Trial Outcomes & Findings for Mechanisms Underlying Hypotensive Response to ARB/NEP Inhibition

Results Overview

Mean arterial pressure (MAP) will be measured before and after administration of LCZ696 on each of the four study days.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

46 participants

Primary outcome timeframe

Eight hours

Results posted on

2026-08-11

Participant Flow

Participant milestones

Participant milestones
Measure	Placebo, Icatibant, Placebo, Icatibant After a 48-hr washout, participants will be given LCZ696 50 mg and placebo (vehicle). After a 96-hr washout period, subjects will be given LCZ696 50 mg and icatibant. Participants will then undergo uptitration of LCZ696 over seven weeks. On the 7th and 10th days of the 200 mg bid or highest tolerated dose of LCZ696, participants will receive placebo and icatibant, respectively. LCZ 696: Treatment with LCZ696 is unblinded in this study. After the two acute study days, subjects will be provided LCZ696 50 mg bid for two weeks. At the end of those two weeks subjects will report to the Clinical Research Center (CRC) for a dose escalation visit. If their tolerance, blood pressure, potassium, and eGFR meet escalation criteria they will be given LCZ696 100 mg bid for three weeks. (If they do not meet escalation criteria they will be continued on LCZ696 50 mg bid.) After three weeks, they will return to the CRC for the next escalation visit. If they meet criteria for escalation they will be given LCZ 200 mg bid for ten days. (If they do not meet escalation criteria they will be continued on the highest tolerated dose). Icatibant: Icatibant will be given intravenously at 100 µg/kg over one hour followed by 20 µg/kg/hr during each study day. placebo: Placebo (vehicle) will be given at the same rate as icatibant.	Placebo, Icatibant, Icatibant, Placebo After a 48-hr washout, participants in this arm will be given LCZ696 50 mg and placebo (vehicle). After a 96-hr washout period, subjects will be given LCZ696 50 mg and icatibant. Participants will then undergo uptitration of LCZ696 over seven weeks. On the 7th and 10th days of the 200 mg bid or highest tolerated dose of LCZ696, participants in this arm will receive icatibant and placebo, respectively. LCZ 696: Treatment with LCZ696 is unblinded in this study. After the two acute study days, subjects will be provided LCZ696 50 mg bid for two weeks. At the end of those two weeks subjects will report to the Clinical Research Center (CRC) for a dose escalation visit. If their tolerance, blood pressure, potassium, and eGFR meet escalation criteria they will be given LCZ696 100 mg bid for three weeks. (If they do not meet escalation criteria they will be continued on LCZ696 50 mg bid.) After three weeks, they will return to the CRC for the next escalation visit. If they meet criteria for escalation they will be given LCZ 200 mg bid for ten days. (If they do not meet escalation criteria they will be continued on the highest tolerated dose). Icatibant: Icatibant will be given intravenously at 100 µg/kg over one hour followed by 20 µg/kg/hr during each study day. placebo: Placebo (vehicle) will be given at the same rate as icatibant.	Icatibant, Placebo, Placebo, Icatibant After a 48-hr washout, participants in this arm will be given LCZ696 50 mg and icatibant. After a 96-hr washout period, subjects will be given LCZ696 50 mg and placebo. Participants will then undergo uptitration of LCZ696 over seven weeks. On the 7th and 10th days of the 200 mg bid or highest tolerated dose of LCZ696, participants in this arm will receive placebo and icatibant, respectively. LCZ 696: Treatment with LCZ696 is unblinded in this study. After the two acute study days, subjects will be provided LCZ696 50 mg bid for two weeks. At the end of those two weeks subjects will report to the Clinical Research Center (CRC) for a dose escalation visit. If their tolerance, blood pressure, potassium, and eGFR meet escalation criteria they will be given LCZ696 100 mg bid for three weeks. (If they do not meet escalation criteria they will be continued on LCZ696 50 mg bid.) After three weeks, they will return to the CRC for the next escalation visit. If they meet criteria for escalation they will be given LCZ 200 mg bid for ten days. (If they do not meet escalation criteria they will be continued on the highest tolerated dose). Icatibant: Icatibant will be given intravenously at 100 µg/kg over one hour followed by 20 µg/kg/hr during each study day. placebo: Placebo (vehicle) will be given at the same rate as icatibant.	Icatibant, Placebo, Icatibant Placebo After a 48-hr washout, participants in this arm will be given LCZ696 50 mg and icatibant. After a 96-hr washout period, subjects will be given LCZ696 50 mg and placebo. Participants will then undergo uptitration of LCZ696 over seven weeks. On the 7th and 10th days of the 200 mg bid or highest tolerated dose of LCZ696, participants in this arm will receive icatibant and placebo, respectively. LCZ 696: Treatment with LCZ696 is unblinded in this study. After the two acute study days, subjects will be provided LCZ696 50 mg bid for two weeks. At the end of those two weeks subjects will report to the Clinical Research Center (CRC) for a dose escalation visit. If their tolerance, blood pressure, potassium, and eGFR meet escalation criteria they will be given LCZ696 100 mg bid for three weeks. (If they do not meet escalation criteria they will be continued on LCZ696 50 mg bid.) After three weeks, they will return to the CRC for the next escalation visit. If they meet criteria for escalation they will be given LCZ 200 mg bid for ten days. (If they do not meet escalation criteria they will be continued on the highest tolerated dose). Icatibant: Icatibant will be given intravenously at 100 µg/kg over one hour followed by 20 µg/kg/hr during each study day. placebo: Placebo (vehicle) will be given at the same rate as icatibant.
Overall Study STARTED	12	9	7	12
Overall Study COMPLETED	7	8	6	9
Overall Study NOT COMPLETED	5	1	1	3

