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Comparison of Pre- and Post-discharge Initiation of LCZ696 Therapy in HFrEF Patients After an Acute Decompensation Event

A Multicenter, Randomized, Open Label, Parallel Group Study Comparing Pre-discharge and posT-discharge tReatment Initiation With LCZ696 in heArt Failure patieNtS With Reduced ejectIon-fracTion hospItalized for an Acute decOmpensation eveNt (ADHF)

Status
Completed
Phases
Phase 4
Study type
Interventional
Source
ClinicalTrials.gov
Registry ID
NCT02661217
Acronym
TRANSITION
Enrollment
1002
Registered
2016-01-22
Start date
2016-02-12
Completion date
2018-06-20
Last updated
2021-04-26

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Heart Failure With Reduced Ejection Fraction

Keywords

Acute decompensated heart failure, Reduced ejection fraction, Pre-discharge treatment, Post-discharge treatment, Angiotensin receptor neprilysine inhibitor, HFrEF

Brief summary

To explore two modalities of treatment initiation (Pre-discharge, and Post-discharge) with LCZ696 in HFrEF patients following stabilization after an ADHF episode.

Interventions

DRUGLCZ696

LCZ696 film-coated tables were supplied to the investigators. Tablets were taken with a glass of water, and were administered with or without food. The target dose of LCZ696 was 200 mg twice daily. Starting dose of LCZ696 was either 50 or 100 mg, twice daily. The dose of LCZ696 should be doubled every 2-4 weeks to achieve the target dose of 200 mg twice daily, as tolerated by the patient.

Sponsors

Novartis Pharmaceuticals
Lead SponsorINDUSTRY

Study design

Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
SINGLE (Outcomes Assessor)

Eligibility

Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No

Inclusion criteria

1. Patients hospitalized due to acute decompensated HF episode (ADHF) as primary diagnosis) and consistent Signs & Symptoms 2. Diagnosis of HF New York Heart Association class II-to-IV and reduced ejection fraction: Left ventricular ejection fraction ≤ 40% at Screening 3. Patients did not receive any IV vasodilators (except nitrates), and/or any IV inotropic therapy from the time of presentation for ADHF to Randomization 4. Stabilized (while in the hospital) for at least 24 hours leading to Randomization. 5. Meeting one of the following criteria: * Patients on any dose of ACEI or ARB at screening * ACEI/ARB naïve patients and patients not on ACEI or ARB for at least 4 weeks before screening.

Exclusion criteria

1. History of hypersensitivity to the sacubitril, valsartan, or any ARBs, NEP inhibitors or to any of the LCZ696 excipients. 2. Symptomatic hypotension and/or a SBP below 110 mm Hg or SBP above 180 mm Hg prior to randomization 3. End stage renal disease at Screening; or estimated GFR below 30 mL/min/1.73 m2 (as measured by MDRD formula at Randomization. 4. Serum potassium above 5.4 mmol/L at Randomization. 5. Known history of hereditary or idiopathic angioedema or angioedema related to previous ACE inhibitor or ARB therapy 6. Severe hepatic impairment, biliary cirrhosis and cholestasis

Design outcomes

Primary

MeasureTime frameDescription
Percentage of Patients Achieving the Target Dose of LCZ696 200 mg Bid at 10 Weeks Post Randomization10 weeks after RandomizationPercentage of patients achieving and maintaining LCZ696 200 mg bid for at least 2 weeks leading to Week 10

Secondary

MeasureTime frameDescription
Percentage of Patients Achieving and Maintaining Either LCZ696 100 mg and/or 200 mg Bid10 weeks after RandomizationPercentage of patients achieving and maintaining either LCZ696 100 mg and/or 200 mg bid for at least 2 weeks leading to Week 10
Percentage of Patients Achieving and Maintaining Any Dose of LCZ69610 weeks after RandomizationPercentage of patients achieving any dose of LCZ696 for at least 2 weeks leading to 10 weeks of treatment
Percentage of Patients Permanently Discontinued From Treatment10 weeks after Randomization AND 26 weeks after randomizationPercentage of patients permanently discontinued from LCZ696 (1) up to week 10 due to AEs, and (2) up to week 26 due to any reasons

Countries

Argentina, Belgium, Canada, Czechia, France, Germany, Italy, Lebanon, Norway, Poland, Portugal, Russia, Saudi Arabia, Slovakia, Spain, Sweden, Switzerland, Turkey (Türkiye), United Kingdom

Participant flow

Recruitment details

Patients were randomized to pre-discharge group or post-discharged group.

