Clinical Trials List
Protocol NumberCLCZ696B2320
NCT Number(ClinicalTrials.gov Identfier)NCT02884206
2018-01-03 - 2021-09-30
Phase III
Terminated4
ICD-10I21.3
ST elevation (STEMI) myocardial infarction of unspecified site
ICD-10I50
Heart failure
ICD-9410.92
Acute myocardial infarction of unspecified site, subsequent episode of care
A Multicenter, Randomized, Double-blind, Active-controlled Study to Evaluate the Effects of LCZ696 Compared to Valsartan on Cognitive Function in Patients With Chronic Heart Failure and Preserved Ejection Fraction
-
Trial Applicant
NOVARTIS (TAIWAN) CO., LTD.
-
Sponsor
Novartis Pharmaceuticals
-
Trial scale
Multi-Regional Multi-Center
-
Update
2025/08/20
Investigators and Locations
Principal Investigator
Co-Principal Investigator
- Ping-Yen Liu Division of Cardiovascular Diseases
- Shih-Hung Chan Division of Cardiovascular Diseases
- 李文煌 Division of Cardiovascular Diseases
- 李貽恆 Division of Cardiovascular Diseases
- Ting-Hsing Chao Division of Cardiovascular Diseases
- Cheng-Han Lee Division of Cardiovascular Diseases
- 李威廷 Division of Cardiovascular Diseases
- Ju-Yi Chen Division of Cardiovascular Diseases
- Wei-Chuan Tsai Division of Cardiovascular Diseases
- Chih-Hsin Hsu Division of Cardiovascular Diseases
- Yen-Wen Liu Division of Cardiovascular Diseases
- 李伯增 Division of Cardiovascular Diseases
- Yi-Heng Li Division of Cardiovascular Diseases
- 林志展 Division of Cardiovascular Diseases
- 黃成偉 Division of Cardiovascular Diseases
- 陳柏偉 Division of Cardiovascular Diseases
The Actual Total Number of Participants Enrolled
0 Terminated
Audit
None
Co-Principal Investigator
- 陳恬恩 Division of Cardiovascular Diseases
- 林晏年 Division of Cardiovascular Diseases
- 吳宏彬 Division of Cardiovascular Diseases
- Lien-Cheng Hsiao Division of Cardiovascular Diseases
- Shih-Sheng Chang Division of Cardiovascular Diseases
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
- Wen-Chung Yu Division of Cardiovascular Diseases
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
Audit
None
Co-Principal Investigator
- CHO-KAI WU Division of Cardiovascular Diseases
- Tzung-Dau Wang 未分科
- Yi-Chih Wang 未分科
- 林俊立 未分科
- 游治節 未分科
The Actual Total Number of Participants Enrolled
0 Terminated
Condition/Disease
Chronic Heart Failure (CHF)
Objectives
Primary objective To evaluate the effects of LCZ696 compared to valsartan on cognitive function over 3 yearsin patients with HFpEF as assessed by the CogState cognitive assessment batterySecondary objectives To evaluate the effect of LCZ696 compared to valsartan on -amyloid deposition in thebrain in a subset of patients using positron emission tomography amyloid (PET) imagingover 3 years. To evaluate the effects of LCZ696 compared to valsartan on individual cognitive domains(memory, executive function, and attention) as assessed by the individual components of theCogState battery over 3 years To compare LCZ696 to valsartan in evaluating changes in instrumental activities of dailyliving (IADL) as assessed with Functional Activity Questionnaire (FAQ) over 3 years.
Test Drug
LCZ696
Active Ingredient
Sacubitril/Valsartan as Sacubitril Valsartan sodium salt complex
Dosage Form
film-coated tablets
Dosage
50/ 100/ 200
Endpoints
Primary Outcome Measures :
Change from baseline in the CogState Global Cognitive Composite Score (GCCS) [ Time Frame: baseline, week 156 ]
Change in cognition is assessed as a change in a Global Cognitive Composite Z score. The cognitive composite comprises cognitive domains including attention, memory, and executive function. A negative change from baseline will indicate worsening performance.
Secondary Outcome Measures :
Change from baseline in cortical composite standardized uptake value ratio (SUVr) [ Time Frame: Baseline, week 156 ]
Changes in amyloid plaque deposition over time will be assessed using florbetapir-18F. The longitudinal change in the standardized uptake value ratio will be determined.
Change from baseline in individual cognitive domains (memory, executive function, and attention) [ Time Frame: Baseline, week 156 ]
Specific cognitive domains to be assessed include memory, executive function, and attention. A negative change from baseline will indicate worsening performance.
