Study of Efficacy of Oral Sacubitril/Valsartan in Adult Patients With Non-obstructive Hypertrophic Cardiomyopathy

Phase 2

Completed

• Conditions: Cardiomyopathy, Hypertrophic
• Interventions: Drug: LCZ696; Drug: Placebo

• Registration Number: NCT04164732
• Lead Sponsor: Novartis Pharmaceuticals

Brief Summary

The purpose of this study was to determine if LCZ696 can improve functional capacity (via improved peak VO2) in non-obstructive hypertrophic cardiomyopathy (HCM) patient population over the course of 50 weeks of treatment.

Detailed Description

This was a multi-center, placebo-controlled, patient and investigator-blinded study in non-obstructive HCM patients.

The study comprised a ≤ 35-day screening/baseline period, a 4-week single-blind treatment run-in period, followed by a 46-week double-blind placebo-controlled treatment period (total treatment period of 50 weeks), and a follow-up period approximately 30 days after the last dose.

The treatment run-in period was planned to ensure that as large a proportion as possible of patients:

1. had stable symptoms and could comply with study visits, and

2. could tolerate at least low dose LCZ696. During the run-in period, all patients received oral (p.o.) placebo b.i.d. for 2 weeks followed by 50 mg p.o. of active LCZ696 b.i.d. for 2 weeks. Patients who were unable to tolerate either placebo or the 50 mg p.o. b.i.d. dose level, were considered treatment run-in failures and were neither randomized into the double-blind, placebo-controlled study, nor included in the efficacy analysis.

In the double-blind treatment period, participants were randomized 1:1 to placebo or LCZ696. In the LCZ696 arm, participants started at a LCZ696 100 mg p.o. b.i.d dose. After approximately 14 days, patients who tolerated the 100 mg p.o. b.i.d. dose were up-titrated to 200 mg p.o. b.i.d. dose, whereas those who did not meet the safety criteria were titrated back down to the 50 mg b.i.d. dose.

Study Timeline

• Study First Submitted: 2019-11-13
• Study First Submitted QC: 2019-11-13
• Study First Posted: 2019-11-15
• Study Start: 2020-01-08
• Primary Completion: 2023-08-22
• Study Completion: 2023-08-22
• Status Verified: 2024-08
• Results First Submitted: 2024-08-05
• Results First Submitted QC: 2024-08-05
• Last Update Submitted: 2024-08-05
• Results First Posted: 2024-08-29
• Last Update Posted: 2024-08-29

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 46

Inclusion Criteria

• Diagnosed with Hypertrophic Cardiomyopathy with a left ventricular wall thickness greater than or equal to 13mm as determined by the echocardiogram obtained during the screening/baseline period

• Left ventricular ejection fraction (LVEF) greater than or equal to 50% as determined by echocardiogram obtained during the screening/baseline period

• Symptoms consistent with New York Heart Association (NYHA) Class II-III heart failure by physician assessment, or asymptomatic/NYHA Class I patients with:

  • NT-proBNP blood sample levels above 250 pg/ml and
  • peak VO2 of less than or equal to 80% of predicted based on age and gender as determined by cardiopulmonary exercise testing

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Exclusion Criteria

• Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for ≥7 days after stopping study drug
• Patients with a resting or provokable left ventricular outflow tract gradient of greater than or equal to 30mm Hg
• Septal reduction procedure within 3 months of the screening/baseline visit
• History of atrial fibrillation within 6 months of the screening/baseline visit or placement of ICD for secondary prevention
• Patients with a peak VO2 on the screening/baseline cardiopulmonary exercise test of > 80% of predicted based on age and gender
• Patients who require treatment with ACE inhibitors, angiotensin receptor blockers (ARBs), or renin inhibitors
• Known infiltrative or storage disorder such as Fabry disease, or amyloidosis
• Known or suspected symptomatic coronary artery diseases or evidence of prior myocardial infarction
• Systolic blood pressure of <100 mmHg or symptomatic hypotension during the screening/baseline period or treatment run-in period
• Contraindication to ARB administration or prior history of angioedema
• Persistent uncontrolled hypertension

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
LCZ696 BID	LCZ696	Patients were treated with LCZ696. The target dose level was 200 mg p.o. b.i.d.
Placebo BID	Placebo	Placebo to LCZ696

Primary Outcome Measures

Name	Time	Method
Change From Baseline in Peak VO2 as Measured by Cardiopulmonary Exercise Test (CPET)	Baseline to 50 weeks	The primary analysis assessed the effect of LCZ696 on the change from baseline in peak Volume of Oxygen (VO2) (ml/kg/min) at week 50 compared to placebo, where baseline peak VO2 came from the screening/baseline CPET.; An increase in peak VO2 (mL/kg/min)/positive change is considered beneficial for the patient.

Trial Locations

Locations (1)

Novartis Investigative Site; 🇬🇧 London, United Kingdom