic for observation/monitoring for 3 days. 12. Willing to self-administer all SC injections. Exclusion Criteria: 1. Patients with blood pressure \> 180 mmHg or persistent heart rate \> 130 bpm at Screening. 2. History of symptomatic hypotension. 3. History of orthostatic hypotension. 4. Temperature \> 38.5°C (oral or equivalent) or sepsis or active infection requiring antimicrobial treatment. 5. Clinical evidence of acute coronary syndrome (ACS) currently or within 30 days prior to Screening. 6. Acute Heart Failure (AHF) due to significant arrhythmias, which include any of the following: sustained ventricular tachycardia, bradycardia with sustained ventricular rate \< 45 bpm or atrial fibrillation/flutter with sustained ventricular response of \> 130 bpm. 7. The daily use of IV or oral steroids (including but not limited to the use of IV or oral steroids for respiratory disorders or COPD). Note, inhaled steroids are allowed. 8. IV antimicrobial treatment for sepsis or active infection. 9. Patients with severe renal impairment defined at Screening eGFR \< 20 mL/min/1.73m2 (calculated using the CKD-EPI Equation), and/or those receiving current or planned dialysis or ultrafiltration. 10. Patients with hemoglobin \< 10 g/dL, or a history of blood transfusion within the 14 days prior to screening, or active life-threatening gastrointestinal bleeding. 11. Known hepatic impairment (as evidenced by total bilirubin \> 3 mg/dL, or increased ammonia levels, if performed) or history of cirrhosis with evidence of portal hypertension such as varices. 12. Significant, uncorrected, left ventricular outflow obstruction, such as obstructive hypertrophic cardiomyopathy or severe aortic stenosis (i.e., aortic valve area \< 1.0 cm2 or mean gradient \> 40 mmHg on echocardiogram), and/or severe mitral stenosis. 13. Severe aortic insufficiency or severe mitral regurgitation for which surgical or percutaneous intervention is indicated. 14. Documented, prior to or at the time of screening, restrictive amyloid myocardiopathy, or acute myocarditis or hypertrophic obstructive, restrictive, or constrictive cardiomyopathy. 15. Any major solid organ transplant recipient or planned/ anticipated organ transplant within 1 year. 16. Major surgery, including implantable devices (e.g., implantable cardioverter defibrillator, cardiac resynchronization therapy), or major neurologic event including cerebrovascular events, within 30 days prior to screening. 17. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past year with a current life expectancy less than 1 year due to the malignancy. 18. Pregnant or nursing (lactating) women, where pregnancy was defined as the state of a female after conception and until the termination of gestate, confirmed by a positive human chorionic gonadotropin laboratory test. 19. Use of other investigational drugs within 30 days prior to Screening. 20. History of known hypersensitivity/prior exposure to R2R01 or serelaxin. 21. Any other medical condition(s) that might put the patient at risk or influence study results in the Investigator's opinion, or that the Investigator deems unsuitable for the study including drug or alcohol abuse or psychiatric, behavioral, or cognitive disorders sufficient to interfere with the patient's ability to understand and comply with the protocol instructions or follow-up procedures.