Chronic Heart Failure (CHF)
Conditions
Keywords
heart failure, cognition, positron emission tomography, magnetic resonance imaging, LCZ696, valsartan, Chronic heart failure, CHF
Brief summary
This study was a multi-center, randomized, double-blind, parallel group, active comparator trial designed to evaluate the overall effect of LCZ696 compared to valsartan on cognitive function as assessed by the CogState comprehensive cognitive battery in patients with Heart failure and preserved ejection fraction (HFpEF).
Detailed description
The Screening epoch of approximately 3 weeks was used to assess eligibility. Eligible patients then entered the single-blind treatment run-in epoch (Active Run-In Epoch), which was designed to assess patient's tolerability to study drug and to determine patients who were likely to stay on study drug for the duration of the trial. The treatment run-in consisted of valsartan 40 mg bid (if necessary), followed by valsartan 80 mg bid, and then followed by LCZ696 100 mg bid, over 3 to 8 weeks duration. Patients unable to tolerate either valsartan or LCZ696 at the prescribed doses during the treatment run-in were not eligible for randomization and were discontinued from the study. At randomization (Visit 199/201), eligible patients were randomized 1:1 to receive either LCZ696 200 mg bid or valsartan 160 mg bid (double-blind period). Patients who terminated the study early were expected, and were encouraged, to attend all the protocol specified study visits, to perform all measurements as stipulated in the visit schedule and to remain in follow up for the duration of the trial.
Interventions
DRUGLCZ696
LCZ696 50, 100, and 200 mg tablets taken orally twice daily with matching placebo for valsartan
DRUGValsartan
Valsartan 40, 80, and 160 mg tablets taken orally twice daily with matching placebo for LCZ696
Placebo to match LCZ696 50 mg, 100 mg, and 200 mg tablets
Placebo to match valsartan 40 mg, 80 mg, and 160 mg tablets
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
60 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Chronic heart failure with current symptoms NYHA class II-IV * Left ventricular ejection fraction \> 40% * NT-proBNP \>= 125 pg/mL at screening visit * Patient with evidence of adequate functioning to complete study assessments Key
Exclusion criteria
* Patients with acute decompensated heart failure requiring augmented therapy with diuretics, vasodilators and/or inotropic drugs * Acute coronary syndrome (including myocardial infarction (MI)), cardiac surgery, other major CV surgery, or urgent percutaneous coronary intervention (PCI), carotid surgery or carotid angioplasty, history of stroke or transient ischemic attack within the 3 months prior to Screening visit or an elective PCI within 30 days prior to Screening visit * Patients with history of hereditary or idiopathic angioedema or angioedema related to previous ACEi or ARB therapies * Patients who require treatment with 2 or more of the following: an ACEi, an ARB or a renin inhibitor * Patients with one of the following: 1. Patients with serum potassium \>5.2 mmol/L (mEq/L) at Screening visit 2. Patients with serum potassium \>5.4 mmol/L (mEq/L) at any visit during run-in treatment period or at randomization visit 3. Systolic blood pressure (SBP) ≥180 mmHg at Screening visit, or 4. SBP \<110 mmHg at Screening visit, or 5. SBP \<100 mmHg or symptomatic hypotension as determined by the investigator at Visit 103 or at randomization visit 6. Body mass index (BMI) \>45 kg/m\^2 * Patients with 1. known pericardial constriction, genetic hypertrophic cardiomyopathy, infiltrative cardiomyopathy 2. hemodynamically significant obstructive valvular disease * Life-threatening or uncontrolled dysrhythmia, including symptomatic or sustained ventricular tachycardia and atrial fibrillation or flutter with a resting ventricular rate \>110 beats per minute * Inability to perform cognitive battery or other study evaluations based on significant motor (e.g. hemiplegia, muscular-skeletal injury) or sensory (blindness, decreased or uncorrected visual or auditory acuity) skill * Clinically significant cerebral pathology for example large cerebral aneurysm or space occupying lesion that may impact cognition as assessed by central MRI reader * Mini mental state examination score less than 24 at screening * Patients with a clinical diagnosis of Alzheimer's disease or other dementia syndromes or any indication for or current treatment with cholinesterase inhibitors and/or another prescription AD treatment (e.g. memantine).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the CogState Global Cognitive Composite Score (GCCS) | Baseline, month 36 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Cortical Composite Standardized Uptake Value Ratio (SUVr) | Baseline, month 36 | The effects of LCZ696 compared to valsartan on Aβ deposition in the brain over 3 years were evaluated in a subset of patients using amyloid positron emission tomography (PET) imaging by assessing the change from baseline in cortical composite SUVr. PET imaging was performed at selected PET-capable centers on all eligible patients participating in the substudy. Sites with patients performing the PET scan were a subset of the overall patient population and overall sites for the study. Change from baseline to 3 years was analyzed based on an ANCOVA model with treatment, age, MMSE, amyloid status (+ve/-ve) stratification factors, region, APOE4 status and cerebrovascular disease burden as fixed effects, with baseline SUVr and treatment-by-baseline SUVr interaction as covariates for each of these imputed datasets. Results were obtained by applying Rubin's rules on the estimates from the imputed datasets. |