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Mechanisms Underlying Hypotensive Response to ARB/NEP Inhibition - Aim 2

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo, Icatibant, Placebo, Icatibant n=7 Participants After a 48-hr washout, participants will be given LCZ696 50 mg and placebo (vehicle). After a 96-hr washout period, subjects will be given LCZ696 50 mg and icatibant. Participants will then undergo uptitration of LCZ696 over seven weeks. On the 7th and 10th days of the 200 mg bid or highest tolerated dose of LCZ696, participants will receive placebo and icatibant, respectively. LCZ 696: Treatment with LCZ696 is unblinded in this study. After the two acute study days, subjects will be provided LCZ696 50 mg bid for two weeks. At the end of those two weeks subjects will report to the Clinical Research Center (CRC) for a dose escalation visit. If their tolerance, blood pressure, potassium, and eGFR meet escalation criteria they will be given LCZ696 100 mg bid for three weeks. (If they do not meet escalation criteria they will be continued on LCZ696 50 mg bid.) After three weeks, they will return to the CRC for the next escalation visit. If they meet criteria for escalation they will be given LCZ 200 mg bid for ten days. (If they do not meet escalation criteria they will be continued on the highest tolerated dose). Icatibant: Icatibant will be given intravenously at 100 µg/kg over one hour followed by 20 µg/kg/hr during each study day. placebo: Placebo (vehicle) will be given at the same rate as icatibant.	Placebo, Icatibant, Icatibant, Placebo n=8 Participants After a 48-hr washout, participants in this arm will be given LCZ696 50 mg and placebo (vehicle). After a 96-hr washout period, subjects will be given LCZ696 50 mg and icatibant. Participants will then undergo uptitration of LCZ696 over seven weeks. On the 7th and 10th days of the 200 mg bid or highest tolerated dose of LCZ696, participants in this arm will receive icatibant and placebo, respectively. LCZ 696: Treatment with LCZ696 is unblinded in this study. After the two acute study days, subjects will be provided LCZ696 50 mg bid for two weeks. At the end of those two weeks subjects will report to the Clinical Research Center (CRC) for a dose escalation visit. If their tolerance, blood pressure, potassium, and eGFR meet escalation criteria they will be given LCZ696 100 mg bid for three weeks. (If they do not meet escalation criteria they will be continued on LCZ696 50 mg bid.) After three weeks, they will return to the CRC for the next escalation visit. If they meet criteria for escalation they will be given LCZ 200 mg bid for ten days. (If they do not meet escalation criteria they will be continued on the highest tolerated dose). Icatibant: Icatibant will be given intravenously at 100 µg/kg over one hour followed by 20 µg/kg/hr during each study day. placebo: Placebo (vehicle) will be given at the same rate as icatibant.	Icatibant, Placebo, Placebo, Icatibant n=6 Participants After a 48-hr washout, participants in this arm will be given LCZ696 50 mg and icatibant. After a 96-hr washout period, subjects will be given LCZ696 50 mg and placebo. Participants will then undergo uptitration of LCZ696 over seven weeks. On the 7th and 10th days of the 200 mg bid or highest tolerated dose of LCZ696, participants in this arm will receive placebo and icatibant, respectively. LCZ 696: Treatment with LCZ696 is unblinded in this study. After the two acute study days, subjects will be provided LCZ696 50 mg bid for two weeks. At the end of those two weeks subjects will report to the Clinical Research Center (CRC) for a dose escalation visit. If their tolerance, blood pressure, potassium, and eGFR meet escalation criteria they will be given LCZ696 100 mg bid for three weeks. (If they do not meet escalation criteria they will be continued on LCZ696 50 mg bid.) After three weeks, they will return to the CRC for the next escalation visit. If they meet criteria for escalation they will be given LCZ 200 mg bid for ten days. (If they do not meet escalation criteria they will be continued on the highest tolerated dose). Icatibant: Icatibant will be given intravenously at 100 µg/kg over one hour followed by 20 µg/kg/hr during each study day. placebo: Placebo (vehicle) will be given at the same rate as icatibant.	