Pre-assignment details

The study consisted of 3 Epochs: the Screening Epoch (from signing of informed consent form to randomization), the treatment epoch (10 weeks following randomization), and a 16 weeks Follow-up Epoch following treatment epoch.

Participants by arm

ArmCount
LCZ696 Pre-discharge Treatment Initiation
Patients received first dose at any point after Randomization but no later than 12 h before discharge.
500
LCZ696 Post-discharge Treatment Initiation
Patients received first dose after discharge and up to 14 days thereafter.
502
Total1,002

Withdrawals & dropouts

PeriodReasonFG000FG001
Overall StudyAdverse Event108
Overall StudyDeath2115
Overall StudyDeath - no study drug received12
Overall StudyDid not enter follow-up epoch710
Overall StudyLost to Follow-up14
Overall StudyMis-randomized (not in treatment epoch)31
Overall StudyNon-compliance with study treatment55
Overall StudyPhysician Decision1215
Overall StudyProtocol Deviation04
Overall StudyWithdrawal by Subject1519

Baseline characteristics

CharacteristicLCZ696 Pre-discharge Treatment InitiationLCZ696 Post-discharge Treatment InitiationTotal
Age, Continuous66.7 years
STANDARD_DEVIATION 12.27
67.0 years
STANDARD_DEVIATION 11.67
66.8 years
STANDARD_DEVIATION 11.97
Race/Ethnicity, Customized
Asian
7 Participants3 Participants10 Participants
Race/Ethnicity, Customized
Black
5 Participants8 Participants13 Participants
Race/Ethnicity, Customized
Caucasian
488 Participants486 Participants974 Participants
Race/Ethnicity, Customized
Native American
0 Participants1 Participants1 Participants
Race/Ethnicity, Customized
Other
0 Participants1 Participants1 Participants
Race/Ethnicity, Customized
Pacific Islander
0 Participants1 Participants1 Participants
Race/Ethnicity, Customized
Unknown
0 Participants2 Participants2 Participants
Sex: Female, Male
Female
126 Participants125 Participants251 Participants
Sex: Female, Male
Male
374 Participants377 Participants751 Participants

Adverse events

Event typeEG000
affected / at risk
EG001
affected / at risk
EG002
affected / at risk
deaths
Total, all-cause mortality
23 / 49313 / 48936 / 982
other
Total, other adverse events
200 / 493201 / 489401 / 982
serious
Total, serious adverse events
159 / 493134 / 489293 / 982

Outcome results

Primary

Percentage of Patients Achieving the Target Dose of LCZ696 200 mg Bid at 10 Weeks Post Randomization

Percentage of patients achieving and maintaining LCZ696 200 mg bid for at least 2 weeks leading to Week 10

Time frame: 10 weeks after Randomization

Population: Safety Population (SAF). The SAF consisted of all randomized subjects who received at least one dose of study drug with the exception of those patients who were inadvertently randomized into the study. Subjects were analyzed according to treatment actually received.

ArmMeasureValue (COUNT_OF_PARTICIPANTS)
LCZ696 Pre-discharge Treatment InitiationPercentage of Patients Achieving the Target Dose of LCZ696 200 mg Bid at 10 Weeks Post Randomization224 Participants
LCZ696 Post-discharge Treatment InitiationPercentage of Patients Achieving the Target Dose of LCZ696 200 mg Bid at 10 Weeks Post Randomization248 Participants
p-value: 0.09995% CI: [0.786, 1.021]Cochran-Mantel-Haenszel
Secondary

Percentage of Patients Achieving and Maintaining Any Dose of LCZ696

Percentage of patients achieving any dose of LCZ696 for at least 2 weeks leading to 10 weeks of treatment

Time frame: 10 weeks after Randomization

Population: Safety Population (SAF). The SAF consisted of all randomized subjects who received at least one dose of study drug with the exception of those patients who were inadvertently randomized into the study. Subjects were analyzed according to treatment actually received.

