Trial Outcomes & Findings for Efficacy and Safety of LCZ696 in Comparison to Olmesartan in Japanese Patients With Essential Hypertension (NCT NCT01599104)

NCT ID: NCT01599104

Last Updated: 2015-10-16

Results Overview

Sitting BP measurements were performed at screening through the end of study at every visit. Four separate sitting BP were obtained with a full two-minute interval between measurements. The 4 measurements were summed and averaged, and then the baseline BP value was subtracted from the average value to get the change from baseline.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 1161 participants
• Primary outcome timeframe: Baseline, 8 weeks
• Results posted on: 2015-10-16

Participant Flow

The study consisted of 3 epochs: 1)screening, 2) single blind run-in and 3) double blind treatment. During the run-in epoch, eligible participants received placebo to both treatments for 2 to 4 weeks. After the run-in epoch, a total of 1161 eligible participants continued into the double blind treatment epoch for 8 weeks.

Participant milestones

Measure	LCZ696 200 mg LCZ696 200 mg tablet and a placebo tablet once daily for eight weeks	LCZ696 400 mg LCZ696 200 mg tablet and a placebo tablet once daily for one week, then up-titrated to 400 mg once daily for the remaining 7 weeks	Olmesartan 20 mg Olmesartan 20 mg tablet and a placebo tablet once daily for 8 weeks
Overall Study STARTED	387	385	389
Overall Study COMPLETED	371	371	363
Overall Study NOT COMPLETED	16	14	26

Reasons for withdrawal

Measure	LCZ696 200 mg LCZ696 200 mg tablet and a placebo tablet once daily for eight weeks	LCZ696 400 mg LCZ696 200 mg tablet and a placebo tablet once daily for one week, then up-titrated to 400 mg once daily for the remaining 7 weeks	Olmesartan 20 mg Olmesartan 20 mg tablet and a placebo tablet once daily for 8 weeks
Overall Study Withdrawal by Subject	1	1	2
Overall Study Technical Problems	1	0	0
Overall Study Physician Decision	3	2	2
Overall Study Non-compliance with study treatment	0	1	0
Overall Study Lack of Efficacy	4	4	10
Overall Study Adverse Event	7	6	12

Baseline Characteristics

Efficacy and Safety of LCZ696 in Comparison to Olmesartan in Japanese Patients With Essential Hypertension

Baseline characteristics by cohort

Measure	LCZ696 200 mg n=387 Participants LCZ696 200 mg tablet and a placebo tablet once daily for eight weeks	LCZ696 400 mg n=385 Participants LCZ696 200 mg tablet and a placebo tablet once daily for one week, then up-titrated to 400 mg once daily for the remaining 7 weeks	Olmesartan 20 mg n=389 Participants Olmesartan 20 mg tablet and a placebo tablet once daily for 8 weeks	Total n=1161 Participants Total of all reporting groups
Age, Continuous	57.9 Years STANDARD_DEVIATION 10.87 • n=5 Participants	58.7 Years STANDARD_DEVIATION 10.50 • n=7 Participants	59.6 Years STANDARD_DEVIATION 10.50 • n=5 Participants	58.7 Years STANDARD_DEVIATION 10.64 • n=4 Participants
Sex: Female, Male Female	123 Participants n=5 Participants	117 Participants n=7 Participants	103 Participants n=5 Participants	343 Participants n=4 Participants
Sex: Female, Male Male	264 Participants n=5 Participants	268 Participants n=7 Participants	286 Participants n=5 Participants	818 Participants n=4 Participants

PRIMARY outcome

Timeframe: Baseline, 8 weeks

Population: Full Analysis Set (FAS): The full analysis set included all randomized participants who received study medication and had both baseline and post-baseline BP assessments.

Sitting BP measurements were performed at screening through the end of study at every visit. Four separate sitting BP were obtained with a full two-minute interval between measurements. The 4 measurements were summed and averaged, and then the baseline BP value was subtracted from the average value to get the change from baseline.

Outcome measures

Measure	LCZ696 200 mg n=387 Participants LCZ696 200 mg tablet and a placebo tablet once daily for eight weeks	LCZ696 400 mg n=385 Participants LCZ696 200 mg tablet and a placebo tablet once daily for one week, then up-titrated to 400 mg once daily for the remaining 7 weeks	Olmesartan 20 mg n=389 Participants Olmesartan 20 mg tablet and a placebo tablet once daily for 8 weeks
Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP)	-18.21 mmHg Standard Error 0.702	-20.18 mmHg Standard Error 0.704	-13.20 mmHg Standard Error 0.700

SECONDARY outcome

Timeframe: Baseline, 8 weeks

Population: The full analysis set included all randomized participants who received study medication, and had both baseline and post-baseline ABPM measurements. This outcome measure was analyzed in a subset of participants within each treatment group where n = 216 for the LCZ 200 mg group, n = 216 for the LCZ 400 mg group and n = 200 for the Olmesartan group.