| Change From Baseline in Individual Cognitive Domains | Baseline, month 36 | The effects of LCZ696 compared to valsartan on the individual cognitive domains (memory, executive function, and attention) over 3 years were evaluated by assessing the individual components of the CogState cognitive battery. Composite scores for the 3 individual cognitive domains were generated by combining the standardized z-scores of selected tests from the CogState cognitive battery. Each composite score was the average of the non-missing individual test z-scores. A higher score indicated better cognitive function. |
| Change From Baseline in the Summary Score of the Instrumental Activities of Daily Living (IADL) | Baseline, month 36 | The effects of LCZ696 compared to valsartan on the changes in IADL over 3 years were evaluated by as assessing the Functional activities questionnaire (FAQ) summary scores. The FAQ is a 30-point questionnaire that is made up of 10 questions that reflect a patient's ability to perform activities of daily living and to function independently. A score of 0 represents no impairment and a score of 30 represents severe impairment. |
Countries
Argentina, Australia, Belgium, Bulgaria, Canada, Croatia, France, Germany, Italy, Lithuania, Netherlands, Poland, Russia, South Korea, Spain, Switzerland, Taiwan, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
The study was conducted in 137 centers across 20 countries
Pre-assignment details
A total of 1200 patients were screened. Of them, 706 patients entered the run-in period. Patients entered different parts of the treatment run-in phase based on their use of renin angiotensin system blockade medications at the time of enrolment (valsartan 40 mg bid (if necessary), followed by valsartan 80 mg bid, and then followed by LCZ696 100 mg bid, over 3 to 8 weeks duration)
Participants by arm
| Arm | Count |
|---|---|
| LCZ696 200 mg Bid 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. | 295 |
| Valsartan 160 mg Bid 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. | 297 |
| Total | 592 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Double-Blind Period | Adverse Event | 0 | 0 | 3 |
| Double-Blind Period | Death | 0 | 28 | 39 |
| Double-Blind Period | Lost to Follow-up | 0 | 4 | 4 |
| Double-Blind Period | Non-compliance with study treatment | 0 | 0 | 1 |
| Double-Blind Period | Patient/guardian decision | 0 | 10 | 13 |
| Double-Blind Period | Physician Decision | 0 | 2 | 0 |
| LCZ696 Run-in Period | Adverse Event | 38 | 0 | 0 |
| LCZ696 Run-in Period | Death | 2 | 0 | 0 |
| LCZ696 Run-in Period | Lost to Follow-up | 1 | 0 | 0 |
| LCZ696 Run-in Period | Non-compliance with study treatment | 3 | 0 | 0 |
| LCZ696 Run-in Period | Patient/guardian decision | 16 | 0 | 0 |
| LCZ696 Run-in Period | Physician Decision | 1 | 0 | 0 |
| LCZ696 Run-in Period | Protocol deviation | 6 | 0 | 0 |
| Valsartan Run-in Period | Adverse Event | 31 | 0 | 0 |
| Valsartan Run-in Period | Death | 1 | 0 | 0 |
| Valsartan Run-in Period | Non-compliance with study treatment | 1 | 0 | 0 |
| Valsartan Run-in Period | Patient/guardian decision | 9 | 0 | 0 |
| Valsartan Run-in Period | Physician Decision | 1 | 0 | 0 |
| Valsartan Run-in Period | Protocol deviation | 4 | 0 | 0 |
Baseline characteristics
| Characteristic | LCZ696 200 mg Bid | Valsartan 160 mg Bid | Total |
|---|---|---|---|
| Age, Continuous | 72.27 years STANDARD_DEVIATION 6.749 | 72.61 years STANDARD_DEVIATION 7.043 | 72.44 years STANDARD_DEVIATION 6.895 |
| Race/Ethnicity, Customized Asian | 11 Participants | 12 Participants | 23 Participants |
| Race/Ethnicity, Customized Black | 6 Participants | 9 Participants | 15 Participants |
| Race/Ethnicity, Customized Caucasian | 273 Participants | 271 Participants | 544 Participants |
| Race/Ethnicity, Customized Native American | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 3 Participants | 5 Participants |
| Race/Ethnicity, Customized Unknown | 1 Participants | 2 Participants | 3 Participants |
| Sex: Female, Male Female | 134 Participants | 143 Participants | 277 Participants |
| Sex: Female, Male Male | 161 Participants | 154 Participants | 315 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 318 | 1 / 675 | 2 / 659 | 28 / 295 | 39 / 297 |
| other Total, other adverse events | 40 / 318 | 76 / 675 | 136 / 659 | 238 / 295 | 245 / 297 |
| serious Total, serious adverse events | 3 / 318 | 6 / 675 | 27 / 659 | 145 / 295 | 161 / 297 |
Outcome results
Primary
Change From Baseline in the CogState Global Cognitive Composite Score (GCCS)
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.
