Chronic Heart Failure With Reduced Ejection Fraction
Conditions
Keywords
LCZ696, chronic heart failure, ARNI, Congestive heart failure (CHF), heart failure (HF), acute heart failure syndrome, congestive cardiac failure (CCF)
Brief summary
The purpose of this study was to collect safety and tolerability data on LCZ696 in eligible PARADIGM-HF patients who received open-label investigational drug. The parent PARADIGM-HF (NCT01035255) trial was terminated early due to compelling efficacy of LCZ696 in patients with heart failure with reduced ejection fraction (HFrEF) after the final pre-specified interim analysis in March 2014.
Interventions
DRUGLCZ696
Angiotensin receptor antagonist neprilysin inhibitor (ARNI) with target dose of 200 mg bid
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
1. Written informed consent for the extension must be obtained before any assessment is performed. 2. Patients who have completed PARADIGM-HF (protocol CLCZ696B2314) and are able to be safely enrolled into the open-label trial as judged by the investigator.
Exclusion criteria
1. Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of enrollment, whichever is longer 2. History of hypersensitivity or allergy to any of the study drugs, drugs of similar chemical classes, ACEIs, ARBs, or NEP inhibitors as well as known or suspected contraindications to LCZ696 3. Known history of angioedema 4. Requirement of simultaneous treatment with both ACEIs and ARBs 5. Current acute decompensated HF (exacerbation of chronic HF manifested by signs and symptoms that may require intravenous therapy) 6. Symptomatic hypotension and/or a SBP \< 100 mmHg at Visit 1 (screening) 7. Estimated GFR \< 30 mL/min/1.73m\^2 as measured by the simplified MDRD formula at Visit 1 (screening) 8. Presence of bilateral renal artery stenosis 9. Serum potassium \> 5.2 mmol/L at Visit 1 (screening) 10. Evidence of hepatic disease as determined by any one of the following: AST or ALT values exceeding 3 x ULN at Visit 1, history of hepatic encephalopathy, history of esophageal varices, or history of portacaval shunt 11. Pregnant or nursing (lactating) women 12. Women of child-bearing potential 13. Any condition, not identified in the protocol, that in the opinion of the investigator is likely to prevent the patient from safely tolerating LCZ696 or complying with the requirements of the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Treatment Emergent Adverse Events (AEs), Serious Adverse Events (SAEs) and Deaths as a Measure of Safety and Tolerability of LCZ696 | From first dose of study treatment to 30 days after last dose of study treatment, up to 30 months. | The primary assessments for safety were the reporting of angioedema, AEs suspected to be related to LCZ696, AEs leading to study drug discontinuation and serious adverse events (SAE) including death. The assessment of safety were based primarily on the frequency of adverse events of special interest, sitting systolic and diastolic blood pressure, heart rate, and serious adverse events suspected by the investigators to be related to LCZ696 for the Safety set. Only descriptive analysis done. |
Countries
Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Czechia, Denmark, Estonia, Finland, France, Germany, Guatemala, Hong Kong, Hungary, India, Israel, Italy, Latvia, Lithuania, Malaysia, Mexico, Netherlands, Panama, Peru, Philippines, Poland, Portugal, Romania, Russia, Singapore, Slovakia, South Africa, South Korea, Spain, Sweden, Taiwan, Thailand, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
This study was conducted at 417 sites in 41 countries worldwide.
Pre-assignment details
The total number in the participant flow and baseline characteristics sections reflects the number of participants treated (1980).
Participants by arm
| Arm | Count |
|---|---|
| LCZ696 Angiotensin receptor antagonist neprilysin inhibitor (ARNI) with target dose of 200 mg bid | 1,980 |
| Total | 1,980 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 60 |
| Overall Study | Death | 172 |
| Overall Study | Lost to Follow-up | 13 |
| Overall Study | missing treatment disposition pages | 2 |
| Overall Study | Non-compliance with study drug | 10 |
| Overall Study | Physician Decision | 21 |
| Overall Study | Protocol deviation | 1 |
| Overall Study | Study terminated by sponsor | 1 |
| Overall Study | Technical problems | 4 |
| Overall Study | Withdrawal by parent/guardian | 36 |
Baseline characteristics
| Characteristic | LCZ696 |
|---|---|
| Age, Continuous | 67.2 years STANDARD_DEVIATION 10.56 |
| Race (NIH/OMB) American Indian or Alaska Native | 39 Participants |
| Race (NIH/OMB) Asian | 305 Participants |
| Race (NIH/OMB) Black or African American | 80 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 106 Participants |
| Race (NIH/OMB) White | 1450 Participants |
| Sex: Female, Male Female | 453 Participants |
| Sex: Female, Male Male | 1527 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 186 / 1,980 |
| other Total, other adverse events | 352 / 1,980 |
| serious Total, serious adverse events | 555 / 1,980 |
Outcome results
Primary
Percentage of Participants With Treatment Emergent Adverse Events (AEs), Serious Adverse Events (SAEs) and Deaths as a Measure of Safety and Tolerability of LCZ696
The primary assessments for safety were the reporting of angioedema, AEs suspected to be related to LCZ696, AEs leading to study drug discontinuation and serious adverse events (SAE) including death. The assessment of safety were based primarily on the frequency of adverse events of special interest, sitting systolic and diastolic blood pressure, heart rate, and serious adverse events suspected by the investigators to be related to LCZ696 for the Safety set. Only descriptive analysis done.
Time frame: From first dose of study treatment to 30 days after last dose of study treatment, up to 30 months.
Population: Safety Set (SAF), which consisted of all enrolled participants who received at least one dose of open-label study medication, was considered. Only descriptive analysis done.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| LCZ696 | Percentage of Participants With Treatment Emergent Adverse Events (AEs), Serious Adverse Events (SAEs) and Deaths as a Measure of Safety and Tolerability of LCZ696 | AEs by Primary System Organ Class (SOC) | 1289 Participants |
| LCZ696 | Percentage of Participants With Treatment Emergent Adverse Events (AEs), Serious Adverse Events (SAEs) and Deaths as a Measure of Safety and Tolerability of LCZ696 | SAEs by Primary System Organ Class (SOC) | 555 Participants |
| LCZ696 | Percentage of Participants With Treatment Emergent Adverse Events (AEs), Serious Adverse Events (SAEs) and Deaths as a Measure of Safety and Tolerability of LCZ696 | Deaths by Primary System Organ Class (SOC) | 186 Participants |