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A Randomized, Double-blind Controlled Study Comparing LCZ696 to Medical Therapy for Comorbidities in HFpEF Patients (PARALLAX)

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ClinicalTrials.gov Identifier: NCT03066804
Recruitment Status : Completed
First Posted : February 28, 2017
Results First Posted : February 8, 2021
Last Update Posted : October 11, 2021
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:
The purpose of this study is to demonstrate the superiority of LCZ696 over individualized medical therapy for comorbidities in reducing N-terminal pro-brain natriuretic peptide (NT-proBNP) and improving exercise capacity and HF symptoms in patients with heart failure with preserved ejection fraction (HFpEF).

Condition or disease Intervention/treatment Phase
Heart Failure With Preserved Ejection Fraction Drug: sacubitril/valsartan Drug: Enalapril Drug: Valsartan Drug: Placebo to match sacubitril/valsartan Drug: Placebo to match enalapril Drug: Placebo to match valsartan Phase 3

Expanded Access : Novartis Pharmaceuticals has indicated that access to an investigational treatment associated with this study is available outside the clinical trial.  

Detailed Description:

This study was a 24-week, randomized, double-blind, multi-center, parallel group, active controlled study to evaluate sacubitril/valsartan compared to individualized medical therapy on NT proBNP, exercise capacity, symptoms and QoL in patients with heart failure and preserved left ventricular ejection (HFpEF) fraction (LVEF > 40%). Patients were initially stratified into one of three strata according to prior treatment for comorbidities: Angiotensin converting enzyme inhibitor (ACEi), angiotensin receptor blocker (ARB) or no prior renin angiotensin system inhibitors (RASi). Patients in each stratum were randomized in a 1:1 ratio and received either sacubitril/valsartan or comparator (i.e.

enalapril for patients in ACEi strata, valsartan for patients in the ARB strata and placebo for patients in the No RASi strata). There was no designated proportion of patients planned in each stratum; the strata were populated based upon the patient's prior treatment regimen. The study consisted of a screening epoch of up to 2 weeks and a randomized treatment epoch of 24 weeks, which included a 1 to 4 week study drug up-titration epoch followed by a 20 to 23 week maintenance epoch. Uptitration to target doses was recommended to occur within the first four weeks of the study, and was performed by Investigator's discretion based on the patient's clinical status.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 2572 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A 24-week, Randomized, Double-blind, Multi-center, Parallel LCZ696 on NT-proBNP, Exercise Capacity, Symptoms and Safety Compared to Individualized Medical Management of Comorbidities in Patients With Heart Failure and Preserved Ejection Fraction
Actual Study Start Date : August 22, 2017
Actual Primary Completion Date : October 28, 2019
Actual Study Completion Date : October 28, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Heart Failure

Arm Intervention/treatment
Experimental: sacubitril/valsartan (LCZ696)

All patients who fulfill the inclusion/exclusion criteria will be stratified before randomization based upon prior therapy for comorbidities to one of 3 strata: ACEi, ARB or no RASi. Patients in the ACEi strata will receive LCZ696 or enalapril. Patients in the ARB strata will receive LCZ696 or valsartan. Patients in the no RASi strata will receive LCZ696 or matching placebo.

Patients in the ACEi and ARB strata will take two pills twice daily for each dose: one tablet from the LCZ696 pack and one tablet from the comparator pack. Patients in the no RASi strata will take only one tablet twice daily (LCZ696 or matching placebo).

In the LCZ696 arm, patients will receive active LCZ696 in titrated doses from level 1 up to level 3 (50 mg, 100 mg and 200 mg twice daily orally).

Drug: sacubitril/valsartan
Sacubitril/valsartan is available as 24 mg/26 mg, 49 mg/51 mg, 97 mg/103 mg, respectively in tablet form to be taken orally

Drug: Placebo to match enalapril
Placebo to match enalapril 2.5 mg, 5 mg, 10 mg tablet form to be taken orally

Drug: Placebo to match valsartan
Placebo to match valsartan 40 mg, 80 mg, 160 mg tablet form to be taken orally

Active Comparator: Comparator

Patients randomized to the comparator arm will receive either enalapril (ACE stratum) valsartan (ARB stratum) or LCZ696 matching placebo (no RASi stratum).

