Clinical trial NCT04164732: Study of Efficacy of Oral Sacubitril/Valsartan in Adult Patients With Non-obstructive Hypertrophic Cardiomyopathy
Official title: A Multi-center, Randomized, Placebo-controlled Patient and Investigator-blinded Study to Explore the Efficacy of Oral Sacubitril/Valsartan in Adult Patients With Non-obstructive Hypertrophic Cardiomyopathy (nHCM)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Cardiomyopathy, Hypertrophic
Keywords: non-obstructive
hypertrophic cardiomyopathy
genetic cardiomyopathy
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2019-11-15
Enrollment: 46
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Change From Baseline in Peak VO2 as Measured by Cardiopulmonary Exercise Test (CPET)
timeFrame: Baseline to 50 weeks
Secondary outcomes:
Other outcomes:
Locations:
city: Stanford
country: United States
facility: Novartis Investigative Site
state: California
city: Boston
country: United States
facility: Novartis Investigative Site
state: Massachusetts
city: Ann Arbor
country: United States
facility: Novartis Investigative Site
state: Michigan
city: Morristown
country: United States
facility: Novartis Investigative Site
state: New Jersey
city: Portland
country: United States
facility: Novartis Investigative Site
state: Oregon
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Hamburg
country: Germany
facility: Novartis Investigative Site
city: Heidelberg
country: Germany
facility: Novartis Investigative Site
city: Kiel
country: Germany
facility: Novartis Investigative Site
city: Athens
country: Greece
facility: Novartis Investigative Site
state: GR
city: Heraklion Crete
country: Greece
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Valencia
country: Spain
facility: Novartis Investigative Site
state: Comunidad Valenciana
city: El Palmar
country: Spain
facility: Novartis Investigative Site
state: Murcia
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: