Cardiomyopathy, Hypertrophic
Conditions
Keywords
non-obstructive, hypertrophic cardiomyopathy, genetic cardiomyopathy
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.
Interventions
DRUGLCZ696
LCZ696 orally twice daily
DRUGPlacebo
placebo
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
Investigator and subject will be blinded to treatment allocation during the treatment period
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
Germany, Greece, South Korea, Spain, United Kingdom, United States
Participant flow
Recruitment details
Germany (4 sites), Greece (2 sites), Korea (2 sites), Spain (4 sites), United Kingdom (1 site), United States (5 sites)
Pre-assignment details
Patients who met eligibility criteria entered a single-blind treatment run-in period. 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 not randomized into the double-blind, placebo-controlled study
Participants by arm
| Arm | Count |
|---|---|
| Run-in (All Participants) All patients received oral (p.o.) placebo b.i.d. for 2 weeks, followed by 50 mg p.o. b.i.d. of active LCZ696 for 2 weeks | 6 |
| LCZ696 BID Patients were treated with LCZ696. The target dose level was 200 mg p.o. b.i.d. | 20 |
| Placebo BID Placebo to LCZ696 | 20 |
| Total | 46 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Randomized Treatment Period | Adverse Event | 0 | 1 | 0 |
| Randomized Treatment Period | Protocol Deviation | 0 | 1 | 1 |
| Randomized Treatment Period | Withdrawal by Subject | 0 | 1 | 0 |
| Treatment run-in Period | Adverse Event | 4 | 0 | 0 |
| Treatment run-in Period | Physician Decision | 1 | 0 | 0 |
| Treatment run-in Period | Screen Failure | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Run-in (All Participants) | LCZ696 BID | Placebo BID | Total |
|---|---|---|---|---|
| Age, Continuous | 54.5 years STANDARD_DEVIATION 17.19 | 54.5 years STANDARD_DEVIATION 11.84 | 57.2 years STANDARD_DEVIATION 14.29 | 55.7 years STANDARD_DEVIATION 13.42 |
| Race/Ethnicity, Customized Asian | 1 Participants | 2 Participants | 3 Participants | 6 Participants |
| Race/Ethnicity, Customized White | 5 Participants | 18 Participants | 17 Participants | 40 Participants |
| Sex: Female, Male Female | 3 Participants | 3 Participants | 6 Participants | 12 Participants |
| Sex: Female, Male Male | 3 Participants | 17 Participants | 14 Participants | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 46 | 0 / 43 | 0 / 20 | 0 / 1 | 0 / 20 | 0 / 17 | 0 / 20 | 0 / 46 |
| other Total, other adverse events | 4 / 46 | 4 / 43 | 10 / 20 | 1 / 1 | 6 / 20 | 7 / 17 | 12 / 20 | 26 / 46 |
| serious Total, serious adverse events | 0 / 46 | 0 / 43 | 0 / 20 | 0 / 1 | 1 / 20 | 2 / 17 | 3 / 20 | 3 / 46 |
Outcome results
Primary
Change From Baseline in Peak VO2 as Measured by Cardiopulmonary Exercise Test (CPET)
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.
Time frame: Baseline to 50 weeks
Population: Patients in the per protocol analysis set with and available value for the outcome measure at baseline and Week 50 .~Per protocol analysis set consists of all randomized patients who had no major protocol deviations with relevant impact on PD/efficacy data and who are at least 80% compliant with the overall study drug administration.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| LCZ696 BID | Change From Baseline in Peak VO2 as Measured by Cardiopulmonary Exercise Test (CPET) | 1.00 mL/kg/min |
| Placebo BID | Change From Baseline in Peak VO2 as Measured by Cardiopulmonary Exercise Test (CPET) | 0.39 mL/kg/min |
p-value: 0.550680% CI: [-0.71, 1.94]longitudinal mixed effects (MMRM) model