Ignite Creation Date:
2024-05-06 @ 1:45 PM
Last Modification Date:
2024-10-26 @ 1:19 PM
Study NCT ID:
NCT04113109
Status:
RECRUITING
Last Update Posted:
2024-03-05
First Post:
2019-09-26
Brief Title:
Mechanisms Underlying Hypotensive Response to ARBNEP Inhibition - Aim 2
Sponsor:
Vanderbilt University Medical Center
Organization:
Vanderbilt University Medical Center
Study Overview
Official Title:
Mechanisms Underlying Hypotensive Response to ARBNEP Inhibition - Aim 2
Status:
RECRUITING
Status Verified Date:
2024-03
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
LCZ696 a molecular complex of the angiotensin receptor blocker ARB valsartan with an inhibitor of neprilysin NEP neutral endopeptidase-2411 sacubitril improved mortality compared to enalapril in patients with heart failure HF reduced ejection fraction EF and increased brain natriuretic peptide BNP or N-terminal pro-BNP NT-proBNP in the PARADIGM-HF trial1 The PIONEER-HF study demonstrated the efficacy of LCZ696 in preventing rehospitalization in patients with acutely decompensated HF2
LCZ696 has been underutilized in heart failure in part due to concerns about hypotension NEP degrades several vasodilator peptides including bradykinin substance P and brain-type natriuretic peptide Decreased degradation of endogenous bradykinin could contribute to hypotension at initiation of LCZ696 through vasodilation or through increased natriuresis and diuresis Inhibition of the bradykinin B2 receptor using icatibant would be expected to prevent this effect
Objectives
The main objectives of this mechanistic randomized double-blind crossover-design study are
The primary objective is to test the hypothesis that endogenous bradykinin contributes to effects of ARBNEP inhibition on blood pressure natriuresis and diuresis at initiation
The secondary objective is to test the hypothesis endogenous bradykinin contributes to effects of ARBNEP inhibition on blood pressure natriuresis and diuresis after up-titration
Eighty 80 subjects with stable heart failure who meet all inclusionexclusion criteria will be enrolled Subjects who qualify will collect their urine for 24 hours before each study day for measurement of volume sodium and potassium At the start of the study they will stop their regular angiotensin-converting enzyme ACE inhibitor or ARB After a 48-hour washout they will undergo a study day in which they are given a single dose of 50 mg LCZ696 They will also receive either the bradykinin B2 receptor antagonist icatibant or placebo vehicle in random order double-blind After a 96-hour washout they will repeat the study day and receive a single dose of 50 mg LCZ696 and the opposite study drug icatibant or placebo After completion of the two acute study days subjects will take LCZ696 50 mg bid for two weeks followed by LCZ696 100 mg bid for three weeks and then LCZ696 200 mg bid following the conservative up-titration protocol from the TITRATION study3 Criteria for continuing up-titration appear in the full study protocol On the 7th and 10th day of the 200 mg bid or highest tolerated dose subjects will again undergo two more study days three days apart in which they are randomized to receive either icatibant or vehicle
LCZ696 has been underutilized in heart failure in part due to concerns about hypotension NEP degrades several vasodilator peptides including bradykinin substance P and brain-type natriuretic peptide Decreased degradation of endogenous bradykinin could contribute to hypotension at initiation of LCZ696 through vasodilation or through increased natriuresis and diuresis Inhibition of the bradykinin B2 receptor using icatibant would be expected to prevent this effect
Objectives
The main objectives of this mechanistic randomized double-blind crossover-design study are
The primary objective is to test the hypothesis that endogenous bradykinin contributes to effects of ARBNEP inhibition on blood pressure natriuresis and diuresis at initiation
The secondary objective is to test the hypothesis endogenous bradykinin contributes to effects of ARBNEP inhibition on blood pressure natriuresis and diuresis after up-titration
Eighty 80 subjects with stable heart failure who meet all inclusionexclusion criteria will be enrolled Subjects who qualify will collect their urine for 24 hours before each study day for measurement of volume sodium and potassium At the start of the study they will stop their regular angiotensin-converting enzyme ACE inhibitor or ARB After a 48-hour washout they will undergo a study day in which they are given a single dose of 50 mg LCZ696 They will also receive either the bradykinin B2 receptor antagonist icatibant or placebo vehicle in random order double-blind After a 96-hour washout they will repeat the study day and receive a single dose of 50 mg LCZ696 and the opposite study drug icatibant or placebo After completion of the two acute study days subjects will take LCZ696 50 mg bid for two weeks followed by LCZ696 100 mg bid for three weeks and then LCZ696 200 mg bid following the conservative up-titration protocol from the TITRATION study3 Criteria for continuing up-titration appear in the full study protocol On the 7th and 10th day of the 200 mg bid or highest tolerated dose subjects will again undergo two more study days three days apart in which they are randomized to receive either icatibant or vehicle
Detailed Description:
None
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None