Trial Outcomes & Findings for A Study to Evaluate the Effects of LCI699 on Cortisol in Participants With Hypertension (NCT NCT00817414)

Last Updated: 2021-06-02

Results Overview

As per the protocol, MTD is the dose at which 4 participants exhibited ACTH-stimulated cortisol results \<400 nanomoles per liter (nmol/L). The change in the distribution across the treatments were analyzed using 1- way analysis of variance (ANOVA) for continuous variables.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

63 participants

Primary outcome timeframe

Up to Week 6

Results posted on

2021-06-02

Participant Flow

Participants were enrolled at 10 investigative sites in the United States and Iceland from 14 January 2009 to 12 August 2009.

A total of 63 participants with essential hypertension taking at least one anti-hypertensive treatment were randomized to receive LCI699 in comparison with placebo in an escalated dose design for 6 weeks.

Participant milestones

Participant milestones
Measure	Cohort A: LCI699 0.5 mg QD Participants received LCI699 0.5 mg, capsules, orally, once daily (QD), with or without food for up to 6 weeks.	Cohort A: LCI699 1 mg QD Participants received LCI699 1.0 mg, capsules, orally, QD, with or without food for up to 6 weeks.	Cohort B1: LCI699 1 mg BID Participants received LCI699 1.0 mg, capsules, orally, twice daily (BID), with or without food for up to 6 weeks.	Cohort B1: LCI699 2 mg QD Participants received LCI699 2.0 mg, capsules, orally, QD, with or without food for up to 6 weeks.	Placebo Participants received LCI699-matching placebo, capsules, orally, QD or BID with or without food for up to 6 weeks.
Overall Study STARTED	12	12	13	13	13
Overall Study COMPLETED	10	9	9	1	11
Overall Study NOT COMPLETED	2	3	4	12	2

Reasons for withdrawal

Reasons for withdrawal
Measure	Cohort A: LCI699 0.5 mg QD Participants received LCI699 0.5 mg, capsules, orally, once daily (QD), with or without food for up to 6 weeks.	Cohort A: LCI699 1 mg QD Participants received LCI699 1.0 mg, capsules, orally, QD, with or without food for up to 6 weeks.	Cohort B1: LCI699 1 mg BID Participants received LCI699 1.0 mg, capsules, orally, twice daily (BID), with or without food for up to 6 weeks.	Cohort B1: LCI699 2 mg QD Participants received LCI699 2.0 mg, capsules, orally, QD, with or without food for up to 6 weeks.	Placebo Participants received LCI699-matching placebo, capsules, orally, QD or BID with or without food for up to 6 weeks.
Overall Study Adverse Event	1	1	1	0	0
Overall Study Low Adrenocorticotropic Hormone (ACTH)- Stimulated Cortisol	0	1	2	4	0
Overall Study Withdrawal by Subject	1	1	0	0	0
Overall Study Lost to Follow-up	0	0	1	1	1
Overall Study Dose Arm Exceeds Maximum Tolerated Dose (MTD)	0	0	0	7	0
Overall Study Protocol Violation	0	0	0	0	1

Baseline Characteristics

A Study to Evaluate the Effects of LCI699 on Cortisol in Participants With Hypertension

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Cohort A: LCI699 0.5 mg QD n=12 Participants Participants received LCI699 0.5 mg, capsules, orally, once daily (QD), with or without food for up to 6 weeks.	Cohort A: LCI699 1 mg QD n=12 Participants Participants received LCI699 1.0 mg, capsules, orally, QD, with or without food for up to 6 weeks.	Cohort B1: LCI699 1 mg BID n=13 Participants Participants received LCI699 1.0 mg, capsules, orally, twice daily (BID), with or without food for up to 6 weeks.	Cohort B1: LCI699 2 mg QD n=13 Participants Participants received LCI699 2.0 mg, capsules, orally, QD, with or without food for up to 6 weeks.	Placebo n=13 Participants Participants received LCI699-matching placebo, capsules, orally, QD or BID with or without food for up to 6 weeks.	Total n=63 Participants Total of all reporting groups
Age, Continuous	56.1 years STANDARD_DEVIATION 6.37 • n=93 Participants	54.2 years STANDARD_DEVIATION 16.01 • n=4 Participants	57.9 years STANDARD_DEVIATION 9.09 • n=27 Participants	56.2 years STANDARD_DEVIATION 10.37 • n=483 Participants	56.8 years STANDARD_DEVIATION 10.08 • n=36 Participants	56.3 years STANDARD_DEVIATION 10.52 • n=10 Participants
Sex: Female, Male Female	4 Participants n=93 Participants	5 Participants n=4 Participants	3 Participants n=27 Participants	5 Participants n=483 Participants	4 Participants n=36 Participants	21 Participants n=10 Participants
Sex: Female, Male Male	8 Participants n=93 Participants	7 Participants n=4 Participants	10 Participants n=27 Participants	8 Participants n=483 Participants	9 Participants n=36 Participants	42 Participants n=10 Participants