Patients in the ACE stratum randomized to comparator, will receive enalapril in titrated doses from level 1 up to level 3 (2.5 mg, 5 mg and 10 mg twice daily).

Patients in the ARB stratum randomized to comparator will receive valsartan in titrated doses from level 1 up to level 3 (40 mg , 80 mg and 160 mg twice daily).

Patients in the no RASi stratum randomized to comparator will receive LCZ696 matching placebo.

Drug: Enalapril
Enalapril is available as 2.5 mg, 5 mg, and 10 mg tablet form to be taken orally

Drug: Valsartan
Valsartan is available as 40 mg, 80 mg, 160 mg tablet form to be taken orally

Drug: Placebo to match sacubitril/valsartan
Placebo to match LCZ696 50 mg, 100 mg, 200 mg tablet form to be taken orally




Primary Outcome Measures :
  1. Change From Baseline in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) at Week 12 [ Time Frame: Baseline, week 12 ]
    To demonstrate that LCZ696 is superior to individualized medical therapy for comorbidities in reducing NT-proBNP from baseline at Week 12 in patients with HFpEF

  2. Change From Baseline in 6 Minute Walk Distance (6MWD) at Week 24 [ Time Frame: Baseline, week 24 ]
    Change from baseline in 6-minute walk distance (6MWD) will be reported at Week 24. The 6 MWT will be performed in accordance with the guidelines of the American Thoracic Society 2002.


Secondary Outcome Measures :
  1. Mean Change From Baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score (CSS) at Week 24 [ Time Frame: Baseline, Week 24 ]
    The KCCQ is a self-administered questionnaire that requires 4 to 6 minutes to complete. It contains 23 items, covering physical function, clinical symptoms, social function, self-efficacy and knowledge, and Quality of Life (QoL). The CSS is a combined score based upon the clinical symptoms and physical function domains of the questionnaire. Scores are transformed to a range of 0 - 100, in which higher scores reflect better health status.

  2. Percentage of Patients With ≥ 5-points Deterioration in KCCQ Clinical Symptom Score(CSS) at Week 24 [ Time Frame: Baseline, Week 24 ]
    Percentage of patients with KCCQ CSS deterioration ≥ 5-points will be reported at Week 24. The KCCQ is a self-administered questionnaire that requires 4 to 6 minutes to complete. It contains 23 items, covering physical function, clinical symptoms, social function, self-efficacy and knowledge, and Quality of Life (QoL). The CSS is a combined score based upon the clinical symptoms and physical function domains of the questionnaire. Scores are transformed to a range of 0 - 100, in which higher scores reflect better health status.

  3. Percentage of Patients With ≥ 5-points Improvement in KCCQ Clinical Symptom Score(CSS) at Week 24 [ Time Frame: Baseline, Week 24 ]
    Percentage of patients with KCCQ CSS improvement ≥ 5-points will be reported at Week 24. The KCCQ is a self-administered questionnaire that requires 4 to 6 minutes to complete. It contains 23 items, covering physical function, clinical symptoms, social function, self-efficacy and knowledge, and Quality of Life (QoL). The CSS is a combined score based upon the clinical symptoms and physical function domains of the questionnaire. Scores are transformed to a range of 0 - 100, in which higher scores reflect better health status.

  4. Change From Baseline in NYHA Functional Class at Week 24 [ Time Frame: Baseline, week 24 ]

    NYHA classification is a subjective physician's assessment of patient's functional capacity and symptomatic status and can change frequently over time.

    Class I - No limitation of physical activity. Ordinary physical activity does not cause symptoms of HF Class II - Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in symptoms of HF Class III - Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes symptoms of HF Class IV - Unable to carry on any physical activity without symptoms of HF, or symptoms of HF at rest

    The NYHA class change will be analyzed as a three category ordinal variable with levels: "improved", "unchanged", and "worsened", defined by at least one class improvement, no change, at least one class worsening, in NYHA class, respectively.


