Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Also known as sacubitril, valsartan, LCZ
LCZ696 · 75 trials · 29 indications
The International Index of Erectile Function (IIEF-15) was used to assess erectile function in male patients with chronic heart failure. The IIEF-15 is a patient self-reported assessment of erectile dysfunction (ED) and consists of 15 questions assessing different aspects associated with ED. The domain evaluating erectile function consists of items 1, 2, 3, 4, 5 \& 15 and its total score was used here. Total score range =1-30. Items 1-5 is 6-point Likert-type scale from '0' (= No sexual activity), '1' (=Almost never or never) to '5' (= Almost always or always). Items 15 is 5-point Likert-type scale from '1' (= very low) to '5 '(= very high). Higher score indicates better outcome
The impact of LCZ696 (Sacubitril/Valsartan) and Enalapril on functional exercise capacity was measured by the Six Minute Walk Test at 12 weeks. The 6MWT measures the distance an individual is able to walk over a total of six minutes on a hard, flat surface. The goal is for the individual to walk as far as possible in six minutes. The individual is able to self-pace and rest as needed as they traverse back and forth along a marked walkway.
Non-sedentary physical activity is defined as \>= 178.50 activity counts per minute; the average number of minutes per day spent in non-sedentary physical activity is being calculated over 14 days before randomization (baseline i.e. week -2 to week 0) and the last 14 days of treatment (i.e. week 10 to week 12).
A confirmed composite endpoint includes cardiovascular (CV) death, heart failure (HF) hospitalization, or outpatient heart failure
The CogState cognitive battery was composed of 7 tests, which were administered electronically by the patients at scheduled visits. For each test, a standardized z-score was calculated. The GCCS was the average of the non-missing individual test z-scores. A higher score indicated better cognitive function. CogState GCCS changes from baseline (randomization) were analyzed using a repeated measures ANCOVA in which treatment, age stratification factor, Mini mental state examination stratification factor, education level, Apolipoprotein E ε4 allele status, cerebrovascular disease burden at screening, visit and treatment-by-visit interaction are included as fixed-effect factor, and baseline (randomization) GCCS and visit-by- baseline GCCS as covariates with a common unstructured covariance matrix among visits between treatment groups. The analysis was based on a direct likelihood method with an assumption of Missing at random.
Composite endpoint is defined as either cardiovascular (CV) death or heart failure (HF) hospitalization in Japanese patients with chronic heart failure (CHF) and reduced ejection fraction. The composite endpoint events occurred on and after End-of-study (EOS) declaration were reported by investigators but those events were not required to be adjudicated by Clinical Endpoint Committee (CEC) and not included in the efficacy analysis.
Composite endpoint is defined as either cardiovascular (CV) death or heart failure (HF) hospitalization in Japanese patients with chronic heart failure (CHF) and reduced ejection fraction. EAIR = n/T where n = Total number of events included in the analysis. T (100 patient years) = total up-to-event/censoring duration-time summarized over participants in the respective treatment group. The composite endpoint events occurred on and after EOS declaration were reported by investigators but those events were not required to be adjudicated by CEC and not included in the efficacy analysis.
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.
The primary objective of this study is to compare LCZ696 to valsartan in reducing the rate of the composite endpoint of CV death and total (first and recurrent) HF hospitalizations, in HF patients (New York Heart Association \[NYHA\] Class II-IV) with preserved ejection fraction (left ventricular ejection fraction \[LVEF\] ≥45%). The treatment arm with the lower rate of events will be deemed as having a successful response.
Twenty-four hour mean ambulatory blood pressure measurements (ABPM) will be performed at baseline and at end of study (week 8). The first 24-hour ABPM will be performed beginning at 24 hours prior to baseline visit and the second will be performed 24 hours prior to week 8 visit.
Sitting BP measurements will be performed at screening through end of study at every visit. Four separate sitting BP measurements will be obtained with a full two minute interval between measurements.
The change in mean 24 hour ambulatory systolic blood pressure (maSBP) from baseline to end of the study (week 8) in the 2 groups was measured. A greater reduction from baseline in the LCZ696 group indicates a positive treatment effect.
Adverse events, serious adverse events deaths were monitored from screening to week 8.
Sitting BP measurements were performed at screening through the end of study at every visit. Four separate sitting BP were obtained with a full two-minute interval between measurements. The 4 measurements were summed and averaged, and then the baseline BP value was subtracted from the average value to get the change from baseline.
Percentage of patients with total adverse events, serious adverse events and death were reported.
Sitting blood pressure was measured using a calibrated standard sphygmomanometer after the participants remained in sitting position for 5 minutes at clinic during the visit. The repeat sitting measurements were made at 2 to 3 minute intervals and the mean of three sSBP measurements were used as the average sitting office blood pressure for that visit.
Sitting blood pressure was measured using a calibrated standard sphygmomanometer after the participants remained in sitting position for 5 minutes at clinic during the visit. The repeat sitting measurements were made at 2 to 3 minute intervals and the mean of three sDBP measurements were used as the average sitting office blood pressure for that visit.
Three arterial blood pressure (BP) determinations were made after the participant was in the sitting position for 5 minutes according to the American Heart Association guidelines using a calibrated standard aneroid or mercury sphygmomanometer or a calibrated standard sphygmomanometer. The change in the MSDBP was calculated comparing the Week 8 readings to the readings taken at Baseline. The change from baseline in MSDBP was analyzed using an analysis of covariance model (ANCOVA) with treatment and center (pooled as appropriate) as factors and centered baseline MSDBP as a covariate.
Sitting blood pressure was measured using a calibrated standard sphygmomanometer after the participant remained in sitting position for 5 minutes at clinic during the visit. The repeat sitting measurements were made at 1-2 minute intervals and the mean of three SDBP measurements were used as the average sitting office blood pressure for that visit. Negative change from Baseline indicates improvement.
An AE was defined as any unfavourable and unintended sign, symptom, or disease temporally associated with the use of study drug, whether or not related to study drug. A SAE was defined as an event which was fatal or life threatening, required or prolonged hospitalization, was significantly or permanently disabling or incapacitating, constituted a congenital anomaly or a birth defect, or encompassed any other clinically significant event that could jeopardize the participant or require medical or surgical intervention to prevent one of the aforementioned outcomes.
