A Study to Evaluate Efficacy and Safety of LCI699 in Participants With Essential Hypertension

Study Overview
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Brief Summary
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This study was a proof-of-efficacy, dose finding study of LCI699 in participants with mild-to-moderate uncomplicated essential hypertension in order to assess the blood pressure (BP) lowering effect, safety and tolerability of LCI699 as compared to placebo and eplerenone.

Official Title
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A Multi-center, Randomized, Double-blind, Placebo and Active Controlled, Parallel Group, Dose Finding Study to Evaluate the Efficacy and Safety of LCI699 Compared to Placebo After 8 Weeks Treatment in Patients With Essential Hypertension

Conditions
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Essential Hypertension

Intervention / Treatment
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* Drug: LCI699
* Drug: Eplerenone
* Drug: LCI699-matching Placebo
* Drug: Eplerenone-matching Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and non-fertile females. 18-75 years inclusive. Participants with mild-to-moderate uncomplicated essential hypertension. Exclusion Criteria: All women of child bearing potential. Female participants on hormone replacement therapy. Severe hypertension. History or evidence of a secondary form of hypertension. Known moderate or malignant retinopathy. History of angina pectoris, myocardial infarction, coronary bypass surgery,ischemic heart disease, surgical or percutaneous arterial intervention of any kind (coronary, carotid or peripheral vessels), stroke, transient ischemic attack (TIA), carotid artery stenosis, aortic aneurysm or peripheral arterial disease. Type 1 or type 2 diabetes mellitus. Clinically significant valvular heart disease. Congestive heart failure (New York Heart Association [NYHA] class II-IV). Cardiac electrical abnormalities indicating significant risk of safety for participant taking part in the study. History of malignancy of any organ system, treated or untreated, within the past 5 years. Liver disease such as cirrhosis or chronic active hepatitis. Any surgical or medical conditions that may significantly alter the absorption, distribution, metabolism or excretion of any drug substance Any surgical or medical conditions, not identified in the protocol that in the opinion of the investigator or the monitor, place the participant at higher risk from his/her participation in the study, or is likely to prevent the participant from complying with the requirements of the study or completing the trial period. Participant unwilling or not able to discontinue safely the use of current antihypertensive medications during the study period Any contraindication or history of hypersensitivity to any of the study drugs or to drugs with similar chemical structures. Chronic oral or parenteral corticosteroid treatment. Treatment with potassium supplement or potassium sparing diuretics. Treatment with potent cytochrome P450 3A4 (CYP3A4) inhibitors during the study period. Use of other investigational drugs at Visit 1, or within 30 days or 5 half-lives of Visit 1, whichever is longer, unless local health authority guidelines mandate a longer period. Serum potassium > 5.2 milliequivalents per liter (mEq/L) or < 3.5 mEq/L at Visit 1. Serum sodium < 132 mEq/L at Visit 1. Aspartate aminotransferase (ALT) or alanine aminotransferase (AST) > 2 times the upper limit of the normal range (ULN) at Visit 1. Bilirubin (total) > 1.5 x ULN at Visit 1. Modification of diet in renal disease estimated glomerular filtration rate (MDRD eGFR) < 60 milliliters per minute (ml/min)/1.73 m^2 at Visit 1. Other clinically significant laboratory abnormalities, confirmed by repeat measurements, at Visit 1. History of active substance abuse (including alcohol). Participants with night-shift employment.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Core Period: LCI699 0.25 mg QD<br>Participants received LCI699 0.25 mg capsules, orally, once daily (QD), with or without food for up to 8 weeks. | Drug: LCI699<br>* LCI699 oral capsules<br>|