Ambulatory blood pressure monitoring (ABPM) over a 24-hour period was conducted at two time-points during the study in a subset of participants.

Outcome measures

Measure	LCZ696 200 mg n=216 Participants LCZ696 200 mg tablet and a placebo tablet once daily for eight weeks	LCZ696 400 mg n=216 Participants LCZ696 200 mg tablet and a placebo tablet once daily for one week, then up-titrated to 400 mg once daily for the remaining 7 weeks	Olmesartan 20 mg n=200 Participants Olmesartan 20 mg tablet and a placebo tablet once daily for 8 weeks
Change From Baseline in Mean 24-hour Ambulatory SBP (maSBP) at Week 8	-13.44 mmHg Standard Error 0.445	-14.99 mmHg Standard Error 0.445	-8.78 mmHg Standard Error 0.462

SECONDARY outcome

Timeframe: Baseline, 8 weeks

Population: The full analysis set included all randomized participants who received study medication, and had both baseline and post-baseline BP measurements.

Sitting BP measurement was performed at screening through the end of study at every visit. Four separate sitting BP were obtained with a full two-minute interval between measurement. The 4 measurements were summed and averaged, and then the baseline BP value was subtracted from the average value to get the change from baseline.

Outcome measures

Measure	LCZ696 200 mg n=387 Participants LCZ696 200 mg tablet and a placebo tablet once daily for eight weeks	LCZ696 400 mg n=385 Participants LCZ696 200 mg tablet and a placebo tablet once daily for one week, then up-titrated to 400 mg once daily for the remaining 7 weeks	Olmesartan 20 mg n=389 Participants Olmesartan 20 mg tablet and a placebo tablet once daily for 8 weeks
Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP)	-7.76 mmHg Standard Error 0.404	-8.79 mmHg Standard Error 0.406	-5.91 mmHg Standard Error 0.404

SECONDARY outcome

Timeframe: 8 weeks

Population: The full analysis set included all randomized participants who received study medication, and had both baseline and post-baseline BP measurements.

A successful response in overall BP control rate was defined as msSBP < 140 mmHg and msDBP <90 mmHg.

Outcome measures

Measure	LCZ696 200 mg n=387 Participants LCZ696 200 mg tablet and a placebo tablet once daily for eight weeks	LCZ696 400 mg n=385 Participants LCZ696 200 mg tablet and a placebo tablet once daily for one week, then up-titrated to 400 mg once daily for the remaining 7 weeks	Olmesartan 20 mg n=389 Participants Olmesartan 20 mg tablet and a placebo tablet once daily for 8 weeks
Percentage of Participants Achieving a Successful Response in Overall Blood Pressure Control at Week 8	43.9 Percentage of participants	46.5 Percentage of participants	32.9 Percentage of participants

SECONDARY outcome

Timeframe: 8 weeks

Population: The full analysis set included all randomized participants who received study medication, and had both baseline and post-baseline BP measurements.

Successful msSBP response was defined as < 140 mmHg or ≥ 20 mmHg reduction from baseline.

Outcome measures

Measure	LCZ696 200 mg n=387 Participants LCZ696 200 mg tablet and a placebo tablet once daily for eight weeks	LCZ696 400 mg n=385 Participants LCZ696 200 mg tablet and a placebo tablet once daily for one week, then up-titrated to 400 mg once daily for the remaining 7 weeks	Olmesartan 20 mg n=389 Participants Olmesartan 20 mg tablet and a placebo tablet once daily for 8 weeks
Percentage of Participants Achieving a Successful msSBP Response	57.9 Percentage of participants	63.1 Percentage of participants	42.9 Percentage of participants

SECONDARY outcome

Timeframe: 8 weeks

Population: The full analysis set included all randomized participants who received study medication, and had both baseline and post-baseline BP measurements.

Successfull msDBP response was defined as <90 mmHg or ≥10 mmHg reduction from baseline.

Outcome measures

Measure	LCZ696 200 mg n=387 Participants LCZ696 200 mg tablet and a placebo tablet once daily for eight weeks	LCZ696 400 mg n=385 Participants LCZ696 200 mg tablet and a placebo tablet once daily for one week, then up-titrated to 400 mg once daily for the remaining 7 weeks	Olmesartan 20 mg n=389 Participants Olmesartan 20 mg tablet and a placebo tablet once daily for 8 weeks
Percentage of Participants Achieving a Successful msDBP Response	69.5 Percentage of participants	70.1 Percentage of participants	60.7 Percentage of participants

SECONDARY outcome

Timeframe: Baseline, 8 weeks

Population: The full analysis set included all randomized participants who received study medication, and had both baseline and post-baseline ABPM measurements. This outcome measure was analyzed in a subset of participants within each treatment group where n = 216 for the LCZ 200 mg group, n = 216 for the LCZ 400 mg group and n = 200 for the Olmesartan group.