No new unexpected AE's were observed in long-term treatment with VAA 80/5 mg. There were no deaths during the study. The SAEs were rare, with 9 patients (2.5%) reporting 10 events (1 patient experienced 2 SAEs). These events were not clustered to any particular primary system organ class and only 2 events the investigators could not excluded a relationship to study drug. The events that occurred were expected in this study population and/or were known to be associated with either valsartan or amlodipine. AEs leading to discontinuation occurred in 14 patients (3.8%).
Blood pressure (BP) was measured with a calibrated aneroid or mercury sphygmomanometer. The arm in which the highest sitting diastolic BP was found at study entry was used for all subsequent readings. At each visit, after the patient was in a sitting position for five minutes, systolic/diastolic BP was measured 3 times at 1-2-minute intervals. The mean of the 3 measurements was calculated. A negative change score indicates lowered BP.
Blood pressure (BP) was measured at trough (24±3 hours post-dose). The arm in which the highest sitting diastolic BP was found at study entry was used for all subsequent readings. If there was \< 0. 5 mmHg difference in BP between the 2 arms, the non-dominant arm was used. At each visit, after the patient was in a sitting position with the back supported and both feet placed on the floor for 5 minutes, systolic and diastolic BP were measured 3 times with an automated BP monitor and appropriate size cuff. Means of the 3 measurements were calculated. A negative change indicates lowered BP.
Only occurrences of peripheral edema quantified as a reported adverse event coded as peripheral edema were included in the analysis. If a patient experienced more than one occurrence of peripheral edema between Day 1 and Week 8, it was only counted once in the analysis.
Progression to diabetes was determined by (a) an algorithm based on central laboratory measurements of fasting plasma glucose and/or a 2 hour oral glucose tolerance test or (b) adjudication by the Diabetes Endpoint Adjudication Committee.
The extended cardiovascular endpoint was defined as a cardiovascular morbidity/mortality event including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, revascularization procedure, hospitalization for congestive heart failure, and hospitalization for unstable angina.
The core cardiovascular endpoint was defined as a cardiovascular morbidity/mortality event including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke and hospitalization for congestive heart failure.
Progression to diabetes was determined by (a) an algorithm based on central laboratory measurements of fasting plasma glucose and/or a 2 hour oral glucose tolerance test or (b) adjudication by the Diabetes Endpoint Adjudication Committee.
The extended cardiovascular endpoint was defined as a cardiovascular morbidity/mortality event including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, revascularization procedure, hospitalization for congestive heart failure, and hospitalization for unstable angina.
The core cardiovascular endpoint was defined as a cardiovascular morbidity/mortality event including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke and hospitalization for congestive heart failure.
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.
The analyses of Cmax was based on plasma concentrations of three sacubitril/valsartan analytes (AHU377 (sacubitril), LBQ657 (sacubitrilat), and valsartan). The plasma levels of sacubitril/valsartan analytes were determined using a validated LCMS/MS method with a lower limit of quantitation (LLOQ) of 1 ng/mL for sacubitril, 20 ng/mL for LBQ657, and 10 ng/mL for valsartan. The PK parameters were determined using the non-compartmental method(s).
The analyses of Tmax was based on plasma concentrations of three sacubitril/valsartan analytes (AHU377 (sacubitril), LBQ657 (sacubitrilat), and valsartan). The plasma levels of sacubitril/valsartan analytes were determined using a validated LCMS/MS method with a lower limit of quantitation (LLOQ) of 1 ng/mL for sacubitril, 20 ng/mL for LBQ657, and 10 ng/mL for valsartan. The PK parameters were determined using the non-compartmental method(s).
The analyses of AUCinf was based on plasma concentrations of three sacubitril/valsartan analytes (AHU377 (sacubitril), LBQ657 (sacubitrilat), and valsartan). The plasma levels of sacubitril/valsartan analytes were determined using a validated LCMS/MS method with a lower limit of quantitation (LLOQ) of 1 ng/mL for sacubitril, 20 ng/mL for LBQ657, and 10 ng/mL for valsartan. The PK parameters were determined using the non-compartmental method(s).
As prespecified in protocol and SAP the analysis of this outcome measure was done based on dose of LCZ696 administered within the different age groups.
The analyses was based on plasma concentrations of two sacubitril/valsartan analytes (AHU377 (sacubitril), and valsartan). The plasma levels of sacubitril/valsartan analytes were determined using a validated LCMS/MS method with a lower limit of quantitation (LLOQ) of 1 ng/mL for sacubitril, 20 ng/mL for LBQ657, and 10 ng/mL for valsartan. The PK parameters were determined using the non-compartmental method(s). CL/F was not estimated for LBQ657 as it is a metabolite.
The analyses of T1/2 was based on plasma concentrations of sacubitril. The plasma levels of sacubitril/valsartan analytes were determined using a validated LCMS/MS method with a lower limit of quantitation (LLOQ) of 1 ng/mL for sacubitril, 20 ng/mL for LBQ657, and 10 ng/mL for valsartan. The PK parameters were determined using the non-compartmental method(s). T1/2 for other analytes of LCZ696 (LBQ657 and Valsartan) was not estimable due to the short sample collection timeframe.
Biomarkers were used to assess the PD effects of LCZ696. Blood biomarkers of potential interest included plasma BNP. Biomarkers related to heart failure or the mechanism of action of the study drug were measured. Summary statistics for change from baseline at each time point is presented. The baseline assessment is defined as the last non-missing assessment (scheduled or unscheduled) prior to (the first dose time of the study drug within the dose associated period). For each post-dose time point, participants are included if and only if the participant has both pre-dose assessment and current time point assessment observed.
Biomarkers were used to assess the PD effects of LCZ696. Blood biomarkers of potential interest included plasma NTproBNP. Biomarkers related to heart failure or the mechanism of action of the study drug were measured. Summary statistics for change from baseline at each time point is presented. The baseline assessment is defined as the last non-missing assessment (scheduled or unscheduled) prior to (the first dose time of the study drug within the dose associated period). For each post-dose time point, participants are included if and only if the participant has both pre-dose assessment and current time point assessment observed.