Icatibant, Placebo, Icatibant Placebo n=9 Participants After a 48-hr washout, participants in this arm will be given LCZ696 50 mg and icatibant. After a 96-hr washout period, subjects will be given LCZ696 50 mg and placebo. Participants will then undergo uptitration of LCZ696 over seven weeks. On the 7th and 10th days of the 200 mg bid or highest tolerated dose of LCZ696, participants in this arm will receive icatibant and placebo, respectively. LCZ 696: Treatment with LCZ696 is unblinded in this study. After the two acute study days, subjects will be provided LCZ696 50 mg bid for two weeks. At the end of those two weeks subjects will report to the Clinical Research Center (CRC) for a dose escalation visit. If their tolerance, blood pressure, potassium, and eGFR meet escalation criteria they will be given LCZ696 100 mg bid for three weeks. (If they do not meet escalation criteria they will be continued on LCZ696 50 mg bid.) After three weeks, they will return to the CRC for the next escalation visit. If they meet criteria for escalation they will be given LCZ 200 mg bid for ten days. (If they do not meet escalation criteria they will be continued on the highest tolerated dose). Icatibant: Icatibant will be given intravenously at 100 µg/kg over one hour followed by 20 µg/kg/hr during each study day. placebo: Placebo (vehicle) will be given at the same rate as icatibant.	Total n=30 Participants Total of all reporting groups
Age, Continuous	59.5 years STANDARD_DEVIATION 14.1 • n=54 Participants	61.0 years STANDARD_DEVIATION 11.2 • n=54 Participants	68.3 years STANDARD_DEVIATION 12.7 • n=27 Participants	61.4 years STANDARD_DEVIATION 13.8 • n=26 Participants	62.3 years STANDARD_DEVIATION 12.7 • n=161 Participants
Sex: Female, Male Female	2 Participants n=54 Participants	3 Participants n=54 Participants	0 Participants n=27 Participants	1 Participants n=26 Participants	6 Participants n=161 Participants
Sex: Female, Male Male	5 Participants n=54 Participants	5 Participants n=54 Participants	6 Participants n=27 Participants	8 Participants n=26 Participants	24 Participants n=161 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=54 Participants	0 Participants n=54 Participants	0 Participants n=27 Participants	0 Participants n=26 Participants	0 Participants n=161 Participants
Race (NIH/OMB) Asian	1 Participants n=54 Participants	0 Participants n=54 Participants	0 Participants n=27 Participants	0 Participants n=26 Participants	1 Participants n=161 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=54 Participants	0 Participants n=54 Participants	0 Participants n=27 Participants	0 Participants n=26 Participants	0 Participants n=161 Participants
Race (NIH/OMB) Black or African American	0 Participants n=54 Participants	1 Participants n=54 Participants	1 Participants n=27 Participants	2 Participants n=26 Participants	4 Participants n=161 Participants
Race (NIH/OMB) White	6 Participants n=54 Participants	7 Participants n=54 Participants	5 Participants n=27 Participants	7 Participants n=26 Participants	25 Participants n=161 Participants
Race (NIH/OMB) More than one race	0 Participants n=54 Participants	0 Participants n=54 Participants	0 Participants n=27 Participants	0 Participants n=26 Participants	0 Participants n=161 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=54 Participants	0 Participants n=54 Participants	0 Participants n=27 Participants	0 Participants n=26 Participants	0 Participants n=161 Participants