PRIMARY outcome

Timeframe: Up to Week 6

Population: Safety set population included all participants who were randomized and received at least 1 dose of study drug.

Outcome measures

Outcome measures
Measure	LCI699 n=63 Participants Participants received LCI699 capsules, orally, QD or BID, with or without food for up to 6 weeks.	Cohort A: LCI699 1.0 mg QD Participants received LCI699 1.0 mg, capsules, orally, QD, with or without food for up to 6 weeks.	Cohort B1: LCI699 1.0 mg BID Participants received LCI699 1.0 mg, capsules, orally, twice daily (BID), with or without food for up to 6 weeks.	Cohort B1: LCI699 2.0 mg QD Participants received LCI699 2.0 mg, capsules, orally, QD, with or without food for up to 6 weeks.	Placebo Participants received LCI699-matching placebo, capsules, orally, QD or BID, with or without food for up to 6 weeks.
Maximum Tolerated Dose (MTD) of LCI699 With Respect to Effect on the Adrenocorticotropic Hormone (ACTH)-Stimulated Cortisol Response Following ACTH Stimulation in Hypertensive Participants	1.30 milligrams (mg) Interval 0.88 to 1.81	—	—	—	—

SECONDARY outcome

Timeframe: Up to Week 6

Population: Safety set population included all participants who were randomized and received at least 1 dose of study drug. Number analyzed is the number of participants with data available for analyses at the given timepoint.

Exposure-response relationship was assessed using ACTH stimulation test. Tests were done 2 hours after study drug administration (i.e., at peak LCI699 concentrations). An increase in cortisol greater than \>500 nmol at 60 minutes after ACTH administration was expected.

Outcome measures

Outcome measures
Measure	LCI699 n=11 Participants Participants received LCI699 capsules, orally, QD or BID, with or without food for up to 6 weeks.	Cohort A: LCI699 1.0 mg QD n=12 Participants Participants received LCI699 1.0 mg, capsules, orally, QD, with or without food for up to 6 weeks.	Cohort B1: LCI699 1.0 mg BID n=12 Participants Participants received LCI699 1.0 mg, capsules, orally, twice daily (BID), with or without food for up to 6 weeks.	Cohort B1: LCI699 2.0 mg QD n=13 Participants Participants received LCI699 2.0 mg, capsules, orally, QD, with or without food for up to 6 weeks.	Placebo n=12 Participants Participants received LCI699-matching placebo, capsules, orally, QD or BID, with or without food for up to 6 weeks.
LCI699 Exposure-response Relationship on Cortisol Levels Following ACTH Stimulation in Hypertensive Participants Day 7	690.0 nanomoles per liter (nmol/L) Standard Error 32.288	669.40 nanomoles per liter (nmol/L) Standard Error 30.903	625.06 nanomoles per liter (nmol/L) Standard Error 30.965	562.04 nanomoles per liter (nmol/L) Standard Error 30.325	799.06 nanomoles per liter (nmol/L) Standard Error 31.161
LCI699 Exposure-response Relationship on Cortisol Levels Following ACTH Stimulation in Hypertensive Participants Day 28	634.87 nanomoles per liter (nmol/L) Standard Error 32.181	573.41 nanomoles per liter (nmol/L) Standard Error 30.642	554.79 nanomoles per liter (nmol/L) Standard Error 29.466	539.09 nanomoles per liter (nmol/L) Standard Error 32.826	804.86 nanomoles per liter (nmol/L) Standard Error 29.786
LCI699 Exposure-response Relationship on Cortisol Levels Following ACTH Stimulation in Hypertensive Participants Day 42	647.51 nanomoles per liter (nmol/L) Standard Error 45.593	626.08 nanomoles per liter (nmol/L) Standard Error 45.441	539.68 nanomoles per liter (nmol/L) Standard Error 37.146	479.91 nanomoles per liter (nmol/L) Standard Error 48.865	812.91 nanomoles per liter (nmol/L) Standard Error 39.096

SECONDARY outcome

Timeframe: Predose and 3 hours post-dose on Day 7

Population: Pharmacokinetic (PK) set population included all participants with sufficient LCI699 plasma samples at post-baseline visits.