Change from baseline in the summary score of the instrumental activities of daily living (IADL) [ Time Frame: Baseline, week 156 ]
Instrumental activities of daily living will be assessed using the functional activities questionnaire. The functional activities questionnaire will be used as a standardized assessment of activities of daily living. This questionnaire is typically used to distinguish normal subjects from subjects with mild to moderate cognitive impairment. The test is made up of 10 questions that reflect a subject's ability to perform activities of daily living and to function independently. Test scores range from 0 to 30, a score of 0 is completely normal where as a higher score denotes impairment. Each of 10 questions is scored from 0, representing normal to 3, dependent on someone else to perform the activity. A negative change from baseline denotes improvement.
Change from baseline in the CogState Global Cognitive Composite Score (GCCS) [ Time Frame: baseline, week 156 ]
Change in cognition is assessed as a change in a Global Cognitive Composite Z score. The cognitive composite comprises cognitive domains including attention, memory, and executive function. A negative change from baseline will indicate worsening performance.
Secondary Outcome Measures :
Change from baseline in cortical composite standardized uptake value ratio (SUVr) [ Time Frame: Baseline, week 156 ]
Changes in amyloid plaque deposition over time will be assessed using florbetapir-18F. The longitudinal change in the standardized uptake value ratio will be determined.
Change from baseline in individual cognitive domains (memory, executive function, and attention) [ Time Frame: Baseline, week 156 ]
Specific cognitive domains to be assessed include memory, executive function, and attention. A negative change from baseline will indicate worsening performance.
Change from baseline in the summary score of the instrumental activities of daily living (IADL) [ Time Frame: Baseline, week 156 ]
Instrumental activities of daily living will be assessed using the functional activities questionnaire. The functional activities questionnaire will be used as a standardized assessment of activities of daily living. This questionnaire is typically used to distinguish normal subjects from subjects with mild to moderate cognitive impairment. The test is made up of 10 questions that reflect a subject's ability to perform activities of daily living and to function independently. Test scores range from 0 to 30, a score of 0 is completely normal where as a higher score denotes impairment. Each of 10 questions is scored from 0, representing normal to 3, dependent on someone else to perform the activity. A negative change from baseline denotes improvement.
Inclution Criteria
Inclusion criteria:
1. Written informed consent including consent for APOE4 gene testing must be obtained
before any assessment is performed.
2. Male or female patients aged ≥60 years of age.
3. Chronic heart failure with current symptom(s) (NYHA class II-IV) at Screening visit.
4. LVEF >40%
a. By any method using most recent assessment within 6 months prior to screening visit.
OR
b. By an echocardiogram performed during the Screening visit, if previous assessment
is not available.
5. NT-proBNP ≥ 125 pg/mL at Screening visit
6. Patient with evidence of adequate functioning (e.g.: intellectual, motor, visual and auditory)
to complete the study assessments and has elementary education or 6 years of sustained
employment.
1. Written informed consent including consent for APOE4 gene testing must be obtained
before any assessment is performed.
2. Male or female patients aged ≥60 years of age.
3. Chronic heart failure with current symptom(s) (NYHA class II-IV) at Screening visit.
4. LVEF >40%
a. By any method using most recent assessment within 6 months prior to screening visit.
OR
b. By an echocardiogram performed during the Screening visit, if previous assessment
is not available.
5. NT-proBNP ≥ 125 pg/mL at Screening visit
6. Patient with evidence of adequate functioning (e.g.: intellectual, motor, visual and auditory)
to complete the study assessments and has elementary education or 6 years of sustained
employment.
Exclusion Criteria
Exclusion criteria:
1. Current acute decompensated HF requiring augmented therapy with diuretics, vasodilators
and/or inotropic drugs. If hospitalized for any medical conditions including heart failure
patients should be clinically stable and be discharged from hospital for at least 2 weeks prior
to screening.
2. 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.
3. Patients with history of hereditary or idiopathic angioedema or angioedema related to
previous ACEi or ARB therapies.
4. Patients with one of the following:
a. Patients with serum potassium >5.2 mmol/L (mEq/L) at Screening visit
b. Patients with serum potassium >5.4 mmol/L (mEq/L) at any visit during run-in
treatment period or at randomization visit
c. Systolic blood pressure (SBP) ≥180 mmHg at Screening visit, or
d. SBP <110 mmHg at Screening visit, or
e. SBP <100 mmHg or symptomatic hypotension as determined by the investigator at
Visit 103 or at randomization visit
f. Body mass index (BMI) >45 kg/m2
5. Patients who require treatment with 2 or more of the following: an ACEi, an ARB or a renin
inhibitor.
6. Patients with
a. known pericardial constriction, genetic hypertrophic cardiomyopathy, infiltrative
cardiomyopathy or
b. hemodynamically significant obstructive valvular disease.