| Experimental: Core Period: LCI699 0.5 mg QD<br>Participants received LCI699 0.5 mg capsules, orally, QD, with or without food for up to 8 weeks. | Drug: LCI699<br>* LCI699 oral capsules<br>|
| Experimental: Core Period: LCI699 1.0 mg QD<br>Participants received LCI699 1 mg capsules, orally, QD, with or without food for up to 8 weeks. | Drug: LCI699<br>* LCI699 oral capsules<br>|
| Experimental: Core Period: LCI699 0.5 mg BID<br>Participants received LCI699 0.5 mg capsules, orally, twice daily (BID), with or without food for up to 8 weeks. | Drug: LCI699<br>* LCI699 oral capsules<br>|
| Active Comparator: Core Period: Eplerenone 50 mg BID<br>Participants received eplerenone 50 mg capsules, orally, BID, with or without food for up to 8 weeks. | Drug: Eplerenone<br>* Eplerenone oral capsules<br>|
| Placebo Comparator: Core Period: Placebo<br>Participants received LCI699-matching placebo or eplerenone-matching placebo, capsules, orally, QD or BID, with or without food for up to 8 weeks. | Drug: LCI699-matching Placebo<br>* LCI699-matching placebo oral capsules<br>Drug: Eplerenone-matching Placebo<br>* Eplerenone-matching placebo oral capsules<br>|
| Experimental: Withdrawal Period: LCI699 0.25 mg QD<br>Participants received LCI699 0.25 mg capsules, orally, QD, with or without food for up to 1 week (Week 8 to Week 9). | Drug: LCI699<br>* LCI699 oral capsules<br>|
| Placebo Comparator: Withdrawal Period: LCI699 0.25 mg QD Placebo<br>Participants received LCI699 matching placebo capsules, orally, QD, with or without food for up to 1 week (Week 8 to Week 9). | Drug: LCI699-matching Placebo<br>* LCI699-matching placebo oral capsules<br>|
| Experimental: Withdrawal Period: LCI699 0.5 mg QD<br>Participants received LCI699 0.5 mg capsules, orally, QD, with or without food for up to 1 week (Week 8 to Week 9). | Drug: LCI699<br>* LCI699 oral capsules<br>|
| Placebo Comparator: Withdrawal Period: LCI699 0.5 mg QD Placebo<br>Participants received LCI699 matching placebo capsules, orally, QD, with or without food for up to 1 week (Week 8 to Week 9). | Drug: LCI699-matching Placebo<br>* LCI699-matching placebo oral capsules<br>|
| Experimental: Withdrawal Period: LCI699 1.0 mg QD<br>Participants received LCI699 1 mg capsules, orally, QD, with or without food for up to 1 week (Week 8 to Week 9). | Drug: LCI699<br>* LCI699 oral capsules<br>|
| Placebo Comparator: Withdrawal Period: LCI699 1.0 mg QD Placebo<br>Participants received LCI699 matching placebo capsules, orally, QD, with or without food for up to 1 week (Week 8 to Week 9). | Drug: LCI699-matching Placebo<br>* LCI699-matching placebo oral capsules<br>|
| Experimental: Withdrawal Period: LCI699 0.5 mg BID<br>Participants received LCI699 0.5 mg capsules, orally, BID, with or without food for up to 1 week (Week 8 to Week 9). | Drug: LCI699<br>* LCI699 oral capsules<br>|
| Placebo Comparator: Withdrawal Period: LCI699 0.5 mg BID Placebo<br>Participants received LCI699 matching placebo capsules, orally, BID, with or without food for up to 1 week (Week 8 to Week 9). | Drug: LCI699-matching Placebo<br>* LCI699-matching placebo oral capsules<br>|
| Active Comparator: Withdrawal Period: Eplerenone 50 mg BID<br>Participants received eplerenone 50 mg capsules, orally, BID, with or without food for up to 1 week (Week 8 to Week 9). | Drug: Eplerenone<br>* Eplerenone oral capsules<br>|
| Placebo Comparator: Withdrawal Period: Eplerenone 50 mg BID Placebo<br>Participants received eplerenone matching placebo capsules, orally, BID, with or without food for up to 1 week (Week 8 to Week 9). | Drug: Eplerenone-matching Placebo<br>* Eplerenone-matching placebo oral capsules<br>|