Outcome measures

Outcome measures
Measure	LCI699 n=11 Participants Participants received LCI699 capsules, orally, QD or BID, with or without food for up to 6 weeks.	Cohort A: LCI699 1.0 mg QD n=12 Participants Participants received LCI699 1.0 mg, capsules, orally, QD, with or without food for up to 6 weeks.	Cohort B1: LCI699 1.0 mg BID n=13 Participants Participants received LCI699 1.0 mg, capsules, orally, twice daily (BID), with or without food for up to 6 weeks.	Cohort B1: LCI699 2.0 mg QD n=13 Participants Participants received LCI699 2.0 mg, capsules, orally, QD, with or without food for up to 6 weeks.	Placebo Participants received LCI699-matching placebo, capsules, orally, QD or BID, with or without food for up to 6 weeks.
LCI699 Plasma Concentration Post LCI699 Administration at Day 7	1.51 nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 36	2.88 nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 41	3.92 nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 31	6.73 nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 23	—

SECONDARY outcome

Timeframe: Days 7, 28: Pre-dose and 3 hours post-dose; Day 30: Pre-dose; Day 42: Pre-dose and 0.5, 1, 2, 3, 4, and 8-hours post-dose

Population: PK set population included all participants with sufficient LCI699 plasma samples at post-baseline visits. Overall number analysed is the number of participants with data available for these analyses.

Outcome measures

Outcome measures
Measure	LCI699 n=10 Participants Participants received LCI699 capsules, orally, QD or BID, with or without food for up to 6 weeks.	Cohort A: LCI699 1.0 mg QD n=7 Participants Participants received LCI699 1.0 mg, capsules, orally, QD, with or without food for up to 6 weeks.	Cohort B1: LCI699 1.0 mg BID n=12 Participants Participants received LCI699 1.0 mg, capsules, orally, twice daily (BID), with or without food for up to 6 weeks.	Cohort B1: LCI699 2.0 mg QD n=4 Participants Participants received LCI699 2.0 mg, capsules, orally, QD, with or without food for up to 6 weeks.	Placebo Participants received LCI699-matching placebo, capsules, orally, QD or BID, with or without food for up to 6 weeks.
Maximum Plasma Concentration (Cmax) of LCI699	1.42 ng/mL Geometric Coefficient of Variation 36	2.94 ng/mL Geometric Coefficient of Variation 35	4.62 ng/mL Geometric Coefficient of Variation 35	8.86 ng/mL Geometric Coefficient of Variation 21	—

SECONDARY outcome

Timeframe: Days 7, 28: Pre-dose and 3 hours post-dose; Day 30: Pre-dose; Day 42: Pre-dose and 0.5, 1, 2, 3, 4, and 8-hours post-dose

Outcome measures

Outcome measures
Measure	LCI699 n=10 Participants Participants received LCI699 capsules, orally, QD or BID, with or without food for up to 6 weeks.	Cohort A: LCI699 1.0 mg QD n=7 Participants Participants received LCI699 1.0 mg, capsules, orally, QD, with or without food for up to 6 weeks.	Cohort B1: LCI699 1.0 mg BID n=12 Participants Participants received LCI699 1.0 mg, capsules, orally, twice daily (BID), with or without food for up to 6 weeks.	Cohort B1: LCI699 2.0 mg QD n=4 Participants Participants received LCI699 2.0 mg, capsules, orally, QD, with or without food for up to 6 weeks.	Placebo Participants received LCI699-matching placebo, capsules, orally, QD or BID, with or without food for up to 6 weeks.
Time of Maximum Plasma Concentration (Tmax) of LCI699	2.21 hour (hr) Interval 1.0 to 4.0	1.00 hour (hr) Interval 1.0 to 4.0	1.00 hour (hr) Interval 0.5 to 4.0	1.00 hour (hr) Interval 1.0 to 3.0	—