7. 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.
8. Evidence of hepatic disease as determined by any one of the following: SGOT (aspartate
aminotransferase (AST)) or SGPT (alanine aminotransferase (ALT)) values exceeding 3 x
the upper limit of normal (ULN), bilirubin >1.5 mg/dl at screening visit.
9. Patients with one of the following:
a. eGFR <30 mL/min/1.73m2
as calculated by the Modification of Diet in Renal Disease
(MDRD) formula at Screening visit, or
b. eGFR <25 mL/min/1.73m2
at Visit 103 or at end of run-in/randomization visit, or
c. eGFR reduction >35% (compared to Visit 1) at Visit 103 or Visit 199/201
10. Presence of known functionally significant bilateral renal artery stenosis
11. MMSE score <24 at screening visit
12. 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).
13. Any history of medical or neurological condition likely to affect the participant’s cognition
(e.g., clinically significant brain trauma with loss of consciousness >3 minutes within 6
months prior to screening, Huntington’s disease, Parkinson’s disease, Lyme’s disease,
syphilis, HIV dementia, uncontrolled seizure disorder) or clinically significant abnormalities
in thyroid function tests, Vitamin B12 or folate deficiency requiring treatment at screening
(Patients who are adequately treated may be included at investigator discretion).
14. 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.
15. Score “yes” on item 4 or item 5 of the Suicidal Ideation section of the C-SSRS, if this
ideation occurred in the past 6 months, or “yes” on any item of the Suicidal Behavior section,
except for the “Non-Suicidal Self-Injurious Behavior” (item also included in the Suicidal
Behavior section), if this behavior occurred in the past 2 years.
16. Clinically significant cerebral pathology, for example large cerebral aneurysm, space
occupying lesion etc. that may impact cognition as assessed by MRI central reader.
17. Any contraindication or intolerance to MRI or PET investigations (with fluorinated
radiopharmaceuticals), including but not limited to: presence of pacemakers not compatible
with MRI, aneurysm clips, artificial heart valves, ear implants, or foreign metal objects in
the eyes, skin, or body that would contraindicate an MRI scan; or any other clinical history
or examination finding that, in the judgment of the investigator, would pose a potential
hazard in combination with MRI.
18. Previous or planned Nuclear Medicine Radiology research that will exceed the dosimetry
acceptable exposure in the country, when adding the scheduled study PET scans.
19. Any surgical or medical condition, which in the opinion of the investigator, may place the
patient at higher risk from his/her participation in the study, or is likely to prevent the patient
from complying with the requirements of the study or completing the study.
20. Any surgical or medical condition which might significantly alter the absorption,
distribution, metabolism, or excretion of study drugs, including but not limited to history of
pancreatic injury, pancreatitis or evidence of impaired pancreatic function/injury within the
last 5 years
21. History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes.
22. History of non-compliance to medical regimens and patients who are considered potentially
unreliable.
23. History or evidence of drug or alcohol abuse within the last 12 months
24. History or presence of any other disease with a life expectancy of <3 years
25. Women of child bearing potential defined as all women physiologically capable of
becoming pregnant. Women are considered post-menopausal and not of child bearing
potential if they have had 12 months of natural (spontaneous) amenorrhea with an
appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have
had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least
six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the
woman has been confirmed by follow up hormone level assessment.
26. Persons directly involved in the execution of this protocol
27. Use of other investigational drugs at the time of enrollment, or within 30 days, or within 5
half-lives of enrollment, whichever is longer.
28. Patients who previously received treatment with LCZ696.
Patients who are on current treatment with sedative hypnotics, selective serotonin re-uptake
inhibitors (SSRIs, e.g. paroxetine, sertraline, citalopram, escitalopram), serotonin norepinephrine
re-uptake inhibitors (SNRIs, e.g. venlafaxine, duloxetine), atypical antipsychotics, and low dose
tricyclic anti-depressants should be on a stable regimen (defined as no change to the participant’s
medication intake pattern rather than adherence to the prescribed regimen) for at least 12 weeks
prior to screening.
1. Current acute decompensated HF requiring augmented therapy with diuretics, vasodilators
and/or inotropic drugs. If hospitalized for any medical conditions including heart failure
patients should be clinically stable and be discharged from hospital for at least 2 weeks prior
to screening.
2. 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.
3. Patients with history of hereditary or idiopathic angioedema or angioedema related to
previous ACEi or ARB therapies.