Time frame: Baseline, month 36
Population: The overall number of participants analyzed represents the participants in the Safety Set (SAF) with non-missing value of CogState GCCS at both, baseline and month 36.~The SAF comprised all randomized patients who received at least one dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LCZ696 200 mg Bid | Change From Baseline in the CogState Global Cognitive Composite Score (GCCS) | -0.0902 Global Cognitive Composite Score | Standard Error 0.0372 |
| Valsartan 160 mg Bid | Change From Baseline in the CogState Global Cognitive Composite Score (GCCS) | -0.0722 Global Cognitive Composite Score | Standard Error 0.0383 |
Comparison: Repeated measure ANCOVAp-value: 0.736395% CI: [-0.123, 0.087]ANCOVA
Secondary
Change From Baseline in Cortical Composite Standardized Uptake Value Ratio (SUVr)
The effects of LCZ696 compared to valsartan on Aβ deposition in the brain over 3 years were evaluated in a subset of patients using amyloid positron emission tomography (PET) imaging by assessing the change from baseline in cortical composite SUVr. PET imaging was performed at selected PET-capable centers on all eligible patients participating in the substudy. Sites with patients performing the PET scan were a subset of the overall patient population and overall sites for the study. Change from baseline to 3 years was analyzed based on an ANCOVA model with treatment, age, MMSE, amyloid status (+ve/-ve) stratification factors, region, APOE4 status and cerebrovascular disease burden as fixed effects, with baseline SUVr and treatment-by-baseline SUVr interaction as covariates for each of these imputed datasets. Results were obtained by applying Rubin's rules on the estimates from the imputed datasets.
Time frame: Baseline, month 36
Population: The overall number of participants analyzed represents the participants in the PET substudy set (PET) with non-missing value at both, baseline and month 36.~The PET comprised SAF patients who participated in PET substudy and had non-missing baseline assessment.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| LCZ696 200 mg Bid | Change From Baseline in Cortical Composite Standardized Uptake Value Ratio (SUVr) | Global cortical composite | 0.0273 value ratio (SUVr) | Standard Error 0.0114 |
| LCZ696 200 mg Bid | Change From Baseline in Cortical Composite Standardized Uptake Value Ratio (SUVr) | Cingulum posterior composite | 0.0416 value ratio (SUVr) | Standard Error 0.0113 |
| LCZ696 200 mg Bid | Change From Baseline in Cortical Composite Standardized Uptake Value Ratio (SUVr) | Frontal lobe composite | 0.0218 value ratio (SUVr) | Standard Error 0.0117 |
| LCZ696 200 mg Bid | Change From Baseline in Cortical Composite Standardized Uptake Value Ratio (SUVr) | Parietal lobe composite | 0.0231 value ratio (SUVr) | Standard Error 0.0119 |
| LCZ696 200 mg Bid | Change From Baseline in Cortical Composite Standardized Uptake Value Ratio (SUVr) | Temporal lobe composite | 0.0249 value ratio (SUVr) | Standard Error 0.011 |
| LCZ696 200 mg Bid | Change From Baseline in Cortical Composite Standardized Uptake Value Ratio (SUVr) | White matter composite | 0.0061 value ratio (SUVr) | Standard Error 0.0094 |
| Valsartan 160 mg Bid | Change From Baseline in Cortical Composite Standardized Uptake Value Ratio (SUVr) | Temporal lobe composite | 0.0418 value ratio (SUVr) | Standard Error 0.0097 |
| Valsartan 160 mg Bid | Change From Baseline in Cortical Composite Standardized Uptake Value Ratio (SUVr) | Global cortical composite | 0.0564 value ratio (SUVr) | Standard Error 0.0101 |
| Valsartan 160 mg Bid | Change From Baseline in Cortical Composite Standardized Uptake Value Ratio (SUVr) | Parietal lobe composite | 0.0532 value ratio (SUVr) | Standard Error 0.0104 |