SECONDARY outcome

Timeframe: Day 42: Pre-dose and 0.5, 1, 2, 3, 4, and 8-hours post-dose

Outcome measures

Outcome measures
Measure	LCI699 n=10 Participants Participants received LCI699 capsules, orally, QD or BID, with or without food for up to 6 weeks.	Cohort A: LCI699 1.0 mg QD n=7 Participants Participants received LCI699 1.0 mg, capsules, orally, QD, with or without food for up to 6 weeks.	Cohort B1: LCI699 1.0 mg BID n=12 Participants Participants received LCI699 1.0 mg, capsules, orally, twice daily (BID), with or without food for up to 6 weeks.	Cohort B1: LCI699 2.0 mg QD n=4 Participants Participants received LCI699 2.0 mg, capsules, orally, QD, with or without food for up to 6 weeks.	Placebo Participants received LCI699-matching placebo, capsules, orally, QD or BID, with or without food for up to 6 weeks.
Area Under the Concentration Time Curve From Time 0 to 8 Hours Post LCI699 Administration (AUC0-8)	6.60 nanogramhour per milliliter (nghr/mL) Geometric Coefficient of Variation 42	14.1 nanogramhour per milliliter (nghr/mL) Geometric Coefficient of Variation 30	24.1 nanogramhour per milliliter (nghr/mL) Geometric Coefficient of Variation 39	46.4 nanogramhour per milliliter (nghr/mL) Geometric Coefficient of Variation 13	—

SECONDARY outcome

Timeframe: Days 7, 28: Pre-dose and 3 hours post-dose; Day 30: Pre-dose; Day 42: Pre-dose and 0.5, 1, 2, 3, 4, and 8-hours post-dose

Outcome measures

Outcome measures
Measure	LCI699 n=9 Participants Participants received LCI699 capsules, orally, QD or BID, with or without food for up to 6 weeks.	Cohort A: LCI699 1.0 mg QD n=6 Participants Participants received LCI699 1.0 mg, capsules, orally, QD, with or without food for up to 6 weeks.	Cohort B1: LCI699 1.0 mg BID n=11 Participants Participants received LCI699 1.0 mg, capsules, orally, twice daily (BID), with or without food for up to 6 weeks.	Cohort B1: LCI699 2.0 mg QD n=4 Participants Participants received LCI699 2.0 mg, capsules, orally, QD, with or without food for up to 6 weeks.	Placebo Participants received LCI699-matching placebo, capsules, orally, QD or BID, with or without food for up to 6 weeks.
Area Under the Concentration Time Curve Over the Dosing Interval (AUC0-τ) for LCI699	9.23 ng*hr/mL Geometric Coefficient of Variation 50	18.8 ng*hr/mL Geometric Coefficient of Variation 51	30.6 ng*hr/mL Geometric Coefficient of Variation 41	68.9 ng*hr/mL Geometric Coefficient of Variation 19	—

SECONDARY outcome

Timeframe: Days 7, 28: Pre-dose and 3 hours post-dose; Day 30: Pre-dose; Day 42: Pre-dose and 0.5, 1, 2, 3, 4, and 8-hours post-dose

Outcome measures

Outcome measures
Measure	LCI699 n=9 Participants Participants received LCI699 capsules, orally, QD or BID, with or without food for up to 6 weeks.	Cohort A: LCI699 1.0 mg QD n=6 Participants Participants received LCI699 1.0 mg, capsules, orally, QD, with or without food for up to 6 weeks.	Cohort B1: LCI699 1.0 mg BID n=11 Participants Participants received LCI699 1.0 mg, capsules, orally, twice daily (BID), with or without food for up to 6 weeks.	Cohort B1: LCI699 2.0 mg QD n=4 Participants Participants received LCI699 2.0 mg, capsules, orally, QD, with or without food for up to 6 weeks.	Placebo Participants received LCI699-matching placebo, capsules, orally, QD or BID, with or without food for up to 6 weeks.
Apparent Terminal Half-life (T1/2) of LCI699	4.67 hr Geometric Coefficient of Variation 37	3.79 hr Geometric Coefficient of Variation 43	5.52 hr Geometric Coefficient of Variation 33	4.90 hr Geometric Coefficient of Variation 17	—

SECONDARY outcome

Timeframe: Up to 8 weeks

Population: Safety set population included all participants who were randomized and received at least 1 dose of study drug.