ABPM over a 24-hour period was conducted at two time-points during the study in a subset of participants.

Outcome measures

Measure	LCZ696 200 mg n=216 Participants LCZ696 200 mg tablet and a placebo tablet once daily for eight weeks	LCZ696 400 mg n=216 Participants LCZ696 200 mg tablet and a placebo tablet once daily for one week, then up-titrated to 400 mg once daily for the remaining 7 weeks	Olmesartan 20 mg n=200 Participants Olmesartan 20 mg tablet and a placebo tablet once daily for 8 weeks
Change From Baseline in Mean 24-hour Ambulatory DBP (maDBP) at Week 8	-7.65 mmHg Standard Error 0.295	-8.44 mmHg Standard Error 0.295	-5.56 mmHg Standard Error 0.307

SECONDARY outcome

Timeframe: Baseline, 8 weeks

Population: The full analysis set included all randomized participants who received study medication, and had both baseline and post-baseline ABPM measurements. This outcome measure was analyzed in a subset of participants within each treatment group where n = 216 for the LCZ 200 mg group, n = 216 for the LCZ 400 mg group and n = 200 for the Olmesartan group.

ABPM over a 24-hour period was conducted at two time-points during the study in a subset of participants.

Outcome measures

Measure	LCZ696 200 mg n=216 Participants LCZ696 200 mg tablet and a placebo tablet once daily for eight weeks	LCZ696 400 mg n=216 Participants LCZ696 200 mg tablet and a placebo tablet once daily for one week, then up-titrated to 400 mg once daily for the remaining 7 weeks	Olmesartan 20 mg n=200 Participants Olmesartan 20 mg tablet and a placebo tablet once daily for 8 weeks
Change From Baseline in maSBP and maDBP for Daytime/Nighttime maDBP daytime	-7.01 mmHg Standard Error 0.506	-8.00 mmHg Standard Error 0.506	-4.95 mmHg Standard Error 0.526
Change From Baseline in maSBP and maDBP for Daytime/Nighttime maSBP daytime	-12.60 mmHg Standard Error 0.747	-14.44 mmHg Standard Error 0.747	-7.87 mmHg Standard Error 0.776
Change From Baseline in maSBP and maDBP for Daytime/Nighttime maSBP nighttime	-15.13 mmHg Standard Error 0.747	-16.09 mmHg Standard Error 0.747	-10.65 mmHg Standard Error 0.776
Change From Baseline in maSBP and maDBP for Daytime/Nighttime maDBP nighttime	-8.82 mmHg Standard Error 0.506	-9.42 mmHg Standard Error 0.506	-6.79 mmHg Standard Error 0.526

SECONDARY outcome

Timeframe: Baseline, 8 weeks

Population: The full analysis set included all randomized participants who received study medication, and had both baseline and post-baseline BP measurements.

Office pulse pressure was calculated as msSBP minus msDBP. Sitting blood pressure (BP) measurement was performed at screening through the end of study at every visit. Four separate sitting BP were obtained with a full two-minute interval between measurement. The 4 measurements were summed and then averaged to calculate the mean BP value. The baseline PP value was subtracted from the week 8 PP value to determine the change from baseline in PP.

Outcome measures

Measure	LCZ696 200 mg n=387 Participants LCZ696 200 mg tablet and a placebo tablet once daily for eight weeks	LCZ696 400 mg n=385 Participants LCZ696 200 mg tablet and a placebo tablet once daily for one week, then up-titrated to 400 mg once daily for the remaining 7 weeks	Olmesartan 20 mg n=389 Participants Olmesartan 20 mg tablet and a placebo tablet once daily for 8 weeks
Change From Baseline in Office Pulse Pressure	-10.49 mmHg Standard Error 0.471	-11.30 mmHg Standard Error 0.472	-7.34 mmHg Standard Error 0.470

SECONDARY outcome

Timeframe: Baseline, 8 weeks

Population: The full analysis set included all randomized participants who received study medication, and had both baseline and post-baseline ABPM measurements. This outcome measure was analyzed in a subset of participants within each treatment group where n = 216 for the LCZ 200 mg group, n = 216 for the LCZ 400 mg group and n = 200 for the Olmesartan group.

Ambulatory pulse pressure was calculated as hourly ambulatory SBP minus hourly ambulatory DBP in a subset of participants.