Biomarkers were used to assess the PD effects of LCZ696. Blood biomarkers of potential interest included plasma cGMP. Biomarkers related to heart failure or the mechanism of action of the study drug were measured. Summary statistics for change from baseline at each time point is presented. The baseline assessment is defined as the last non-missing assessment (scheduled or unscheduled) prior to (the first dose time of the study drug within the dose associated period). For each post-dose time point, participants are included if and only if the participant has both pre-dose assessment and current time point assessment observed.
Biomarkers were used to assess the PD effects of LCZ696. Blood biomarkers of potential interest included urine cGMP. Biomarkers related to heart failure or the mechanism of action of the study drug were measured. Summary statistics for change from baseline at each time point is presented. The baseline assessment is defined as the last non-missing assessment (scheduled or unscheduled) prior to (the first dose time of the study drug within the dose associated period). For each post-dose time point, participants are included if and only if the participant has both pre-dose assessment and current time point assessment observed.
Global ranking is based on 5 categories ranking worst to best outcome:Category 1:Death; United Network for Organ Sharing(UNOS)status 1A listing for heart transplant or equivalent; ventricular assist device(VAD)/extracorporeal membrane oxygenation(ECMO)/mechanical ventilation/intra-aortic balloon pump requirement for life support at end of study. Category 2:Worsening HF(WHF);defined by signs and symptoms of WHF that requires an intensification of HF therapy. Category 3:Worsened; worse New York Heart Association(NYHA)/Ross or worse Patient Global Impression of Severity(PGIS); and further ranking by Pediatric Quality of Life Inventory(PedsQL)physical functioning domain.Category 4:Unchanged; unchanged NYHA/Ross and unchanged PGIS; and further ranking by PedsQL physical functioning domain. Category 5:Improved; improved NYHA/Ross or improved PGIS(neither can be worse);and further ranking by PedsQL physical functioning domain. Participants with worst event in each category are reported here.
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)
Central aortic blood pressure was derived from peripheral pressure waveforms recorded noninvasively from the brachial artery using a cuff-based device. This technique uses the brachial pressure and a signal processing algorithm to transform brachial signals into central blood pressure (BP) waveforms. When the aortic pressure waveform was derived, key pulse wave analysis (PWA) parameters, such as CASP was calculated by the system software. At the first study visit, the arm with the highest systolic blood pressure (SBP) was used for all subsequent PWA. Brachial PWA measurements were performed on the same arm that the office blood pressures were taken. Two pulse waveform measurements, meeting all quality control criteria were captured at baseline and at week 12 visits.
The insulin sensitivity index was assessed by hyperinsulinemic euglycemic clamp (HEGC). A positive change from baseline indicates improvement.
The effect of co-administration of sildenafil on the pharmacokinetics of LCZ696 (analytes of LCZ696: AHU377, LBQ657 and valsartan) was assessed. Blood samples were collected at pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose from day 1 to day 7, 24 hours post-dose from day 7, and day 8 at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose. AUC is a mathematically-derived value from all measurements. AUC is a measure of the area under the curve that is obtained from plotting the plasma concentration by time point. All time-points were used to derive the single PK parameters.
The effect of co-administration of sildenafil on the pharmacokinetics of LCZ696 (analytes of LCZ696: AHU377, LBQ657 and valsartan) was assessed. Blood samples were collected at pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose from day 1 to day 7, 24 hours post-dose from day 7, and day 8 at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose. Cmax is a mathematically-derived value from all measurements. Cmax is a measure of the area under the curve that is obtained from plotting the plasma concentration by time point. All time-points were used to derive the single PK parameters.
The effect of co-administration of sildenafil on the pharmacokinetics of LCZ696 (analytes of LCZ696: AHU377, LBQ657 and valsartan) was assessed. Blood samples were collected at pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose from day 1 to day 7, 24 hours post-dose from day 7, day 8 at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose. Cmin is a mathematically-derived value from all measurements. Cmin is a measure of the area under the curve that is obtained from plotting the plasma concentration by time point. All time-points were used to derive the single PK parameters.
The effect of co-administration of sildenafil on the pharmacokinetics of LCZ696 (analytes of LCZ696: AHU377, LBQ657 and valsartan) was assessed. Blood samples were collected at pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose from day 1 to day 7, 24 hours post-dose from day 7, day 8 at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose. Tmax is a mathematically-derived value from all measurements. Tmax is a measure of the area under the curve that is obtained from plotting the plasma concentration by time point. All time-points were used to derive the single PK parameters.
The effect of co-administration of LCZ696 on the pharmacokinetics of Sildenafil and N-desmethyl-sildenafil was assessed. Blood samples were collected at pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose from day 1 to day 7, 24 hours post-dose from day 7, day 8 at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose. AUC is a mathematically-derived value from all measurements. AUC is a measure of the area under the curve that is obtained from plotting the plasma concentration by time point. All time-points were used to derive the single PK parameters.
The effect of co-administration of LCZ696 on the pharmacokinetics of Sildenafil and N-desmethyl-sildenafil was assessed. Blood samples were collected at pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose from day 1 to day 7, 24 hours post-dose from day 7, day 8 at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose. AUC is a mathematically-derived value from all measurements. AUC is a measure of the area under the curve that is obtained from plotting the plasma concentration by time point. All time-points were used to derive the single PK parameters.
The effect of co-administration of LCZ696 on the pharmacokinetics of Sildenafil and N-desmethyl-sildenafil was assessed. Blood samples were collected at pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose from day 1 to day 7, 24 hours post-dose from day 7, day 8 at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose. T1/2 is a mathematically-derived value from all measurements. T1/2 is a measure of the area under the curve that is obtained from plotting the plasma concentration by time point. All time-points were used to derive the single PK parameters.
The effect of co-administration of LCZ696 on the pharmacokinetics of Sildenafil and N-desmethyl-sildenafil was assessed. Blood samples were collected at pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose from day 1 to day 7, 24 hours post-dose from day 7, day 8 at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose. All time-points were used to mathematically derive the single PK parameter.
The effect of co-administration of LCZ696 on the pharmacokinetics of Sildenafil and N-desmethyl-sildenafil will be assessed. 8pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose from day 1 to day 7, 24 hours post-dose from day 7, day 8 at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose. All time-points were used to mathematically derive the single PK parameter.
Blood samples were taken on Day 1 (treatment day) within 60 minutes prior to dosing, then, 0.5,1,1.5,2,3,4,6,8,12 hours after the dosing and on Days 2, 3, 4 and 5 post dosing
Blood samples were taken on Day 1 (treatment day) within 60 minutes prior to dosing, then, 0.5,1,1.5,2,3,4,6,8,12 hours after the dosing and on Days 2, 3, 4 and 5 post dosing
Blood samples were taken on Day 1 (treatment day) within 60 minutes prior to dosing, then, 0.5,1,1.5,2,3,4,6,8,12 hours after the dosing and on Days 2, 3, 4 and 5 post dosing
Urine will be collected in fractions of 6 to 24 hours post-dose. From each fraction, a sample will be drawn for analysis of sodium Day 1
Urine was collected in 12-hour intervals, and of each pooled 24-hour (daily) sample, sodium concentration was measured. The measure type used for this outcome measure (OM) was Geometric Least square Means (LSM).
Urine was collected in 12-hour intervals, and of each pooled 24-hour (daily) sample, sodium concentration was measured. The measure type used for this outcome measure (OM) was Geometric Least square Means (LSM).
Participants were monitored throughout the study for adverse events, serious adverse events and deaths.
Evaluation of NT-proBNP was performed by a central laboratory. Change from baseline in NT-proBNP was presented as a ratio where the ratio was calculated as the NT-proBNP value at 12 weeks over the NT-proBNP value at baseline. A ratio \< 1 indicates improvement.
Blood samples will be collected for the determination of plasma concentrations of VAL489 (valsartan), AHU377( Sacubitril) and LBQ657 (a human metabolite of sacubitril)
Blood samples will be collected for the determination of plasma concentrations of VAL489 (valsartan), AHU377( Sacubitril) and LBQ657 (a human metabolite of sacubitril)
Blood samples will be collected for the determination of plasma concentrations of VAL489 (valsartan), AHU377( Sacubitril) and LBQ657 (a human metabolite of sacubitril)
Blood samples will be collected for the determination of plasma concentrations of VAL489 (valsartan), AHU377( Sacubitril) and LBQ657 (a human metabolite of sacubitril)
Blood samples will be collected for the determination of plasma concentrations of VAL489 (valsartan), AHU377( Sacubitril) and LBQ657 (a human metabolite of sacubitril)
Blood samples will be collected for the determination of plasma concentrations of VAL489 (valsartan), AHU377( Sacubitril) and LBQ657 (a human metabolite of sacubitril)
Blood samples will be collected for the determination of plasma concentrations of VAL489 (valsartan), AHU377( Sacubitril) and LBQ657 (a human metabolite of sacubitril)
Blood samples will be collected for the determination of plasma concentrations of VAL489 (valsartan), AHU377( Sacubitril) and LBQ657 (a human metabolite of sacubitril)
| Arm | Type | Description |
|---|---|---|
| LCZ696 | EXPERIMENTAL | LCZ696 200 mg (sacubitril/valsartan 97 mg/103 mg bid) |
| Enalapril | ACTIVE_COMPARATOR | Enalapril 10 mg |
| LCZ696 (Sacubitril/Valsartan) | EXPERIMENTAL | After randomization, patients in this arm received LCZ696 (Sacubitril/Valsartan) twice daily and matching placebo of Enalapril depending on the patient's previous ACEI/ARB dose (enalapril equivalent dose) for 2 weeks. Patients could start study medication at dose level 1 (24 mg/26 mg LCZ), 2 (49 mg/51 mg LCZ) or 2a (49 mg/51 mg LCZ) or matching placebo bid. After 2 weeks (visit 3) the doses were up-titrated: patients, who started on dose level 2 or 2a received the target dose of study medication (level 3) at this point. After another 2 weeks (visit 4) all patients were to achieve the target dose of 97 mg/103 mg bid LCZ696(sacubitril/valsartan) and matching placebo, provided no safety and tolerability issues arised during uptitration. |
| Ramipril | ACTIVE_COMPARATOR | Following randomization, patients will receive the Ramipril in titrated doses from level 1 up to level 3 (1.25, 2.5 and 5 mg twice daily). Patients will be required to take a total of two pills, (one capsule from the ramipril pack and one tablet from LCZ696 matching placebo pack) twice a day for the duration of the study. Patients randomized to ramipril who were previously treated with ACE inhibitors receiving the last dose of that agent during the last 36 hours prior to randomization will immediately start on double-blind ramipril; however, to maintain double blind/double dummy of the valsartan bridge, these patients will receive two doses of matching valsartan placebo for 1 day in a blinded manner prior to beginning double-blind LCZ696 placebo. |
| LCZ696 200 mg bid | EXPERIMENTAL | Patients who were able to tolerate the treatment during the single-blind treatment run-in epoch. Following the run-in period, patients randomized in this arm were given LCZ696 at 200 mg twice daily for three years |
| Valsartan 160 mg bid | ACTIVE_COMPARATOR | Patients who were able to tolerate the treatment during the single-blind treatment run-in epoch. Following the run-in period, patients randomized in this arm were given valsartan at 160 mg twice daily for three years. |
| Valsartan | ACTIVE_COMPARATOR | Single Blind Run-in Period (3-8 weeks): Patients will start on Valsartan 80 mg b.i.d. for 1-2 weeks followed by LCZ696 100 mg b.i.d. for 2-4 weeks prior to randomization into the Double Blind period (up to 57 months). Patients can only be randomized from the run-in period if they meet all of the run-in safety criteria. Target dose of Valsartan during the double blind period is 160 mg b.i.d. |
| LCZ696 200 mg | EXPERIMENTAL | Patients will be treated with one LCZ696 200 mg tablet and one placebo of olmesartan 20 mg capsule once daily for 8 weeks. |
| Olmesartan 20 mg | ACTIVE_COMPARATOR | Patients will be treated with one placebo of LCZ696 200 mg tablet and one olmesartan 20 mg capsule once daily for 8 weeks. |
| LCZ696 400 mg | EXPERIMENTAL | Patients will start with one LCZ696 200 mg tablet and one placebo of LCZ696 once daily (qd) for one week, thereafter all patients in the treatment group will be up-titrated to two LCZ696 200 mg tablets (400 mg of LCZ696) qd for the remaining seven weeks. Placebo of Olmesartan 20 mg capsule once daily also will be taken. |
| LCZ696 and amlodipine | EXPERIMENTAL | Participants, first treated with 5 mg of amlodipine for 4 weeks to determine if they were not adequately responding to amlodipine (had an office msSBP ≥145 mmHg and \<180 mmHg) and who met all inclusion and exclusion criteria), were randomized to receive 200mg of LCZ696 in combination with 5 mg of amlodipine for 8 weeks. |
| Amlodipine | ACTIVE_COMPARATOR | Participants, first treated with 5 mg of amlodipine for 4 weeks to determine if they were not adequately responding to amlodipine (had an office msSBP ≥145 mmHg and \<180 mmHg) and who met all inclusion and exclusion criteria), were randomized to receive 5 mg of amlodipine and placebo to LCZ696 for 8 weeks. |
| LCZ696 400 mg plus other hypertension (HTN) medications | EXPERIMENTAL | All participants were started on LCZ696 200 mg once daily on day 1. For participants who received LCZ696 400 mg and did not achieve msDBP \< 90 mmHg and msSBP \< 140 mmHg at or after week 4 and had no signs of safety concerns, another class of antihypertensive drugs (other than Angiotensin II receptor blockers or Angiotensin Converting Enzyme Inhibitor (ACEi) could be added, or the dose of concomitant antihypertensive drugs could be increased as per the package insert. Participants who received LCZ696 400 mg once daily did not change their dose for the remainder of the study. |
| LCZ696 100 mg | EXPERIMENTAL | All participants were started on LCZ696 100 mg once daily on day 1. |
| Valsartan 160 mg | ACTIVE_COMPARATOR | One capsule Valsartan 160 mg and 1 tablet placebo to Valsartan/Amlodipine taken orally once daily at approximately 9:00 AM for 8 weeks |
| Valsartan/amlodipine 160/5 mg | EXPERIMENTAL | One film-coated tablet Valsartan/amlodipine 160/5 mg and 1 capsule Placebo to Valsartan taken orally once daily at approximately 9:00 AM for 8 weeks |
| Single-Blind Run-In Valsartan 160 mg | OTHER | Single-Blind Run-In treatment with one capsule Valsartan 160 mg taken orally once daily at approximately 9:00 AM for 4 weeks. |
| 1 | ACTIVE_COMPARATOR | - |
| 2 | ACTIVE_COMPARATOR | - |
| 3 | ACTIVE_COMPARATOR | - |
| 4 | EXPERIMENTAL | - |
| CKD patients: Valsartan+enalapril | EXPERIMENTAL | - |
| CKD patients: Enalapril | ACTIVE_COMPARATOR | - |
| Non-CKD patients: Valsartan | EXPERIMENTAL | - |
| Non-CKD patients: Enalapril | ACTIVE_COMPARATOR | - |
| Valsartan Open Label | EXPERIMENTAL | Extemporaneous oral suspension prepared from valsartan tablets was administered to participants once daily. The starting dose of valsartan was 1 mg/kg, escalated to 2 mg/kg or 4 mg/kg based on mean sitting systolic blood pressure (MSSBP) control after 2 weeks up to 18 weeks. |
| Low Dose | EXPERIMENTAL | - |
| Medium Dose | EXPERIMENTAL | - |
| High Dose | EXPERIMENTAL | - |
| Amlodipine + Valsartan | EXPERIMENTAL | Participants received 160 mg Valsartan and 5 mg amlodipine orally once a day for 52 weeks. If blood pressure was not normalized at week 4, treatment was uptitrated to valsartan/amlodipine 160/10 mg. Participants with still uncontrolled hypertension could receive add-on antihypertensive medication. |
| Losartan + Hydrochlorothiazide | ACTIVE_COMPARATOR | Participants received 100 mg losartan and 12.5 mg Hydrochlorothiazide (HCT) orally once a day for 52 weeks. If blood pressure was not normalized at week 4, treatment was uptitrated to losartan/HCT 100/25 mg, respectively, until end of study. Participants with still uncontrolled hypertension could receive add-on antihypertensive medication. |
| Valsartan + Amlodipine 80/5 mg | EXPERIMENTAL | Valsartan 80 mg or Amlodipine 5 mg ---\> Valsartan + Amlodipine 80 / 5 mg |
| Valsartan + Amlodipine 80/5 mg + Diuretic | EXPERIMENTAL | Valsartan + Amlodipine 80 / 5 mg + Diuretic |
| Valsartan/amlodipine 80/5 mg | EXPERIMENTAL | - |
| Amlodipine 5 mg | ACTIVE_COMPARATOR | - |
| Valsartan 80 mg | ACTIVE_COMPARATOR | - |
| Valsartan 320 mg | EXPERIMENTAL | - |
| Enalapril 10 mg | ACTIVE_COMPARATOR | - |
| Enalapril 20 mg | ACTIVE_COMPARATOR | - |
| Enalapril 40 mg | ACTIVE_COMPARATOR | - |
| Amlodipine 10 mg | ACTIVE_COMPARATOR | Eight (8) weeks of treatment with amlodipine 10 mg (two 5 mg capsules). Together with the active medication, the patients received a placebo that matched valsartan 160 mg. At Week 8, patients were switched and treated with the combination of valsartan/amlodipine 160/5 mg and a placebo that matched amlodipine 5 mg for an additional 4 weeks until the end of the study. The three capsules were taken by mouth with water once daily in the morning, regardless of meals. Patients were instructed not to take their study medication the morning of their study visits. Instead, they brought the study medication with them to the site and took it there as instructed by the investigator. |
| Valsartan 160 mg + nateglinide 60 mg | EXPERIMENTAL | For the first 2 weeks of treatment, patients took the combination of nateglinide 30 mg (3 times daily, ante cibum \[ac\] before meals) and valsartan 80 mg (once daily \[od\] in the morning). After 2 weeks, patients were up-titrated to nateglinide 60 mg ac and valsartan 160 mg od. |
| Valsartan 160 mg + nateglinide placebo | EXPERIMENTAL | For the first 2 weeks of treatment, patients took valsartan 80 mg capsules (once daily \[od\] in the morning). After 2 weeks, patients were up-titrated to 160 mg valsartan od. Patients also received nateglinide placebo tablets (3 times daily, ante cibum \[ac\] before meals). |
| Nateglinide 60 mg + valsartan placebo | EXPERIMENTAL | For the first 2 weeks of treatment, patients took nateglinide 30 mg tablets (3 times daily, ante cibum \[ac\] before meals). After 2 weeks, patients were uptitrated to 60 mg nateglinide ac. Patients also received valsartan placebo capsules (once daily \[od\] in the morning). |
| Placebo | PLACEBO_COMPARATOR | Patients took 3 nateglinide placebo tablets (3 times daily, ante cibum \[ac\] before meals) and 1 valsartan placebo capsule (once daily \[od\] in the morning). |
| LCZ696 BID | EXPERIMENTAL | Patients were treated with LCZ696. The target dose level was 200 mg p.o. b.i.d. |
| Placebo BID | PLACEBO_COMPARATOR | Placebo to LCZ696 |
| Part 1: LCZ696 open label | EXPERIMENTAL | LCZ696 open label: For Age Groups 1 and 2, either 1) 0.8 mg/kg or 2) 3.1 mg/kg or both. For Age Group 3, either 1) 0.4 mg/kg or 2) 1.6 mg/kg or both. After LCZ696 PK assessment, patients will be maintained on open-label Enalapril provided locally by the study site, or standard of care also provided locally by the study site, for heart failure treatment, if patient intended to participate in Part 2. |
| Part 2: Enalapril | ACTIVE_COMPARATOR | The target dose for enalapril is 0.2 mg/kg bid (0.4 mg/kg total daily dose) with a maximum dose of 10 mg bid (20 mg total daily dose). Administered in a double-blind fashion. |
| Part 2: LCZ696 | EXPERIMENTAL | LCZ696 3.125 mg granules and adult formulation (50, 100, 200 mg) can be given based on patient weight. Administered in a double-blind fashion. |
| LCZ696 Condensed | EXPERIMENTAL | Up-titration to LCZ696 200 mg twice daily (bid) over 3 weeks |
| LCZ696 Conservative | EXPERIMENTAL | Up-titration to LCZ696 200 mg bid over 6 weeks |
| Olmesartan | ACTIVE_COMPARATOR | Randomized patients received olmesartan once daily for four weeks, then force-titrated to a higher dose at Week 4 and stayed on this dose of olmesartan once daily for the remainder of the treatment period. At week 12, patients with uncontrolled BP allowed to have amlodipine then hydrochlorothiazide (HCTZ) added at intervals of 4 weeks from Week 12 up to Week 24. To maintain the double dummy, double-blind design, 2 tablets (LCZ696 matching placebo) and 1 capsule (olmesartan) were given during the entire study. |
| Period 1:Sildenafil;Period 2:LCZ696;Period 3:LCZ696+Sildenafil | EXPERIMENTAL | During Treatment Period 1, on study Day 1, participants received a single dose of sildenafil followed by wash out on Day 2. In Period 2 (study Days 3-7), participants received LCZ696 once daily. In Period 3, on study Day 8, participants received LCZ696 , co-administered at the same time with a single dose of sildenafil. |
| Group 1: mild hepatic impairment | EXPERIMENTAL | LCZ696 200 mg, given as a single oral dose |
| Group 2: moderate hepatic impairment | EXPERIMENTAL | LCZ696 200 mg, given as a single oral dose |
| Group 3: healthy volunteers | EXPERIMENTAL | LCZ696 200 mg, given as a single oral dose. Each healthy volunteer will match in race, age (±5 years), gender, weight (±15%) to an individual subject with hepatic impairment in groups 1 and 2 |
| LCZ696 followed by Valsartan | EXPERIMENTAL | Period 1: LCZ696 400mg QD for 4 weeks then washout followed by Period 2: Valsartan 320mg QD for 4 weeks |
| Valsartan followed by LCZ696 | EXPERIMENTAL | Period 1: Valsartan 320mg QD for 4 weeks then washout followed by Period 2: LCZ696 400mg QD for 4 weeks |
| LCZ696 to Valsartan - Heart Failure (HF) cohort | EXPERIMENTAL | Participants in this arm received Valsartan 160 mg twice daily (bid) during open-label run-in, LCZ696 200 mg bid double blind treatment during period 1, Valsartan 160 mg bid during wash-out, and Valsartan 160 mg bid double blind treatment during period 2. |
| Valsartan to LCZ696 - HF Cohort | EXPERIMENTAL | Participants in this arm received Valsartan 160 mg twice daily bid during open-label run-in, Valsartan 160 mg bid during period 1, Valsartan 160 mg bid during wash-out, and LCZ696 200 mg bid double blind treatment during period 2. |
| LCZ696 to Valsartan - Hypertension (HTN) cohort | EXPERIMENTAL | Participants in this arm received Valsartan 320 mg once daily (qd) during open-label run-in, LCZ696 400 mg qd double blind treatment during period 1, Valsartan 320 mg qd during wash-out, and Valsartan 320 mg qd double blind treatment during period 2. |
| Valsartan to LCZ696 - HTN cohort | EXPERIMENTAL | Participants in this arm received Valsartan 320 mg qd during open-label run-in, Valsartan 320 mg qd during period 1, Valsartan 320 mg qd during wash-out, and LCZ696 400 qd bid double blind treatment during period 2. |
| VAL + AHU 400 mg | EXPERIMENTAL | Participants were started with AHU377 100 mg + valsartan 160 mg every day (qd) for 1 week, then were uptitrated to AHU377 200 mg + valsartan 320 mg qd for another week, and then were uptitrated to AHU377 400 mg + valsartan 320 mg for the remaining 6 weeks. |
| VAL + AHU 200 mg | EXPERIMENTAL | Participants were started with AHU377 100 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 200 mg + valsartan 320 mg qd for the remaining 7 weeks. |
| VAL + AHU 100 mg | EXPERIMENTAL | Participants were started with AHU377 50 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 100 mg + valsartan 320 mg for the remaining 7 weeks. |
| VAL + AHU 50 mg | EXPERIMENTAL | Participants were started with AHU377 50 mg + valsartan 160 mg qd for 1 week and then were uptitrated to AHU377 50 mg + valartan 320 mg qd for the remaining 7 weeks. |
| VAL 320 mg | EXPERIMENTAL | Participants were started with valsartan 160 mg qd for 1 week and then were uptitrated to valsartan 320 mg qd for the remaining 7 weeks. |
| LCZ 400 mg | EXPERIMENTAL | Participants were started with LCZ696 200 mg qd for 1 week and then were uptitrated to LCZ696 400 mg qd for the remaining 7 weeks. |
| Stable heart failure patients | EXPERIMENTAL | - |
| AHU377 200 mg | EXPERIMENTAL | Participants received AHU377 200 mg and matching placebo to LCZ696 and Valsartan (5 tablets and 2 capsules) daily. |
| Valsartan + amlodipine 40/2.5 mg | EXPERIMENTAL | - |
| Valsartan + amlodipine 40/5 mg | EXPERIMENTAL | - |
| Valsartan + amlodipine 80/2.5 mg | EXPERIMENTAL | - |
| Valsartan 40 mg | ACTIVE_COMPARATOR | - |
| Amlodipine 2.5 mg | ACTIVE_COMPARATOR | - |
| Valsartan 20 mg or 40 mg | EXPERIMENTAL | - |
| Name | Type | Description |
|---|---|---|
| LCZ696 | DRUG | sacubitril/valsartan 200 mg = 97 mg/103 mg bid sacubitril/valsartan film-coated tablets |
| Enalapril matching placebo | DRUG | Placebo to Enalapril 10 mg film-coated tablets |
| Enalapril | DRUG | Enalapril 10 mg film-coated tablets |
| LCZ696 matching placebo | DRUG | Placebo to LCZ696 200 mg = 97 mg/103 mg bid sacubitril/valsartan film-coated tablets |
| LCZ696 (Sacubitril/Valsartan) | DRUG | LCZ696 (sacubitril/valsartan) was available in 24 mg/26 mg, 49 mg/51 and 97 mg/103 mg mg film-coated tablets |
| Placebo of LCZ696 (Sacubitril/Valsartan) | DRUG | Placebo of LCZ696 (sacubitril/valsartan) was available to match 24 mg/26 mg, 49 mg/51 and 97 mg/103 mg mg film-coated tablets |
| Placebo of Enalapril | DRUG | Placebo of Enalapril was available to match 2.5 mg, 5 mg and 10 mg film-coated tablets |
| Ramipril | DRUG | Ramipril 1.25 mg, 2.5 mg, and 5 mg oral capsules |
| Placebo of LCZ696 | DRUG | Matching placebo of LCZ696 tablets |
| Placebo of ramipril | DRUG | Matching placebo of ramipril capsule |
| Valsartan | DRUG | Valsartan (VAL489) 40 mg and 80 mg tablets, two doses for 1 day to patients who were previously treated with ACE inhibitors receiving the last dose of that agent during the last 36 hours prior to randomization |
| Placebo of valsartan | DRUG | matching placebo of valsartan for one day to patients who will be randomized to received ramipril |
| Placebo to LCZ696 | DRUG | LCZ696 Placebo 50 mg, 100 mg and 200 mg film-coated tablets |
| Placebo to Enalapril | DRUG | Enalapril Placebo 2.5 mg, 5 mg and 10 mg tablets |
| Olmesartan | DRUG | - |
| Placebo of Olmesartan | DRUG | - |
| Amlodipine | DRUG | Amlodipine will use tablets available at a strength of 5 mg. Patients will be instructed to take the prescribed medication once a day. |
| Placebo | DRUG | Matching placebo to LCZ696 |
| Hydrochlorothiazide | DRUG | added to valsartan after week 8 if the MSSBP and/or MSDBP was higher than 95th percentile for age, gender and height under the maintenance valsartan dose |
| Valsartan/amlodipine 160/5 mg | DRUG | Valsartan/amlodipine 160/5mg film coated tablets taken orally once daily. |
| Valsartan 160 mg | DRUG | Valsartan 160 mg capsule taken orally once daily. |
| Valsartan/hydrochlorothiazide (HCTZ) | DRUG | - |
| Valsartan/amlodipine | DRUG | - |
| Amlodipine/hydrochlorothiazide(HCTZ) | DRUG | - |
| Valsartan/amlodipine/hydrochlorothiazide(HCTZ) | DRUG | - |
| placebo matched to enalapril | DRUG | Placebo matched to enalapril. All study medications were taken orally once daily, at approximately the same time each day, with or without food. |
| placebo matched to valsartan | DRUG | placebo matched to valsartan. All study medications were taken orally once daily, at approximately the same time each day, with or without food. |
| Valsartan 0.25 mg/kg | DRUG | once daily |
| Valsartan 1.0 mg/kg | DRUG | once daily |
| Valsartan 4.0 mg/kg | DRUG | once daily |
| Losartan | DRUG | 100 mg tablets taken orally once daily in the morning. |
| Valsartan + Amlodipine besilate | DRUG | During the run-in period, either Valsartan 80 mg or Amlodipine 5 mg tablet was given once daily. Throughout the Valsartan + Amlodipine treatment period, a Valsartan + Amlodipine tablet 80/5 mg was given once daily at around 8:00 AM in the morning. |
| Valsartan/amlodipine 80/5 mg | DRUG | 1 valsartan/amlodipine 80/5 mg tablet and 1 placebo capsule matching amlodipine 5 mg to be taken with water at approximately 8:00 a.m. once daily, except on the morning of every scheduled study visit, when study drug was taken after the completion of all other study procedures. |
| Amlodipine 5 mg | DRUG | 1 amlodipine 5 mg capsule and 1 placebo tablet matching valsartan/amlodipine 80/5 mg to be taken with water at approximately 8:00 a.m. once daily, except on the morning of every scheduled study visit, when study drug was taken after the completion of all other study procedures. |
| Valsartan 80 mg | DRUG | 1 valsartan 80 mg capsule, 1 placebo tablet to match valsartan/amlodipine 80/5 mg once daily |
| Valsartan 160 mg capsules | DRUG | - |
| Amlodipine 5 mg capsules | DRUG | - |
| valsartan + amlodipine | DRUG | - |
| Valsartan plus Hydrochlorothiazide | DRUG | - |
| Candesartan plus Hydrochlorothiazide | DRUG | - |
| Valsartan + HCTZ | DRUG | - |
| Amlodipine + HCTZ | DRUG | - |
| Valsartan + amlodipine + HCTZ | DRUG | - |
| Valsartan + Hydrochlorothiazide | DRUG | - |
| simvastatin | DRUG | - |
| valsartan + simvastatin | DRUG | - |
| lisinopril | DRUG | - |
| irbesartan | DRUG | - |
| valsartan+amlodipine combination | DRUG | - |
| VALSARTAN, VALSARTAN+HYDROCHLOROTHIAZIDE | DRUG | - |
| valsartan+amlodipine | DRUG | - |
| valsartan+amlodipine combination, valsartan, amlodipine | DRUG | - |
