ClinicalTrials.gov
ClinicalTrials.gov Menu

ARNI in Asymptomatic Patients With Elevated Natriuretic Peptide and Elevated Left Atrial Volume Index eLEvation (PARABLE)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02682719
Recruitment Status : Unknown
Verified February 2016 by The Heartbeat Trust.
Recruitment status was:  Recruiting
First Posted : February 15, 2016
Last Update Posted : February 17, 2016
Sponsor:
Collaborator:
Novartis Ireland Ltd
Information provided by (Responsible Party):
The Heartbeat Trust

Brief Summary:
The purpose of this study is to determine whether LCZ696 (valsartan/sacubitril) is safe and has beneficial effects on the heart and blood vessels in patients with high blood pressure and/or diabetes or other risk factors for developing heart failure (elevated levels of natriuretic peptide and elevated left atrial volume index). Patients will be randomized to receive LCZ696 or valsartan (and matching placebo) for 18 months to assess the impact on left ventricular diastolic function.

Condition or disease Intervention/treatment Phase
Diastolic Dysfunction Drug: LCZ696 Drug: Valsartan Other: Placebo to LCZ696 Other: Placebo to Valsartan Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 250 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Personalised Prospective Comparison of ARni With ArB in Patients With Natriuretic Peptide eLEvation (The PARABLE Study)
Study Start Date : December 2015
Estimated Primary Completion Date : December 2018
Estimated Study Completion Date : December 2018

Resource links provided by the National Library of Medicine

Drug Information available for: Valsartan

Arm Intervention/treatment
Experimental: Valsartan/Sacubitril (LCZ696)

Valsartan/Sacubitril (LCZ696) plus placebo to Valsartan. Standard dosing regime: LCZ696 100mg twice daily for two weeks then increased to 200mg twice daily for the remainder of the study.

Lower dosing regimen (for patients not taking an ARB or ACE inhibitor, subjects previously taking low doses of these agents and for subjects with a systolic BP of ≥100mm to 110mmHg at screening or baseline): LCZ696 50mg twice daily for two weeks then increased to 100mg twice daily for two weeks then further increased to 200mg twice daily for the remainder of the study.

Drug: LCZ696
Other Names:
  • Valsartan and sacubitril
  • Entresto

Other: Placebo to Valsartan
Active Comparator: Valsartan

Valsartan plus placebo to Valsartan/Sacubitril (LCZ696). Standard dosing regime: Valsartan 80mg twice daily for two weeks then increased to 160mg twice daily for the remainder of the study.

Lower dosing regimen (for patients not taking an ARB or ACE inhibitor, subjects previously taking low doses of these agents and for subjects with a systolic BP of ≥100mm to 110mmHg at screening or baseline): Valsartan 40mg twice daily for two weeks then increased to 80mg twice daily for two weeks then further increased to 160mg twice daily for the remainder of the study.

Drug: Valsartan
Other Name: Diovan

Other: Placebo to LCZ696



Primary Outcome Measures :
  1. Change in left atrial volume index (LAVI) [ Time Frame: 18 months ]
    LAVI will be measured by cardiac MRI


Secondary Outcome Measures :
  1. Change in left atrial volume index (LAVI) [ Time Frame: 9 months ]
    LAVI will be measured by cardiac MRI