4. Patients with one of the following:
a. Patients with serum potassium >5.2 mmol/L (mEq/L) at Screening visit
b. Patients with serum potassium >5.4 mmol/L (mEq/L) at any visit during run-in
treatment period or at randomization visit
c. Systolic blood pressure (SBP) ≥180 mmHg at Screening visit, or
d. SBP <110 mmHg at Screening visit, or
e. SBP <100 mmHg or symptomatic hypotension as determined by the investigator at
Visit 103 or at randomization visit
f. Body mass index (BMI) >45 kg/m2
5. Patients who require treatment with 2 or more of the following: an ACEi, an ARB or a renin
inhibitor.
6. Patients with
a. known pericardial constriction, genetic hypertrophic cardiomyopathy, infiltrative
cardiomyopathy or
b. hemodynamically significant obstructive valvular disease.
7. 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.
8. Evidence of hepatic disease as determined by any one of the following: SGOT (aspartate
aminotransferase (AST)) or SGPT (alanine aminotransferase (ALT)) values exceeding 3 x
the upper limit of normal (ULN), bilirubin >1.5 mg/dl at screening visit.
9. Patients with one of the following:
a. eGFR <30 mL/min/1.73m2
as calculated by the Modification of Diet in Renal Disease
(MDRD) formula at Screening visit, or
b. eGFR <25 mL/min/1.73m2
at Visit 103 or at end of run-in/randomization visit, or
c. eGFR reduction >35% (compared to Visit 1) at Visit 103 or Visit 199/201
10. Presence of known functionally significant bilateral renal artery stenosis
11. MMSE score <24 at screening visit
12. 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).
13. Any history of medical or neurological condition likely to affect the participant’s cognition
(e.g., clinically significant brain trauma with loss of consciousness >3 minutes within 6
months prior to screening, Huntington’s disease, Parkinson’s disease, Lyme’s disease,
syphilis, HIV dementia, uncontrolled seizure disorder) or clinically significant abnormalities
in thyroid function tests, Vitamin B12 or folate deficiency requiring treatment at screening
(Patients who are adequately treated may be included at investigator discretion).
14. 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.
15. Score “yes” on item 4 or item 5 of the Suicidal Ideation section of the C-SSRS, if this
ideation occurred in the past 6 months, or “yes” on any item of the Suicidal Behavior section,
except for the “Non-Suicidal Self-Injurious Behavior” (item also included in the Suicidal
Behavior section), if this behavior occurred in the past 2 years.
16. Clinically significant cerebral pathology, for example large cerebral aneurysm, space
occupying lesion etc. that may impact cognition as assessed by MRI central reader.
17. Any contraindication or intolerance to MRI or PET investigations (with fluorinated
radiopharmaceuticals), including but not limited to: presence of pacemakers not compatible
with MRI, aneurysm clips, artificial heart valves, ear implants, or foreign metal objects in
the eyes, skin, or body that would contraindicate an MRI scan; or any other clinical history
or examination finding that, in the judgment of the investigator, would pose a potential
hazard in combination with MRI.
18. Previous or planned Nuclear Medicine Radiology research that will exceed the dosimetry
acceptable exposure in the country, when adding the scheduled study PET scans.
19. Any surgical or medical condition, which in the opinion of the investigator, may place the
patient at higher risk from his/her participation in the study, or is likely to prevent the patient
from complying with the requirements of the study or completing the study.
20. Any surgical or medical condition which might significantly alter the absorption,
distribution, metabolism, or excretion of study drugs, including but not limited to history of
pancreatic injury, pancreatitis or evidence of impaired pancreatic function/injury within the
last 5 years
21. History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes.
22. History of non-compliance to medical regimens and patients who are considered potentially
unreliable.
23. History or evidence of drug or alcohol abuse within the last 12 months
24. History or presence of any other disease with a life expectancy of <3 years
25. Women of child bearing potential defined as all women physiologically capable of
becoming pregnant. Women are considered post-menopausal and not of child bearing
potential if they have had 12 months of natural (spontaneous) amenorrhea with an
appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have
had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least
six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the
woman has been confirmed by follow up hormone level assessment.
26. Persons directly involved in the execution of this protocol
27. Use of other investigational drugs at the time of enrollment, or within 30 days, or within 5
half-lives of enrollment, whichever is longer.
28. Patients who previously received treatment with LCZ696.
Patients who are on current treatment with sedative hypnotics, selective serotonin re-uptake
inhibitors (SSRIs, e.g. paroxetine, sertraline, citalopram, escitalopram), serotonin norepinephrine
re-uptake inhibitors (SNRIs, e.g. venlafaxine, duloxetine), atypical antipsychotics, and low dose
tricyclic anti-depressants should be on a stable regimen (defined as no change to the participant’s
medication intake pattern rather than adherence to the prescribed regimen) for at least 12 weeks
prior to screening.
The Estimated Number of Participants
-
Taiwan
9 participants
-
Global
592 participants