| Valsartan 160 mg Bid | Change From Baseline in Cortical Composite Standardized Uptake Value Ratio (SUVr) | Cingulum posterior composite | 0.0876 value ratio (SUVr) | Standard Error 0.0109 |
| Valsartan 160 mg Bid | Change From Baseline in Cortical Composite Standardized Uptake Value Ratio (SUVr) | White matter composite | -0.0072 value ratio (SUVr) | Standard Error 0.0083 |
| Valsartan 160 mg Bid | Change From Baseline in Cortical Composite Standardized Uptake Value Ratio (SUVr) | Frontal lobe composite | 0.0434 value ratio (SUVr) | Standard Error 0.0104 |
Comparison: Multiple Imputation ANCOVA in Global cortical compositep-value: 0.057995% CI: [-0.0593, 0.001]ANCOVA
Secondary
Change From Baseline in Individual Cognitive Domains
The effects of LCZ696 compared to valsartan on the individual cognitive domains (memory, executive function, and attention) over 3 years were evaluated by assessing the individual components of the CogState cognitive battery. Composite scores for the 3 individual cognitive domains were generated by combining the standardized z-scores of selected tests from the CogState cognitive battery. Each composite score was the average of the non-missing individual test z-scores. A higher score indicated better cognitive function.
Time frame: Baseline, month 36
Population: The overall number of participants analyzed represents the participants in the Safety Set (SAF) with non-missing value at both, baseline and month 36.~The number analyzed per row represents the participants with a valid value for the corresponding domain.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| LCZ696 200 mg Bid | Change From Baseline in Individual Cognitive Domains | Memory domain | -0.0573 Z-scores | Standard Error 0.0477 |
| LCZ696 200 mg Bid | Change From Baseline in Individual Cognitive Domains | Executive function domain | -0.0375 Z-scores | Standard Error 0.048 |
| LCZ696 200 mg Bid | Change From Baseline in Individual Cognitive Domains | Attention domain | -0.1836 Z-scores | Standard Error 0.0614 |
| Valsartan 160 mg Bid | Change From Baseline in Individual Cognitive Domains | Memory domain | -0.0580 Z-scores | Standard Error 0.049 |
| Valsartan 160 mg Bid | Change From Baseline in Individual Cognitive Domains | Executive function domain | -0.0702 Z-scores | Standard Error 0.0493 |
| Valsartan 160 mg Bid | Change From Baseline in Individual Cognitive Domains | Attention domain | -0.0794 Z-scores | Standard Error 0.0634 |
Comparison: Repeated measure ANCOVA for memory domainp-value: 0.991695% CI: [-0.1339, 0.1353]ANCOVA
Comparison: Repeated measure ANCOVA for executive function domainp-value: 0.634895% CI: [-0.1024, 0.1677]ANCOVA
Comparison: Repeated measure ANCOVA for attention domainp-value: 0.240395% CI: [-0.2783, 0.07]ANCOVA
Secondary
Change From Baseline in the Summary Score of the Instrumental Activities of Daily Living (IADL)
The effects of LCZ696 compared to valsartan on the changes in IADL over 3 years were evaluated by as assessing the Functional activities questionnaire (FAQ) summary scores. The FAQ is a 30-point questionnaire that is made up of 10 questions that reflect a patient's ability to perform activities of daily living and to function independently. A score of 0 represents no impairment and a score of 30 represents severe impairment.
Time frame: Baseline, month 36
Population: The overall number of participants analyzed represents the participants in the Safety Set (SAF) with non-missing value at both, baseline and month 36.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LCZ696 200 mg Bid | Change From Baseline in the Summary Score of the Instrumental Activities of Daily Living (IADL) | 0.5983 FAQ scores | Standard Error 0.2064 |
| Valsartan 160 mg Bid | Change From Baseline in the Summary Score of the Instrumental Activities of Daily Living (IADL) | 0.7089 FAQ scores | Standard Error 0.2115 |
Comparison: Repeated measure ANCOVAp-value: 0.708195% CI: [-0.6906, 0.4696]ANCOVA