| Placebo Comparator: Withdrawal Period: Placebo<br>Participants received LCI699-matching placebo or eplerenone-matching placebo, capsules, orally, QD or BID, with or without food for up to 1 week (Week 8 to Week 9). | Drug: LCI699-matching Placebo<br>* LCI699-matching placebo oral capsules<br>Drug: Eplerenone-matching Placebo<br>* Eplerenone-matching placebo oral capsules<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Core Period: Change From Baseline in Mean Sitting Diastolic Blood Pressure (MSDBP) at Week 8 Last Observation Carried Forward (LOCF), as Measured by Office Blood Pressure (OBP) | Automated arterial BP determinations were made after the participant was in the sitting position for 5 minutes according to the Guidelines for management of hypertension: report of the 4th working party of the British Hypertension Society, 2004-BHS IV, using an automated BP device (such as the Omron BP monitor). The change in the MSDBP was calculated comparing the Week 8 readings to the readings taken at Baseline. The change from baseline in MSDBP was analyzed using an analysis of covariance model (ANCOVA) with treatment and region as factors and baseline MSDBP level as a covariate. | Baseline, Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Core Period: Change From Baseline in Mean Sitting Systolic Blood Pressure (MSSBP) at Week 8 LOCF, as Measured by OBP | Automated arterial BP determinations were made after the participant was in the sitting position for 5 minutes according to the Guidelines for management of hypertension: report of the 4th working party of the British Hypertension Society, 2004-BHS IV, using an automated BP device (such as the Omron BP monitor). The change in the MSSBP was calculated comparing the Week 8 readings to the readings taken at Baseline. The change from baseline in MSSBP was analyzed using an ANCOVA with treatment and region as factors and baseline MSSBP levels as a covariate. | Baseline, Week 8 | 
| Core Period: Number of Participants With Adverse Event (AEs), Serious Adverse Events (SAEs), and Deaths | An AE was 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. SAEs were AEs leading to death, are life-threatening, require hospitalizations or prolongation of hospitalizations, represent an innate malformation or a congenital abnormality. | AEs: From start of the study drug treatment up to 8 weeks; SAE: From signing of the informed consent up to 8 weeks | 
| Core Period: Dose Response Relationship of LCI699 as Measured by Change From Baseline in MSDBP at Week 8 | Automated arterial BP determinations were made after the participant was in the sitting position for 5 minutes according to the Guidelines for management of hypertension: report of the 4th working party of the British Hypertension Society, 2004-BHS IV, using an automated BP device (such as the Omron BP monitor). The change in the MSDBP was calculated comparing the Week 8 readings to the readings taken at Baseline. The change from baseline in MSDBP was analyzed using an analysis of covariance model (ANCOVA) with treatment and region as factors and baseline MSDBP level as a covariate. | Baseline, Week 8 | 
| Core Period: Dose Response Relationship of LCI699 as Measured by Change From Baseline in MSSBP at Week 8 | Automated arterial BP determinations were made after the participant was in the sitting position for 5 minutes according to the Guidelines for management of hypertension: report of the 4th working party of the British Hypertension Society, 2004-BHS IV, using an automated BP device (such as the Omron BP monitor). The change in the MSSBP was calculated comparing the Week 8 readings to the readings taken at Baseline. The change from baseline in MSSBP was analyzed using an ANCOVA with treatment and region as factors and baseline MSSBP levels as a covariate. | Baseline, Week 8 | 
| Core Period: Change From Baseline in Mean 24 Hour Ambulatory SBP at Week 8 as Measured by Ambulatory Blood Pressure Monitoring (ABPM) | An ABPM measured a participant's BP over a 24-hour period readings using an automated validated monitoring device from Baseline to Week 8. The 24-hour SBP was calculated by taking the mean of all ambulatory SBP readings for the 24-hour period. | Baseline, Week 8 | 
