Heart Failure With Reduced Ejection Fraction
Conditions
Keywords
Heart failure, reduced ejection fraction, LCZ696, titration, safety, tolerability
Brief summary
The purpose of this study is to assess the safety and tolerability of initiating LCZ696 in heart failure patients with reduced ejection fraction (HF-rEF) using conservative (reaching target dose over 6 weeks) and condensed (reaching target dose over 3 weeks) up-titration regimens.
Interventions
DRUGLCZ696
LCZ696 50 mg/100 mg/200 mg bid
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age ≥ 18 years; CHF with New York Heart Association class II-IV; left ventricular ejection fraction ≤ 35%; on beta blockers
Exclusion criteria
* Potassium \> 5.2 mmol/l; estimated glomerular filtration rate \< 30 ml/min/1.73 m2; systolic blood pressure \<100 mmHg or \> 180 mmHg; history of intolerance to recommended target doses of angiotensin converting enzyme inhibitors or angiotensin receptor blockers Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Experiencing Hypotension, Renal Dysfunction, Hyperkalemia and Angioedema and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low) | 12 weeks | Participants experiencing hypotension, renal dysfunction, hyperkalemia and angioedema and by Renin-Angiotensin-Aldosterone System (RAAS) stratum (high vs. low) High RAAS stratum Patients receiving \> 160 mg of valsartan or \> 10 mg total daily dose of enalapril, or equivalent doses of other ARBs/ACEIs, respectively, at screening Low RAAS stratum: Patients receiving ≤ 160 mg of valsartan or ≤ 10 mg total daily dose of enalapril, or equivalent doses of other ARBs/ACEIs, respectively, at screening. This stratum also included patients who were not on an ACEI or an ARB 4 weeks prior to screening (i.e., ACEI/ARB-naïve patients) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Achieved Treatment Success Over the 12 Weeks and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low) | 12 weeks | Treatment success was defined as the number of participants who achieved and maintained LCZ696 200 mg bid without any dose interruption or down-titration over 12 weeks and by Renin-Angiotensin-Aldosterone System (RAAS) stratum (high vs. low) High RAAS stratum Patients receiving \> 160 mg of valsartan or \> 10 mg total daily dose of enalapril, or equivalent doses of other ARBs/ACEIs, respectively, at screening Low RAAS stratum: Patients receiving ≤ 160 mg of valsartan or ≤ 10 mg total daily dose of enalapril, or equivalent doses of other ARBs/ACEIs, respectively, at screening. This stratum also included patients who were not on an ACEI or an ARB 4 weeks prior to screening (i.e., ACEI/ARB-naïve patients) |
| Number of Participants Who Tolerated Study Medication for at Least the Last Two Weeks of the Study and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low). | 12 weeks | Tolerability was assessed as the number of participants who achieved LCZ696 200 mg bid and maintained this dose for at least 2 weeks before study completion, regardless of previous dose interruption or down-titration and by Renin-Angiotensin-Aldosterone System (RAAS) stratum (high vs. low) High RAAS stratum Patients receiving \> 160 mg of valsartan or \> 10 mg total daily dose of enalapril, or equivalent doses of other ARBs/ACEIs, respectively, at screening Low RAAS stratum: Patients receiving ≤ 160 mg of valsartan or ≤ 10 mg total daily dose of enalapril, or equivalent doses of other ARBs/ACEIs, respectively, at screening. This stratum also included patients who were not on an ACEI or an ARB 4 weeks prior to screening (i.e., ACEI/ARB-naïve patients) |
Countries
Bulgaria, Finland, Germany, Hungary, Italy, Puerto Rico, Slovakia, Spain, Turkey (Türkiye), United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| LCZ696 Condensed Up-titration to LCZ696 200 mg twice daily (bid) over 3 weeks | 247 |
| LCZ696 Conservative Up-titration to LCZ696 200 mg bid over 6 weeks | 251 |
| Total | 498 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | administrative problems | 4 | 1 |
| Overall Study | Adverse Event | 18 | 13 |
| Overall Study | Death | 2 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Physician Decision | 2 | 3 |
| Overall Study | Protocol Deviation | 10 | 7 |
| Overall Study | Withdrawal by Subject | 3 | 4 |
Baseline characteristics
| Characteristic | LCZ696 Condensed | LCZ696 Conservative | Total |
|---|---|---|---|
| Age, Continuous | 64.2 years STANDARD_DEVIATION 11.86 | 63.8 years STANDARD_DEVIATION 10.94 | 64.0 years STANDARD_DEVIATION 11.39 |
| Sex: Female, Male Female | 56 Participants | 50 Participants | 106 Participants |
| Sex: Female, Male Male | 191 Participants | 201 Participants | 392 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 72 / 246 | 52 / 251 |
| serious Total, serious adverse events | 21 / 246 | 14 / 251 |
Outcome results
Primary
Number of Participants Experiencing Hypotension, Renal Dysfunction, Hyperkalemia and Angioedema and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low)
Participants experiencing hypotension, renal dysfunction, hyperkalemia and angioedema and by Renin-Angiotensin-Aldosterone System (RAAS) stratum (high vs. low) High RAAS stratum Patients receiving \> 160 mg of valsartan or \> 10 mg total daily dose of enalapril, or equivalent doses of other ARBs/ACEIs, respectively, at screening Low RAAS stratum: Patients receiving ≤ 160 mg of valsartan or ≤ 10 mg total daily dose of enalapril, or equivalent doses of other ARBs/ACEIs, respectively, at screening. This stratum also included patients who were not on an ACEI or an ARB 4 weeks prior to screening (i.e., ACEI/ARB-naïve patients)