  2. Change in cardiac MRI parameters of left ventricular structure and function [ Time Frame: 9 months ]
  3. Change in cardiac MRI parameters of left ventricular structure and function [ Time Frame: 18 months ]
  4. Change in LAVI measured by doppler echocardiography [ Time Frame: 9 months ]
  5. Change in LAVI measured by doppler echocardiography [ Time Frame: 18 months ]
  6. Correlation between doppler echocardiography measured LAVI and cardiac MRI measured LAVI [ Time Frame: 18 months ]
  7. Change in doppler echocardiographic parameters of left ventricular structure and function [ Time Frame: 9 months ]
  8. Change in doppler echocardiographic parameters of left ventricular structure and function [ Time Frame: 18 months ]
  9. Change in log-scale in NT-proBNP [ Time Frame: 9 months ]
  10. Change in log-scale in NT-proBNP [ Time Frame: 18 months ]
  11. Change in log-scale urinary cGMP [ Time Frame: 9 months ]
  12. Change in log-scale urinary cGMP [ Time Frame: 18 months ]
  13. Change in markers of collagen turnover (PICP) [ Time Frame: 9 months ]
  14. Change in markers of collagen turnover (PICP) [ Time Frame: 18 months ]
  15. Change in markers of collagen turnover (PIIINP) [ Time Frame: 9 months ]
  16. Change in markers of collagen turnover (PIIINP) [ Time Frame: 18 months ]
  17. Change in markers of ECM turnover (MMP-2) [ Time Frame: 9 months ]
  18. Change in markers of ECM turnover (MMP-2) [ Time Frame: 18 months ]
  19. Change in markers of ECM turnover (MMP-9) [ Time Frame: 9 months ]
  20. Change in markers of ECM turnover (MMP-9) [ Time Frame: 18 months ]
  21. Change in markers of ECM turnover (TIMP-1) [ Time Frame: 9 months ]
  22. Change in markers of ECM turnover (TIMP-1) [ Time Frame: 18 months ]
  23. Change in markers of myocardial damage (hsTroponinT) [ Time Frame: 9 months ]
  24. Change in markers of myocardial damage (hsTroponinT) [ Time Frame: 18 months ]
  25. Change in markers of fibrosis (sST-2) [ Time Frame: 9 months ]
  26. Change in markers of fibrosis (sST-2) [ Time Frame: 18 months ]
  27. Change in markers of inflammation (IL-6) [ Time Frame: 9 months ]
  28. Change in markers of inflammation (IL-6) [ Time Frame: 18 months ]
  29. Change in markers of inflammation (TNF-α) [ Time Frame: 9 months ]
  30. Change in markers of inflammation (TNF-α) [ Time Frame: 18 months ]
  31. Change in markers of inflammation (MCP1) [ Time Frame: 9 months ]
  32. Change in markers of inflammation (MCP1) [ Time Frame: 18 months ]
  33. Change in markers of inflammation (GDF15) [ Time Frame: 9 months ]
  34. Change in markers of inflammation (GDF15) [ Time Frame: 18 months ]
  35. Change in markers of inflammation (CT1) [ Time Frame: 9 months ]
  36. Change in markers of inflammation (CT1) [ Time Frame: 18 months ]
  37. Change in markers of renal function (creatinine clearance) [ Time Frame: 18 months ]
    Creatinine clearance will be measured using the estimated glomerular filtration rate (eGFR)


Other Outcome Measures:
  1. Number of treatment-related adverse events [ Time Frame: 18 months ]
  2. Change from baseline to 18 months in overall summary score and individual domain score for health related quality of life [ Time Frame: 18 months ]
    This will be assessed through the administration of the EuroQoL-5D-5L instrument which is designed to assess the current health status of subjects. It consists of five domains and one visual analogue scale. This instrument assesses morbidity, self-care, usual activity, pain and anxiety and depression of subjects.

  3. Change from baseline to 18 months in overall summary score and individual domain score of the standardised MMSE to assess cognitive function. [ Time Frame: 18 months ]
    This will be assessed through the administration of the Standardized Mini-Mental State Examination which is a 30 point test designed to measure various domains of cognitive function including orientation to time and place; registration; concentration; short-term recall; naming familiar items; repeating a common expression; and the ability to read and follow written instructions, write a sentence, construct a diagram, and follow a three-step verbal command

  4. Change from baseline to 18 months in overall summary score and individual domain score of the MoCA to assess cognitive function. [ Time Frame: 18 months ]
    This will be assessed through the administration of the Montreal Cognitive Assessment which is a a 30 point test designed to assess several cognitive domains including short-term memory recall, visuospatial abilities, executive functions, attention, concentration and working memory, language, orientation and place

  5. Number of cardiovascular adverse events [ Time Frame: 18 months ]
    Cardiovascular adverse events are defined as emergency hospitalization for arrhythmia, transient ischemic attack, stroke, myocardial infarction, peripheral or pulmonary thrombosis/embolus, or heart failure.



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.


