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

Novartis

Status and phase: Completed; Phase 2

Conditions: Cardiomyopathy, Hypertrophic

Treatments: Drug: Placebo; Drug: LCZ696

Study type: Interventional

Funder types: Industry

Identifiers

NCT04164732

CLCZ696I12201

2019-003098-24 (EudraCT Number)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 46 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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46 participants in 2 patient groups, including a placebo group

LCZ696 BID

Experimental group

Description:

Patients were treated with LCZ696. The target dose level was 200 mg p.o. b.i.d.

Treatment:

Drug: LCZ696

Placebo BID

Placebo Comparator group

Description:

Placebo to LCZ696

Treatment:

Drug: Placebo