Time frame: 12 weeks
Population: Full Analysis Set (FAS) consisted of all randomized patients with the exception of mis-randomized patients who had not received the study drug, but had been inadvertently randomized into the study. Following the intent-to-treat principle, patients were analyzed according to the treatment to which they were assigned at randomization.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LCZ696 Condensed | Number of Participants Experiencing Hypotension, Renal Dysfunction, Hyperkalemia and Angioedema and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low) | Hypotension High RAAS (n=120, 127) | 5 participants |
| LCZ696 Condensed | Number of Participants Experiencing Hypotension, Renal Dysfunction, Hyperkalemia and Angioedema and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low) | Hypotension Low RAAS (n=127, 124) | 19 participants |
| LCZ696 Condensed | Number of Participants Experiencing Hypotension, Renal Dysfunction, Hyperkalemia and Angioedema and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low) | Hypotension ALL | 24 participants |
| LCZ696 Condensed | Number of Participants Experiencing Hypotension, Renal Dysfunction, Hyperkalemia and Angioedema and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low) | Renal Dysfunction High RAAS (n=120, 127) | 5 participants |
| LCZ696 Condensed | Number of Participants Experiencing Hypotension, Renal Dysfunction, Hyperkalemia and Angioedema and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low) | Renal Dysfunction Low RAAS (n=127, 124) | 13 participants |
| LCZ696 Condensed | Number of Participants Experiencing Hypotension, Renal Dysfunction, Hyperkalemia and Angioedema and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low) | Renal Dysfunction ALL | 18 participants |
| LCZ696 Condensed | Number of Participants Experiencing Hypotension, Renal Dysfunction, Hyperkalemia and Angioedema and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low) | Hyperkalemia High RAAS (n=120, 127) | 8 participants |
| LCZ696 Condensed | Number of Participants Experiencing Hypotension, Renal Dysfunction, Hyperkalemia and Angioedema and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low) | Hyperkalemia Low RAAS (n=127, 124) | 11 participants |
| LCZ696 Condensed | Number of Participants Experiencing Hypotension, Renal Dysfunction, Hyperkalemia and Angioedema and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low) | Hyperkalemia ALL | 19 participants |
| LCZ696 Condensed | Number of Participants Experiencing Hypotension, Renal Dysfunction, Hyperkalemia and Angioedema and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low) | Angioedema High RAAS (n=120, 127) | 0 participants |
| LCZ696 Condensed | Number of Participants Experiencing Hypotension, Renal Dysfunction, Hyperkalemia and Angioedema and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low) | Angioedema Low RAAS (n=127, 124) | 0 participants |
| LCZ696 Condensed | Number of Participants Experiencing Hypotension, Renal Dysfunction, Hyperkalemia and Angioedema and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low) | Angioedema ALL | 0 participants |
| LCZ696 Conservative | Number of Participants Experiencing Hypotension, Renal Dysfunction, Hyperkalemia and Angioedema and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low) | Angioedema Low RAAS (n=127, 124) | 1 participants |
| LCZ696 Conservative | Number of Participants Experiencing Hypotension, Renal Dysfunction, Hyperkalemia and Angioedema and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low) | Hypotension High RAAS (n=120, 127) | 7 participants |
| LCZ696 Conservative | Number of Participants Experiencing Hypotension, Renal Dysfunction, Hyperkalemia and Angioedema and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low) | Hyperkalemia High RAAS (n=120, 127) | 5 participants |
| LCZ696 Conservative | Number of Participants Experiencing Hypotension, Renal Dysfunction, Hyperkalemia and Angioedema and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low) | Hypotension Low RAAS (n=127, 124) | 14 participants |
| LCZ696 Conservative | Number of Participants Experiencing Hypotension, Renal Dysfunction, Hyperkalemia and Angioedema and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low) | Angioedema High RAAS (n=120, 127) | 1 participants |
| LCZ696 Conservative | Number of Participants Experiencing Hypotension, Renal Dysfunction, Hyperkalemia and Angioedema and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low) | Hypotension ALL | 21 participants |
| LCZ696 Conservative | Number of Participants Experiencing Hypotension, Renal Dysfunction, Hyperkalemia and Angioedema and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low) | Hyperkalemia Low RAAS (n=127, 124) | 6 participants |
| LCZ696 Conservative | Number of Participants Experiencing Hypotension, Renal Dysfunction, Hyperkalemia and Angioedema and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low) | Renal Dysfunction High RAAS (n=120, 127) | 9 participants |
| LCZ696 Conservative | Number of Participants Experiencing Hypotension, Renal Dysfunction, Hyperkalemia and Angioedema and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low) | Angioedema ALL | 2 participants |
| LCZ696 Conservative | Number of Participants Experiencing Hypotension, Renal Dysfunction, Hyperkalemia and Angioedema and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low) | Renal Dysfunction Low RAAS (n=127, 124) | 10 participants |