PRIMARY outcome

Timeframe: Eight hours

Mean arterial pressure (MAP) will be measured before and after administration of LCZ696 on each of the four study days.

Outcome measures

Outcome measures
Measure	Placebo n=30 Participants participants who received placebo after seven weeks of therapy with sacubitril/valsartan	Icatibant n=30 Participants participants who received icatibant after seven weeks of therapy with sacubitril valsartan
Mean Arterial Pressure	-11.93 change in mmHg Standard Deviation 9.47	-9.13 change in mmHg Standard Deviation 8.37

PRIMARY outcome

Timeframe: Total urine output from drug administration to six hours following drug administration

Urine sodium excretion will be measured for six hours following study LCZ696 on each of the four study days.

Outcome measures

Outcome measures
Measure	Placebo n=30 Participants participants who received placebo after seven weeks of therapy with sacubitril/valsartan	Icatibant n=30 Participants participants who received icatibant after seven weeks of therapy with sacubitril valsartan
Urine Sodium Excretion	89.9 mmol Standard Deviation 41.1	80.2 mmol Standard Deviation 38.6

SECONDARY outcome

Timeframe: Over six hours on each of four study days

Heart rate (HR) will be measured before and after LCZ696 on each of the four study days.

Outcome measures

Outcome measures
Measure	Placebo n=30 Participants participants who received placebo after seven weeks of therapy with sacubitril/valsartan	Icatibant n=30 Participants participants who received icatibant after seven weeks of therapy with sacubitril valsartan
Heart Rate	8.03 change in beats per minute Standard Deviation 7.18	8.97 change in beats per minute Standard Deviation 6.95

SECONDARY outcome

Timeframe: Over six hours on each of four study days

Urine volume will be measured for six hours following LCZ696 on each of the four study days.

Outcome measures

Outcome measures
Measure	Placebo n=30 Participants participants who received placebo after seven weeks of therapy with sacubitril/valsartan	Icatibant n=30 Participants participants who received icatibant after seven weeks of therapy with sacubitril valsartan
Urine Volume	684.8 mL Standard Deviation 291.9	665.8 mL Standard Deviation 301.5

SECONDARY outcome

Timeframe: Over six hours on each of four study days

Renal plasma flow (RPF) will be calculated from para-aminohippurate clearance prior to and following LCZ696.

Outcome measures

Outcome measures
Measure	Placebo n=30 Participants participants who received placebo after seven weeks of therapy with sacubitril/valsartan	Icatibant n=30 Participants participants who received icatibant after seven weeks of therapy with sacubitril valsartan
Renal Plasma Flow	-33.72 change in mL/min/1.73m2 Standard Deviation 42.20	-45.37 change in mL/min/1.73m2 Standard Deviation 88.22

SECONDARY outcome

Timeframe: Over six hours on each of four study days

Glomerular filtration rate (GFR) will be calculated from the clearance of iohexol prior to and following LCZ66 on each of the four study days.