| Core Period: Change From Baseline in Mean 24 Hour Ambulatory DBP at Week 8, as Measured by ABPM | An ABPM measured a participant's BP over a 24-hour period readings using an automated validated monitoring device from Baseline to Week 8. The 24-hour DBP was calculated by taking the mean of all ambulatory DBP readings for the 24-hour period. | Baseline, Week 8 | 
| Core Period: Trough to Hour Ratio for Change From Baseline in 24-hour Mean Ambulatory DBP at Week 8 | Trough to peak ratios were derived from an ANCOVA model containing treatment, region, hour, treatment by hour interaction as factors with Baseline as a covariate. | Baseline, every hour up to 24 hours post-dose at Week 8 | 
| Core Period: Trough to Hour Ratio for Change From Baseline in 24-hour Mean Ambulatory SBP at Week 8 | Trough to peak ratios were derived from an ANCOVA model containing treatment, region, hour, treatment by hour interaction as factors with Baseline as a covariate. | Baseline, every hour up to 24 hours post-dose at Week 8 | 
| Core Period: Change From Baseline in Plasma Aldosterone Levels at Week 8 | Change from baseline was analyzed using plasma aldosterone values measured at Baseline and Week 8. | Baseline, Week 8 | 
| Core Period: Percentage of Participants With a MSDBP Response and MSDBP Control at Week 8 LOCF | 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. | Baseline, Week 8 | 
| Core Period: Percentage of Participants With a MSSBP Response and MSSBP Control at Week 8 LOCF | MSSBP response was defined as the percentage of participants with a MSSBP <140 mmHg or a >=20 mmHg reduction from baseline reduction from baseline. MSSBP control was defined as the percentage of participants with a MSSBP <140 mmHg. | Baseline, Week 8 | 
| Core Period: Change From Baseline in Plasma Cortisol Levels by Adrenocorticotropic Hormone (ACTH) Stimulation Test | The ACTH stimulation cortisol test was a standard procedure to measure the ability of adrenal cortex to respond to exogenous ACTH and directly assess the adrenal reserve. Serum cortisol concentrations at 1 hour after injection were measured to assess the maximum stimulated cortisol level achieved. Potential adrenal suppression was indicated if the serum cortisol concentration was <500 nanomoles per liter (nmol/L) at 1 hour after the injection. | Baseline, 1 hour post-dose at Week 8 | 
| Withdrawal Period: Change From Week 8 to Week 9 in MSDBP at Week 9, as Measured by OBP | Automated arterial BP determinations were made after the participant was in the sitting position for 5 minutes according to the Guidelines for management of hypertension: report of the 4th working party of the British Hypertension Society, 2004-BHS IV, using an automated BP device (such as the Omron BP monitor). The change in the MSDBP was calculated comparing the Week 9 readings to the readings taken at Week 8 (Baseline). The change from Week 8 to week 9 in MSDBP was analyzed using an ANCOVA with treatment and region as factors and Week 8 MSDBP level as a covariate. | From Week 8 to Week 9 | 
| Withdrawal Period: Change From Week 8 to Week 9 in MSSBP at Week 9 as Measured by OBP | Automated arterial BP determinations were made after the participant was in the sitting position for 5 minutes according to the Guidelines for management of hypertension: report of the 4th working party of the British Hypertension Society, 2004-BHS IV, using an automated BP device (such as the Omron BP monitor). The change in the MSSBP was calculated comparing the Week 9 readings to the readings taken at Week 8 (Baseline). The change from Week 8 to week 9 in MSSBP was analyzed using an ANCOVA with treatment and region as factors and Week 8 MSSBP level as a covariate. | From Week 8 to Week 9 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Essential hypertension, Phase 2 study, Antihypertensive agent