  5. Change From Baseline in The Short Form 36 Health Survey (SF-36) Physical Component Summary (PCS) Score at Week 24 [ Time Frame: Baseline, Week 24 ]
    The SF-36 PCS score reflects the measure of quality of life based on the 36 questions which evaluate the person's physical, emotional, and mental status, including general health. Specifically, the SF-36 PCS score focuses on assessing the person's physical status. The score ranges from 0 to 100 with a higher score indicating a better status of physical wellbeing (range = 0 "worst"-100 "best").



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   45 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Left ventricular ejection fraction (LVEF) >40% by echo within 6 months prior to study entry or during the screening epoch
  • Symptom(s) of heart failure (HF) requiring treatment with diuretics (including loop, or thiazide diuretics, or mineralocorticoid antagonist [MRAs]) for at least 30 days prior to study entry
  • NYHA class II-IV
  • Structural heart disease (left atrial enlargement or left ventricular hypertrophy) documented by echocardiogram.
  • NT-proBNP > 220 pg/mL for patients with no atrial fibrillation/atrial flutter (AF) or >600 pg/mL for patients with AF
  • KCCQ clinical summary score < 75
  • Patients on ACEi or ARB therapy must have a history of HTN

Exclusion Criteria:

  • Any prior measurement of LVEF ≤ 40%, under stable conditions
  • Acute coronary syndrome (including MI), cardiac surgery, other major CV surgery within 3 months , or urgent percutaneous coronary intervention (PCI) within 3 months or an elective PCI within 30 days prior to study entry
  • Any clinical event within the 6 months prior to Visit 1 that could have reduced the LVEF (eg MI, coronary artery bypass graft [CABG]), unless an echo measurement was performed after the event confirming the LVEF to be >40%
  • Current (within 30 days from Visit 1) acute decompensated HF requiring therapy.
  • Current (within 30 days from Visit 1) use of renin inhibitor(s), dual RAS blockade or LCZ696
  • History of hypersensitivity to LCZ696 or its components
  • Patients with a known history of angioedema
  • Walk distance primarily limited by non-cardiac comorbid conditions at study entry
  • Alternative reason for shortness of breath such as: significant pulmonary disease or severe COPD, hemoglobin (Hgb) <10 g/dL males and < 9.5 g/dL females, or body mass index (BMI) > 40 kg/m^2.
  • Systolic blood pressure (SBP) ≥ 180 mmHg at study entry, or SBP >150 mmHg and <180 mmHg at study entry unless the patient is receiving 3 or more antihypertensive drugs, or SBP < 110 mmHg at study entry.
  • Patients with HbA1c > 7.5% not treated for diabetes
  • Patients with prior major organ transplant or intent to transplant (ie on transplant list)
  • eGFR < 30 ml/min/1.73 m^2 as measured by MDRD at screening
  • Serum potassium > 5.2 mmol /L (or equivalent plasma potassium value) at study entry
  • History or presence of any other disease with a life expectancy of < 3 years
  • Pregnant or nursing women or women of child-bearing potential unless they are using highly effective methods of contraception

Other protocol-defined inclusion/exclusion criteria may apply.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03066804


Locations
Show Show 381 study locations
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  Study Documents (Full-Text)

Documents provided by Novartis ( Novartis Pharmaceuticals ):
Study Protocol  [PDF] September 12, 2018
Statistical Analysis Plan  [PDF] October 29, 2019

Additional Information:
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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT03066804    
Other Study ID Numbers: CLCZ696D2302
2016-003410-28 ( EudraCT Number )
First Posted: February 28, 2017    Key Record Dates
Results First Posted: February 8, 2021
Last Update Posted: October 11, 2021
Last Verified: October 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Cardiovascular Diseases
Heart Failure
Heart failure with Preserved Ejection Fraction
NT-proBNP
6 MWT
KCCQ
SF-36
NYHA Class
LCZ696
Enalapril
Valsartan
Angiotensin-Converting Enzyme Inhibitors (ACEi)
Angiotensin II Type 1 Receptor Blockers (ARB)
Renin Angiotensin System Inhibitors (RASi)
Additional relevant MeSH terms:
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Heart Failure
Heart Diseases
Cardiovascular Diseases
Valsartan
Enalapril
Enalaprilat
Sacubitril and valsartan sodium hydrate drug combination
Antihypertensive Agents
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action
Angiotensin-Converting Enzyme Inhibitors
Protease Inhibitors
Enzyme Inhibitors