An AE is an adverse medical event which occurs in a participant of the study and which is not necessarily in a causal relationship with the treatment the participant receives.

Outcome measures

Outcome measures
Measure	LCI699 n=12 Participants Participants received LCI699 capsules, orally, QD or BID, with or without food for up to 6 weeks.	Cohort A: LCI699 1.0 mg QD n=12 Participants Participants received LCI699 1.0 mg, capsules, orally, QD, with or without food for up to 6 weeks.	Cohort B1: LCI699 1.0 mg BID n=13 Participants Participants received LCI699 1.0 mg, capsules, orally, twice daily (BID), with or without food for up to 6 weeks.	Cohort B1: LCI699 2.0 mg QD n=13 Participants Participants received LCI699 2.0 mg, capsules, orally, QD, with or without food for up to 6 weeks.	Placebo n=13 Participants Participants received LCI699-matching placebo, capsules, orally, QD or BID, with or without food for up to 6 weeks.
Number of Participants With Adverse Event (AEs)	6 Participants	9 Participants	10 Participants	10 Participants	10 Participants

SECONDARY outcome

Timeframe: Week 6

Population: FAS population included all participants who were randomized and received at least 1 dose of study drug.

Automated arterial BP determinations was made with an automated BP device (such as the Omron BP monitor) in accordance with the Guidelines for management of hypertension: report of the 4th working party of the British Hypertension Society, 2004-BHS IV. Sitting and standing blood pressure (BP) and heart rate (HR) measurements were performed. MSSBP response was defined as the percentage of participants with a MSSBP \<140 mmHg or a \>=20 mmHg reduction from baseline. MSSBP control was defined as the percentage of participants with a MSSBP \<140 mmHg for non-diabetic participants and \<130mHg for diabetic participants.

Outcome measures

Outcome measures
Measure	LCI699 n=12 Participants Participants received LCI699 capsules, orally, QD or BID, with or without food for up to 6 weeks.	Cohort A: LCI699 1.0 mg QD n=12 Participants Participants received LCI699 1.0 mg, capsules, orally, QD, with or without food for up to 6 weeks.	Cohort B1: LCI699 1.0 mg BID n=13 Participants Participants received LCI699 1.0 mg, capsules, orally, twice daily (BID), with or without food for up to 6 weeks.	Cohort B1: LCI699 2.0 mg QD n=13 Participants Participants received LCI699 2.0 mg, capsules, orally, QD, with or without food for up to 6 weeks.	Placebo n=13 Participants Participants received LCI699-matching placebo, capsules, orally, QD or BID, with or without food for up to 6 weeks.
Percentage of Participants With a Mean Sitting Systolic Blood Pressure (MSSBP) Response and MSSBP Control at Week 6 Last Observation Carried Forward (LOCF), as Measured by Office Blood Pressure (OBP) MSSBP Response	58.3 percentage of participants	50.0 percentage of participants	69.2 percentage of participants	76.9 percentage of participants	61.5 percentage of participants
Percentage of Participants With a Mean Sitting Systolic Blood Pressure (MSSBP) Response and MSSBP Control at Week 6 Last Observation Carried Forward (LOCF), as Measured by Office Blood Pressure (OBP) MSSBP Control	50.0 percentage of participants	41.7 percentage of participants	61.5 percentage of participants	76.9 percentage of participants	53.8 percentage of participants

SECONDARY outcome

Timeframe: Week 6

Population: FAS population included all participants who were randomized and received at least 1 dose of study drug.

Automated arterial BP determinations was made with an automated BP device (such as the Omron BP monitor) in accordance with the Guidelines for management of hypertension: report of the 4th working party of the British Hypertension Society, 2004-BHS IV. Sitting and standing BP and HR measurements were performed. MSDBP response was defined as the percentage of participants with a MSDBP \<90 mmHg or a \>= 10 mmHg reduction from baseline. MSDBP control was defined as the percentage of participants with a MSDBP \<90 mmHg for non-diabetic participants and \<80mHg for diabetic participants.