| Valsartan 160 mg + nateglinide 60 mg | DRUG | The double-blinding of the randomized study medication was maintained by the use of identical placebo and active tablets and capsules for nateglinide and valsartan, respectively. Patients were instructed not to take the morning dose of either medication nor to eat breakfast on the day of a scheduled study visit, but to wait until after the visit was completed. Patients not tolerating the higher dose (Level 2) were down-titrated to receive Level 1. Patients not tolerating the lower dose (Level 1) had a treatment interruption. Starting at Week 2 and throughout the study, attempts were to be made to reach the highest dose level (Level 2), if medically acceptable. Following each change in dose level or re-initiation of treatment, tolerability was assessed after 2 weeks of exposure. |
| Valsartan 160 mg + nateglinide placebo | DRUG | The double-blinding of the randomized study medication was maintained by the use of identical placebo and active tablets and capsules for nateglinide and valsartan, respectively. Patients were instructed not to take the morning dose of either medication nor to eat breakfast on the day of a scheduled study visit, but to wait until after the visit was completed. Patients not tolerating the higher dose (Level 2) were down-titrated to receive Level 1. Patients not tolerating the lower dose (Level 1) had a treatment interruption. Starting at Week 2 and throughout the study, attempts were to be made to reach the highest dose level (Level 2), if medically acceptable. Following each change in dose level or re-initiation of treatment, tolerability was assessed after 2 weeks of exposure. |
| Nateglinide 60 mg + valsartan placebo | DRUG | The double-blinding of the randomized study medication was maintained by the use of identical placebo and active tablets and capsules for nateglinide and valsartan, respectively. Patients were instructed not to take the morning dose of either medication nor to eat breakfast on the day of a scheduled study visit, but to wait until after the visit was completed. Patients not tolerating the higher dose (Level 2) were down-titrated to receive Level 1. Patients not tolerating the lower dose (Level 1) had a treatment interruption. Starting at Week 2 and throughout the study, attempts were to be made to reach the highest dose level (Level 2), if medically acceptable. Following each change in dose level or re-initiation of treatment, tolerability was assessed after 2 weeks of exposure. |
| Valsartan placebo + nateglinide placebo | DRUG | The double-blinding of the randomized study medication was maintained by the use of identical placebo and active tablets and capsules for nateglinide and valsartan, respectively. Patients were instructed not to take the morning dose of either medication nor to eat breakfast on the day of a scheduled study visit, but to wait until after the visit was completed. Patients not tolerating the higher dose (Level 2) were down-titrated to receive Level 1. Patients not tolerating the lower dose (Level 1) had a treatment interruption. Starting at Week 2 and throughout the study, attempts were to be made to reach the highest dose level (Level 2), if medically acceptable. Following each change in dose level or re-initiation of treatment, tolerability was assessed after 2 weeks of exposure. |
| Valsartan and simvastatin | DRUG | - |
| Olmesartan matching placebo | DRUG | Olmesartan matching placebo capsule |
| Sildenafil | DRUG | Sildenafil 50 mg single dose was administered alone for 1 days and in combination with LCZ696 400mg QD for 1 day |
| AHU377 | DRUG | AHU377 was supplied in tablets in blister cards in 50 mg and 100 mg strengths. |
| Hydrochlorothiazide (HCTZ) | DRUG | Optional add-on of hydrochlorothiazide (HCTZ) (12.5-25 mg) was allowed (as applicable per local country regulations) for adequate blood pressure control. |
| Valsartan + amlodipine 40/2.5 mg | DRUG | Valsartan + amlodipine 40/2.5 mg tablet plus 3 tablet and 2 capsule placebos taken once daily |
| Valsartan + amlodipine 40/5 mg | DRUG | Valsartan + amlodipine 40/5mg tablet plus 3 tablet and 2 capsule placebos taken once daily |
| Valsartan + amlodipine 80/2.5 mg | DRUG | Valsartan + amlodipine 80/2.5 mg tablet plus 3 tablet and 2 capsule placebos taken once daily |
| Valsartan + amlodipine 80/5 mg | DRUG | Valsartan + amlodipine 80/5mg tablet plus 3 tablet and 2 capsule placebos taken once daily |
| Valsartan 40 mg | DRUG | Valsartan 40 mg tablet plus 3 tablet and 2 capsule placebos taken once daily |
| Amlodipine 2.5 mg | DRUG | Amlodipine 2.5 mg capsule plus 4 tablet and 1 capsule placebos taken once daily |
| valsartan 160 mg BID | DRUG | - |
| Valsartan (VAL489) | DRUG | - |
Key Inclusion Criteria: * Patients with a diagnosis of chronic heart failure (NYHA class II) and reduced ejection fraction (LVEF \< 40%) * Patients must be living in a stable and sexually active heterosexual partnership for at least 6 months prior study start * Patients must have a mild to moderate...
LCZ696 is being studied for cardiovascular conditions including acute myocardial infarction, chronic heart failure, chronic heart failure with reduced ejection fraction, hypertrophic cardiomyopathy, and essential hypertension. It is an investigational therapy in Phase 3 development, not yet approved for any indication.
LCZ696 is developed by Novartis AG, which trades under the ticker NVS. Novartis is the sponsor of the clinical trials evaluating LCZ696 across multiple cardiovascular indications.
LCZ696 is in Phase 3 clinical development. Six trials have been completed, including Phase 2 and Phase 3 studies, with no active trials currently listed. The Phase 3 program includes the PARADISE-MI trial and other studies in heart failure and related conditions.
LCZ696 has been evaluated in completed trials including NCT04164732 (Phase 2 in hypertrophic cardiomyopathy), NCT03917459 (Phase 3 in heart failure with reduced ejection fraction and erectile dysfunction), NCT02924727 (Phase 3 in acute myocardial infarction), and NCT02900378 (Phase 3 in chronic heart failure with reduced ejection fraction). All are completed.