Heart Failure With Reduced Ejection Fraction (HFrEF), or Heart Failure With Mildly Reduced Ejection Fraction (HFmrEF)
Conditions
Keywords
heart failure, reduced ejection fraction, mildly reduced ejection fraction, HFrEF, HFmrEF, XXB750
Brief summary
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
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.
Interventions
DRUGXXB750
XXB750
DRUGPlacebo
Placebo
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Caregiver)
Masking description
Site will have masked and unmasked investigators. An unmasked investigator will prepare and administer dose while a masked investigator will perform all assessments.
Intervention model description
randomized, placebo-controlled safety study of XXB750
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 91 days (Cohort 1), 146 days (Cohort 2) | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics parameters Cmax | 91 days (Cohort 1), 146 days (Cohort 2) | To evaluate the pharmacokinetics parameters: Peak plasma concentration (Cmax) of XXB750 in adult participants with chronic stable HFrEF/HFmrEF. |
| Pharmacokinetics parameters AUClast for Cohort 1 | 91 days | To evaluate the pharmacokinetics parameters: Area under the plasma concentration curve (AUClast) of XXB750 in adult participants with chronic stable HFrEF/HFmrEF. |
| Pharmacokinetics parameters AUCinf for Cohort 1 | 91 days | To evaluate the pharmacokinetics parameters: Area under the curve (AUCinf) of XXB750 in adult participants with chronic stable HFrEF/HFmrEF. |
| Pharmacokinetics parameters Tmax | 91 days (Cohort 1), 146 days (Cohort 2) | To evaluate the pharmacokinetics: Time to maximum concentation (Tmax) parameters of XXB750 in adult participants with chronic stable HFrEF/HFmrEF. |
| Pharmacokinetics parameters CL/F | 91 days (Cohort 1), 146 days (Cohort 2) | To evaluate the pharmacokinetics parameters: (CL/F) of XXB750 in adult participants with chronic stable HFrEF/HFmrEF. |
| Pharmacokinetics parameters T1/2 | 91 days (Cohort 1), 146 days (Cohort 2) | To evaluate the pharmacokinetics parameters: (T1/2) of XXB750 in adult participants with chronic stable HFrEF/HFmrEF. |
| Pharmacokinetics parameters AUCtau for Cohort 2 | 146 days | To evaluate the pharmacokinetics parameters: Area under the curve (AUCtau) of XXB750 in adult participants with chronic stable HFrEF/HFmrEF. |
| Pharmacokinetics parameters Vz/F | 91 days (Cohort 1), 146 days (Cohort 2) | To evaluate the pharmacokinetics parameters: Vd/F of XXB750 in adult participants with chronic stable HFrEF/HFmrEF. |
Countries
Netherlands, United States
Outcome results
None listed