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

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)

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.

Study Overview

• Status: Completed
• Conditions: Heart Failure With Reduced Ejection Fraction (HFrEF); or Heart Failure With Mildly Reduced Ejection Fraction (HFmrEF)
• Intervention / Treatment: Drug: Placebo; Drug: XXB750

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.

• Study Type: Interventional
• Enrollment (Actual): 27
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Novartis Pharmaceuticals; Phone Number: 1-888-669-6682; Email: novartis.email@novartis.com
• Study Contact Backup: Name: Novartis Pharmaceuticals; Phone Number: +41613241111

Study Locations

• Netherlands
  • Groningen, Netherlands, 9713 GZ
    • Novartis Investigative Site
• United States
  • Florida
    • Inverness, Florida, United States, 34452
      • Novartis Investigative Site
    • Jacksonville, Florida, United States, 32216
      • Novartis Investigative Site
  • Minnesota
    • Saint Paul, Minnesota, United States, 55102
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: XXB750 Cohort 1; XXB750, single dose	Drug: XXB750; XXB750
Placebo Comparator: Placebo Cohort 1; Placebo, single dose	Drug: Placebo; Placebo
Experimental: XXB750 Cohort 2; XXB750, multiple doses	Drug: XXB750; XXB750
Placebo Comparator: Placebo Cohort 2; Placebo, multiple doses	Drug: Placebo; Placebo

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): May 17, 2022
• Primary Completion (Actual): January 18, 2024
• Study Completion (Actual): January 18, 2024

Study Registration Dates

• First Submitted: March 30, 2022
• First Submitted That Met QC Criteria: April 13, 2022
• First Posted (Actual): April 14, 2022

Study Record Updates

• Last Update Posted (Actual): February 8, 2024
• Last Update Submitted That Met QC Criteria: February 7, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: heart failure; HFrEF; reduced ejection fraction; mildly reduced ejection fraction; HFmrEF; XXB750
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure
• Other Study ID Numbers: CXXB750A12101; 2021-006683-24 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No