Safety and Tolerability Study of XXB750 in Heart Failure Participants With Reduced or Mildly Reduced Ejection Fraction (HFrEF/HFmrEF)

Study Overview
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Brief Summary
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This is a multi-center, randomized, sponsor open-label, participant- and investigator-blinded, placebo-controlled, single and multiple dose study to investigate the safety and tolerability of XXB750 in HFrEF/HFmrEF.

Detailed Description
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A screening period of up to 29 days will be used to assess participants' eligibility. This study will consist of 2 cohorts. Cohort 1 will include participants on stable therapies of ACEi/ARB and beta-blockers, in addition to other standard of care medications. Cohort 2 will consist of participants treated with sacubitril/valsartan and beta-blockers, in addition to other standard of care medications. For Cohort 1 participants will be randomized in a 2:1 ratio to receive a single dose of subcutaneous (s.c) XXB750 or placebo. For Cohort 2, participants will be randomized in a 3:1 ratio to receive three doses of either s.c. XXB750 or placebo. Cohort 1: After an initial domiciling period following study drug administration, participants will be followed for 13 weeks post-dosing for safety, tolerability and PK until the End of Study visit on Day 91. Cohort 2: After a domiciling period following first study drug administration of XXB750 or placebo, participants will be followed for 27 days post dosing for safety, tolerability and PK. On Day 28, participants will be re domiciled and receive a second dose of either XXB750 or placebo. Participants will be followed for another 27 days post-dosing for safety and tolerability. On Day 56, participants will be re-domiciled and receive a third dose of either XXB750 or placebo. After the third domiciling period, participants will be followed for 13 weeks post-dosing for safety, tolerability and PK until the End of Study visit on Day 146.

Official Title
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A Randomized, Participant- and Investigator-blinded, Sponsor Open-label, Placebo-controlled, Single and Multiple Dose Study to Investigate the Safety and Tolerability of XXB750 in Heart Failure Participants With Reduced or Mildly Reduced Ejection Fraction (HFrEF/HFmrEF)

Conditions
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Heart Failure With Reduced Ejection Fraction (HFrEF), or Heart Failure With Mildly Reduced Ejection Fraction (HFmrEF)

Intervention / Treatment
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* Drug: XXB750
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: NYHA functional class II-III LVEF ≤ 50% documented at screening Systolic blood pressure 110 - 160 mmHg (cohort 1) or 105-160 mmHg (cohort 2), and heart rate between 50-90 beats per minute, inclusive Treatment with a stable dose of a beta blocker. Cohort 1: Treatment with a stable dose of ACE inhibitor or ARB Cohort 2: Treatment with a stable dose of sacubitril/valsartan. Key Exclusion Criteria Acute decompensated heart failure within 3 months prior to screening. Acute coronary syndrome, stroke, transient ischemic attack, cardiac, carotid, or other major cardiovascular surgery, PCI, or carotid angioplasty within the 6 months prior to screening Hemodynamically significant mitral and/or aortic valve disease, except mitral regurgitation secondary to LV dilatation at screening Implantation of a CRT device within 3 months prior to screening or intent to implant a CRT during the study period History of severe pulmonary disease (e.g. COPD) requiring chronic supplemental oxygen therapy or pulmonary hypertension requiring pharmacology treatment at Screening eGFR <45 mL/min/1.73 m2 at screening Cohort 1 only: Treatment with sacubitril/valsartan currently or within 4 weeks from screening Cohort 2: Treatment with ACE inhibitor or ARB currently or within 4 weeks from screening BMI >40 kg/m2 Other protocol-specific criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: randomized, placebo-controlled safety study of XXB750
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: XXB750 Cohort 1<br>XXB750, single dose | Drug: XXB750<br>* XXB750<br>|
| Placebo Comparator: Placebo Cohort 1<br>Placebo, single dose | Drug: Placebo<br>* Placebo<br>|
| Experimental: XXB750 Cohort 2<br>XXB750, multiple doses | Drug: XXB750<br>* XXB750<br>|
| Placebo Comparator: Placebo Cohort 2<br>Placebo, multiple doses | Drug: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events, which may include abnormal vital signs, safety lab tests, or ECG parameters that induce clinical signs or symptoms, are considered clinically significant or require therapy | To evaluate the safety and tolerability of XXB750 in adult participants with chronic stable heart failure with reduced or mildly reduced ejection fraction (HFrEF/HFmrEF). | 91 days (Cohort 1), 146 days (Cohort 2) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics parameters Tmax | To evaluate the pharmacokinetics: Time to maximum concentation (Tmax) parameters of XXB750 in adult participants with chronic stable HFrEF/HFmrEF. | 91 days (Cohort 1), 146 days (Cohort 2) | 
| Pharmacokinetics parameters Cmax | To evaluate the pharmacokinetics parameters: Peak plasma concentration (Cmax) of XXB750 in adult participants with chronic stable HFrEF/HFmrEF. | 91 days (Cohort 1), 146 days (Cohort 2) | 
| Pharmacokinetics parameters AUClast for Cohort 1 | To evaluate the pharmacokinetics parameters: Area under the plasma concentration curve (AUClast) of XXB750 in adult participants with chronic stable HFrEF/HFmrEF. | 91 days | 
| Pharmacokinetics parameters AUCinf for Cohort 1 | To evaluate the pharmacokinetics parameters: Area under the curve (AUCinf) of XXB750 in adult participants with chronic stable HFrEF/HFmrEF. | 91 days | 
| Pharmacokinetics parameters Vz/F | To evaluate the pharmacokinetics parameters: Vd/F of XXB750 in adult participants with chronic stable HFrEF/HFmrEF. | 91 days (Cohort 1), 146 days (Cohort 2) | 
| Pharmacokinetics parameters CL/F | To evaluate the pharmacokinetics parameters: (CL/F) of XXB750 in adult participants with chronic stable HFrEF/HFmrEF. | 91 days (Cohort 1), 146 days (Cohort 2) | 
| Pharmacokinetics parameters T1/2 | To evaluate the pharmacokinetics parameters: (T1/2) of XXB750 in adult participants with chronic stable HFrEF/HFmrEF. | 91 days (Cohort 1), 146 days (Cohort 2) | 
| Pharmacokinetics parameters AUCtau for Cohort 2 | To evaluate the pharmacokinetics parameters: Area under the curve (AUCtau) of XXB750 in adult participants with chronic stable HFrEF/HFmrEF. | 146 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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heart failure, reduced ejection fraction, mildly reduced ejection fraction, HFrEF, HFmrEF, XXB750