ArmMeasureValue (COUNT_OF_PARTICIPANTS)
LCZ696 Pre-discharge Treatment InitiationPercentage of Patients Achieving and Maintaining Any Dose of LCZ696424 Participants
LCZ696 Post-discharge Treatment InitiationPercentage of Patients Achieving and Maintaining Any Dose of LCZ696438 Participants
p-value: 0.08995% CI: [0.916, 1.006]Cochran-Mantel-Haenszel
Secondary

Percentage of Patients Achieving and Maintaining Either LCZ696 100 mg and/or 200 mg Bid

Percentage of patients achieving and maintaining either LCZ696 100 mg and/or 200 mg bid for at least 2 weeks leading to Week 10

Time frame: 10 weeks after Randomization

Population: Safety Population (SAF). The SAF consisted of all randomized subjects who received at least one dose of study drug with the exception of those patients who were inadvertently randomized into the study. Subjects were analyzed according to treatment actually received.

ArmMeasureValue (COUNT_OF_PARTICIPANTS)
LCZ696 Pre-discharge Treatment InitiationPercentage of Patients Achieving and Maintaining Either LCZ696 100 mg and/or 200 mg Bid306 Participants
LCZ696 Post-discharge Treatment InitiationPercentage of Patients Achieving and Maintaining Either LCZ696 100 mg and/or 200 mg Bid335 Participants
p-value: 0.03495% CI: [0.827, 0.993]Cochran-Mantel-Haenszel
Secondary

Percentage of Patients Permanently Discontinued From Treatment

Percentage of patients permanently discontinued from LCZ696 (1) up to week 10 due to AEs, and (2) up to week 26 due to any reasons

Time frame: 10 weeks after Randomization AND 26 weeks after randomization

Population: Safety Population (SAF). The SAF consisted of all randomized subjects who received at least one dose of study drug with the exception of those patients who were inadvertently randomized into the study. Subjects were analyzed according to treatment actually received.

ArmMeasureGroupValue (COUNT_OF_PARTICIPANTS)
LCZ696 Pre-discharge Treatment InitiationPercentage of Patients Permanently Discontinued From Treatmentup to week 10 due to AEs36 Participants
LCZ696 Pre-discharge Treatment InitiationPercentage of Patients Permanently Discontinued From Treatmentup to week 26 due to any reasons83 Participants
LCZ696 Post-discharge Treatment InitiationPercentage of Patients Permanently Discontinued From Treatmentup to week 10 due to AEs24 Participants
LCZ696 Post-discharge Treatment InitiationPercentage of Patients Permanently Discontinued From Treatmentup to week 26 due to any reasons78 Participants
Post Hoc

All Collected Deaths

Pre-treatment deaths were collected from randomization until first treatment with LCZ696. The period from randomization to first treatment was up to 14 days. On-treatment deaths were collected from first treatment with LCZ696 until 26 weeks post randomization.

Time frame: From randomization until 26 weeks after randomization

Population: Safety Population (SAF) and randomized patients who died prior to first dose of study drug. The SAF consisted of all randomized subjects who received at least one dose of study drug with the exception of those patients who were inadvertently randomized into the study. Subjects were analyzed according to treatment actually received.

ArmMeasureGroupValue (COUNT_OF_PARTICIPANTS)
LCZ696 Pre-discharge Treatment InitiationAll Collected DeathsPre-treatment deaths1 Participants
LCZ696 Pre-discharge Treatment InitiationAll Collected DeathsOn-treatment deaths23 Participants
LCZ696 Pre-discharge Treatment InitiationAll Collected DeathsAll deaths24 Participants
LCZ696 Post-discharge Treatment InitiationAll Collected DeathsPre-treatment deaths2 Participants
LCZ696 Post-discharge Treatment InitiationAll Collected DeathsOn-treatment deaths13 Participants
LCZ696 Post-discharge Treatment InitiationAll Collected DeathsAll deaths15 Participants

Source: ClinicalTrials.gov · Data processed: Feb 26, 2026