Ages Eligible for Study:   40 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age > 40yrs
  2. Cardiovascular risk factor(s) including at least one of:

    • History of hypertension (medicated for greater than one month);
    • History of diabetes;
  3. Elevated NP: BNP>50pg/ml or NT-proBNP >250 pg/ml
  4. LAVI > 28 mL/m2 obtained during Doppler Echocardiography within 6 months prior to screening
  5. Subjects must give written informed consent to participate in the study and before any study related assessments are performed

Exclusion Criteria:

  1. A history of heart failure.
  2. A history of asymptomatic left ventricular systolic dysfunction defined as LVEF reading <50%, at any time.
  3. Systolic blood pressure <100mmHg
  4. Persistent atrial fibrillation.
  5. History of hypersensitivity, allergy or intolerance to LCZ696, ARB or neprilysin therapy or to any of the excipients or other contraindication to their use.
  6. Previous history of intolerance to recommended target doses for ARBs
  7. Subjects who require treatment with both an ACE inhibitor and an ARB
  8. Presence of haemodynamically significant mitral and /or aortic valve disease.
  9. Presence of hemodynamically significant obstructive lesions of left ventricular outflow tract, including aortic stenosis.
  10. Conditions that are expected to compromise survival over the study period.
  11. Serum potassium level > 5.2 mmol/L at screening.
  12. Severe renal insufficiency (eGFR <30 mL per minute per 1.73 m2).
  13. Hepatic dysfunction (Any LFT > 3 times the upper limit of normal (ULN))
  14. Concomitant use of aliskiren
  15. History of angioedema.
  16. History or evidence of drug or alcohol abuse within the last 12 months
  17. Malignancy
  18. Women who are pregnant, breast-feeding, or women of child bearing potential not using estro-progestative oral or intra-uterine contraception or implants, or women using estro-progestative oral or intra-uterine contraception or implants but who consider stopping it during the planned duration of the study. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. (Contraception must be continued for one week following discontinuation of study drug).
  19. Concomitant participation in other intervention trials
  20. Participation in any investigational drug trial within one month of visit 1.
  21. Refusal to provide informed consent
  22. Subjects with contraindications to MRI

    • Hypersensitivity to gadolinium containing contrast agents
    • Brain aneurysm clip
    • Implanted neural stimulator
    • Implanted cardiac pacemaker or defibrillator
    • Cochlear implant
    • Ocular foreign body (e.g. metal shavings)
    • Other implanted medical devices: (e.g. Swan-Ganz catheter)
    • Insulin pump
    • Metal shrapnel or bullet.
  23. Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of study drugs, including but not limited to any of the following:

    • History of major gastrointestinal tract surgery including gastrectomy, gastroenterostomy, or bowel resection.
    • Inflammatory bowel disease during the 12 months prior to Visit 1.
    • Any history of pancreatic injury, pancreatitis or evidence of impaired pancreatic function/injury as indicated by abnormal lipase or amylase.
    • Evidence of hepatic disease as determined by any one of the following: SGOT or SGPT values exceeding 3 x ULN at Visit 1, a history of hepatic encephalopathy, a history of oesophageal varices, or a history of portocaval shunt.

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): NCT02682719


Contacts
Contact: Kenneth McDonald, MD, FRCPI 0035312713071 kenneth.mcdonald@ucd.ie
Contact: Alison Sheerin, RGN 0035312713071 A.Sheerin@stmichaels.ie

Locations
Ireland
The STOP-HF Service, St Michael's Hosptial Recruiting
Dun Laoghaire, Dublin, Ireland
Contact: Alison Sheerin, RGN    0035312713071    A.Sheerin@stmichaels.ie   
Contact: Fiona Ryan, BPharm, PhD    00353861708998    fiona@heartbeat-trust.org   
Sponsors and Collaborators
The Heartbeat Trust
Novartis Ireland Ltd
Investigators
Principal Investigator: Kenneth McDonald, MD, FRCPI St Vincent's University Hospital
Principal Investigator: Mark Ledwidge, BPharm, PhD St Vincent's University Hospital

Publications:

Responsible Party: The Heartbeat Trust
ClinicalTrials.gov Identifier: NCT02682719     History of Changes
Other Study ID Numbers: HBT-GCP-PTCL-01
First Posted: February 15, 2016    Key Record Dates
Last Update Posted: February 17, 2016
Last Verified: February 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes

Keywords provided by The Heartbeat Trust:
Natriuretic peptide, brain
Diabetes Mellitus, Type 2
Hypertension
Cardiovascular prevention
Left atrial volume index
Angiotensin receptor neprilysin inhibitor
LCZ696
Valsartan
Sacubitril

Additional relevant MeSH terms:
Valsartan
LCZ 696
Antihypertensive Agents
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action