Outcome measures

Measure	LCZ696 200 mg n=216 Participants LCZ696 200 mg tablet and a placebo tablet once daily for eight weeks	LCZ696 400 mg n=216 Participants LCZ696 200 mg tablet and a placebo tablet once daily for one week, then up-titrated to 400 mg once daily for the remaining 7 weeks	Olmesartan 20 mg n=200 Participants Olmesartan 20 mg tablet and a placebo tablet once daily for 8 weeks
Change From Baseline in Mean 24-hour Ambulatory Pulse Pressure	-5.79 mmHg Standard Error 0.208	-6.57 mmHg Standard Error 0.207	-3.20 mmHg Standard Error 0.216

SECONDARY outcome

Timeframe: 8 weeks

Population: Safety Set. The safety set included aqll participants who had received study medication.

Participants were monitored for adverse events, serious adverse events and deaths throughout the study.

Outcome measures

Measure	LCZ696 200 mg n=387 Participants LCZ696 200 mg tablet and a placebo tablet once daily for eight weeks	LCZ696 400 mg n=385 Participants LCZ696 200 mg tablet and a placebo tablet once daily for one week, then up-titrated to 400 mg once daily for the remaining 7 weeks	Olmesartan 20 mg n=389 Participants Olmesartan 20 mg tablet and a placebo tablet once daily for 8 weeks
Number of Patients With Adverse Events, Serious Adverse Events and Death Adverse Events (serious and non-serious)	135 Participants	136 Participants	152 Participants
Number of Patients With Adverse Events, Serious Adverse Events and Death Seroius Adverse Events	1 Participants	1 Participants	7 Participants
Number of Patients With Adverse Events, Serious Adverse Events and Death Deaths	0 Participants	0 Participants	0 Participants

Adverse Events

LCZ696 200 mg

Serious events: 1 serious events

Other events: 48 other events

Deaths: 0 deaths

LCZ696 400 mg

Serious events: 1 serious events

Other events: 47 other events

Deaths: 0 deaths

Olmesartan 20 mg

Serious events: 7 serious events

Other events: 46 other events

Deaths: 0 deaths

Serious adverse events

Measure	LCZ696 200 mg n=387 participants at risk LCZ696 200 mg tablet and a placebo tablet once daily for eight weeks	LCZ696 400 mg n=385 participants at risk LCZ696 200 mg tablet and a placebo tablet once daily for one week, then up-titrated to 400 mg once daily for the remaining 7 weeks	Olmesartan 20 mg n=389 participants at risk Olmesartan 20 mg tablet and a placebo tablet once daily for 8 weeks
Cardiac disorders ARTERIOSCLEROSIS CORONARY ARTERY	0.00% 0/387	0.26% 1/385	0.00% 0/389
Cardiac disorders SUPRAVENTRICULAR TACHYCARDIA	0.00% 0/387	0.00% 0/385	0.26% 1/389
Eye disorders CATARACT	0.00% 0/387	0.00% 0/385	0.26% 1/389
Hepatobiliary disorders BILE DUCT STONE	0.00% 0/387	0.00% 0/385	0.26% 1/389
Hepatobiliary disorders HEPATOBILIARY DISEASE	0.00% 0/387	0.26% 1/385	0.00% 0/389
Injury, poisoning and procedural complications RADIUS FRACTURE	0.00% 0/387	0.00% 0/385	0.26% 1/389
Investigations ALANINE AMINOTRANSFERASE INCREASED	0.00% 0/387	0.00% 0/385	0.26% 1/389
Musculoskeletal and connective tissue disorders OSTEOARTHRITIS	0.00% 0/387	0.00% 0/385	0.26% 1/389
Nervous system disorders CEREBRAL INFARCTION	0.00% 0/387	0.00% 0/385	0.26% 1/389
Nervous system disorders SUBARACHNOID HAEMORRHAGE	0.26% 1/387	0.00% 0/385	0.00% 0/389

Other adverse events

Measure	LCZ696 200 mg n=387 participants at risk LCZ696 200 mg tablet and a placebo tablet once daily for eight weeks	LCZ696 400 mg n=385 participants at risk LCZ696 200 mg tablet and a placebo tablet once daily for one week, then up-titrated to 400 mg once daily for the remaining 7 weeks	Olmesartan 20 mg n=389 participants at risk Olmesartan 20 mg tablet and a placebo tablet once daily for 8 weeks
Infections and infestations NASOPHARYNGITIS	12.4% 48/387	12.2% 47/385	11.8% 46/389

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: +1 (862) 778-8300

Results disclosure agreements

• Principal investigator is a sponsor employee The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.
• Publication restrictions are in place

Restriction type: OTHER