| LCZ696 Conservative | Number of Participants Experiencing Hypotension, Renal Dysfunction, Hyperkalemia and Angioedema and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low) | Hyperkalemia ALL | 11 participants |
| LCZ696 Conservative | Number of Participants Experiencing Hypotension, Renal Dysfunction, Hyperkalemia and Angioedema and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low) | Renal Dysfunction ALL | 19 participants |
Secondary
Number of Participants Who Achieved Treatment Success Over the 12 Weeks and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low)
Treatment success was defined as the number of participants who achieved and maintained LCZ696 200 mg bid without any dose interruption or down-titration over 12 weeks and by Renin-Angiotensin-Aldosterone System (RAAS) stratum (high vs. low) High RAAS stratum Patients receiving \> 160 mg of valsartan or \> 10 mg total daily dose of enalapril, or equivalent doses of other ARBs/ACEIs, respectively, at screening Low RAAS stratum: Patients receiving ≤ 160 mg of valsartan or ≤ 10 mg total daily dose of enalapril, or equivalent doses of other ARBs/ACEIs, respectively, at screening. This stratum also included patients who were not on an ACEI or an ARB 4 weeks prior to screening (i.e., ACEI/ARB-naïve patients)
Time frame: 12 weeks
Population: Evaluable patients in FAS with the exception of misrandomized patients who didn't received drug, but had been randomized into the study, excluding patients who discontinued the study prior to completion of 12 wks. Following the intent-to-treat principle, patients were analyzed according to the treatment to which they were assigned at randomization.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LCZ696 Condensed | Number of Participants Who Achieved Treatment Success Over the 12 Weeks and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low) | High RAAS (n=109,117) | 90 participants |
| LCZ696 Condensed | Number of Participants Who Achieved Treatment Success Over the 12 Weeks and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low) | Low RAAS (n=121,119) | 89 participants |
| LCZ696 Condensed | Number of Participants Who Achieved Treatment Success Over the 12 Weeks and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low) | ALL (n=230,236) | 179 participants |
| LCZ696 Conservative | Number of Participants Who Achieved Treatment Success Over the 12 Weeks and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low) | High RAAS (n=109,117) | 98 participants |
| LCZ696 Conservative | Number of Participants Who Achieved Treatment Success Over the 12 Weeks and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low) | Low RAAS (n=121,119) | 101 participants |
| LCZ696 Conservative | Number of Participants Who Achieved Treatment Success Over the 12 Weeks and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low) | ALL (n=230,236) | 199 participants |
Secondary
Number of Participants Who Tolerated Study Medication for at Least the Last Two Weeks of the Study and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low).
Tolerability was assessed as the number of participants who achieved LCZ696 200 mg bid and maintained this dose for at least 2 weeks before study completion, regardless of previous dose interruption or down-titration and by Renin-Angiotensin-Aldosterone System (RAAS) stratum (high vs. low) High RAAS stratum Patients receiving \> 160 mg of valsartan or \> 10 mg total daily dose of enalapril, or equivalent doses of other ARBs/ACEIs, respectively, at screening Low RAAS stratum: Patients receiving ≤ 160 mg of valsartan or ≤ 10 mg total daily dose of enalapril, or equivalent doses of other ARBs/ACEIs, respectively, at screening. This stratum also included patients who were not on an ACEI or an ARB 4 weeks prior to screening (i.e., ACEI/ARB-naïve patients)
Time frame: 12 weeks
Population: Evaluable patients in FAS with the exception of misrandomized patients who didn't received drug, but had been randomized into the study, excluding patients who discontinued the study prior to completion of 12 wks. Following the intent-to-treat principle, patients were analyzed according to the treatment to which they were assigned at randomization.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LCZ696 Condensed | Number of Participants Who Tolerated Study Medication for at Least the Last Two Weeks of the Study and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low). | ALL (n=230,236) | 191 participants |
| LCZ696 Condensed | Number of Participants Who Tolerated Study Medication for at Least the Last Two Weeks of the Study and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low). | High RAAS (n=109,117) | 94 participants |
| LCZ696 Condensed | Number of Participants Who Tolerated Study Medication for at Least the Last Two Weeks of the Study and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low). | Low RAAS (n=121,119) | 97 participants |
| LCZ696 Conservative | Number of Participants Who Tolerated Study Medication for at Least the Last Two Weeks of the Study and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low). | High RAAS (n=109,117) | 103 participants |
| LCZ696 Conservative | Number of Participants Who Tolerated Study Medication for at Least the Last Two Weeks of the Study and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low). | Low RAAS (n=121,119) | 103 participants |
| LCZ696 Conservative | Number of Participants Who Tolerated Study Medication for at Least the Last Two Weeks of the Study and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low). | ALL (n=230,236) | 206 participants |