The COREG And Lisinopril Combination Therapy In Hypertensive Subjects (COSMOS) Trial

Condition(s) targeted: Hypertension

Intervention: lisinopril (Drug); carvedilol controlled release formulation (Drug)

Phase: Phase 3

Status: Completed

Sponsored by: GlaxoSmithKline

Official(s) and/or principal investigator(s):
GSK Clinical Trials, M.D., Study Director, Affiliation: GlaxoSmithKline

This is a randomized, double-blind, double-dummy, parallel group trial employing 15 cells of a 4x4 factorial design (no placebo)to compare the hypertensive effects in patients with Stage 1 and Stage 2 hypertension of carvedilol (20, 40 or 80 mg daily) alone, lisinopril (10, 20 or 40 mg daily) alone, and all combinations of the doses.

Official title: See Detailed Description

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Primary outcome:

Change From Baseline to Week 6 in 24 Hour (hr) Mean Diastolic Blood Pressure

Change From Baseline to Week 6 in Trough Diastolic Blood Pressure

Secondary outcome:

Change From Baseline to Week 6 in 24 Hour Mean Systolic Blood Pressure

Change From Baseline to Week 6 in Trough Systolic Blood Pressure

Dose-response Treatment Estimates: Change From Baseline to Week 6 in 24 Hour Mean DBP by ABPM (Ambulatory Blood Pressure Monitoring)

Change From Baseline to Week 6 in Trough to Peak Ratios of DBP by 24 Hour ABPM (Ambulatory Blood Pressure Monitoring)

Overall Description of Safety in Each Treatment Group Using Adverse Events, Laboratory Evaluations, ECG Changes, Vital Sign Changes, and Withdrawal Rates.

Change From Baseline to Week 6 in Mean SBP and DBP Measured in Morning by 24 Hour ABPM

Change From Baseline to Week 6 in Mean SBP and DBP Measured in Afternoon by 24hr ABPM

Change From Baseline to Week 6 in Mean SBP and DBP Measured at Night by 24hr ABPM

Change From Baseline to Week 6 in Mean Trough Sitting SBP and Sitting DBP by Cuff Assessment

Diastolic Responders, Defined as ≥ 10 mmHg Sitting (s)DBP Reduction From Baseline or a sDBP of <90 / 80 Millimeters (mm) of Mercury (Hg) for Non Diabetic / Diabetic Subjects Respectively (Based on Cuff Trough Measures)

Detailed description: A Randomized, Double-Blind, Double-Dummy, Parallel Group, Factorial Design Trial to Assess the Efficacy and Safety of up to Six Weeks Treatment with 20mg, 40mg, or 80mg QD Doses of Carvedilol Controlled Release Formulation (COREG CR) or 10mg, 20mg, or 40mg QD Doses of Lisinopril (ZESTRIL) or a Combination of One of the Doses of Each Medication

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Subject has given signed informed consent.

- Subject is male or female 18 years of age at the time informed consent is signed.

- At the Screening visit, subject has a documented history or current presentation with

stage 1 or stage 2 hypertension (see Section 15. 1, Appendix 1 and Section 15. 4, Appendix 4) which meets one of the following criteria. Note: All blood pressures are mean sitting cuff pressures: Documented history of hypertension and receiving two antihypertensive medications with mean sDBP <90 mmHg or for diabetic subjects (defined as having an established diagnosis of diabetes or receiving treatment for diabetes), mean sDBP <80 mmHg. Subjects taking beta blockers, clonidine, or other antihypertensive medications where abrupt discontinuation would be of clinical concern must be tapered off the medication during the Washout/Placebo Run-in phase to avoid rebound hypertension. All subjects must be able to be safely withdrawn from all antihypertensive treatment during the Washout/Placebo Run-in phase. Subjects should not be enrolled if the investigator thinks it is likely the subject's mean sDBP will exceed 109 mmHg or their mean sSBP will exceed 180 mmHg during the Washout/Placebo Run-in phase (NOTE: A combination drug containing two antihypertensive agents represents two antihypertensive medications [e. g., Hyzaar is losartan potassium AND hydrochlorothiazide, therefore, counts as two antihypertensive medications].) OR Receiving one antihypertensive medication with mean sDBP =109 mmHg and can be safely withdrawn from all antihypertensive medication during the Washout/Placebo Run-in phase. Any subject who is receiving beta-blockers, clonidine, or other antihypertensive medications where abrupt discontinuation would be of clinical concern must have the dose tapered down during the Washout/Placebo Run-in phase to avoid rebound hypertension. All subjects must be able to be safely withdrawn from all antihypertensive treatment during the Washout/Placebo Run-in phase. Subjects should not be enrolled if the investigator thinks it is likely the subject's mean sDBP will exceed 109 mmHg or their mean sSBP will exceed 180 mmHg during the Washout/Placebo Run-in phase. (NOTE: A combination drug containing two antihypertensive agents represents two antihypertensive medications [e. g., Hyzaar is losartan potassium AND hydrochlorothiazide, therefore, counts as two antihypertensive medications]. OR Untreated/newly diagnosed subjects: mean sDBP =95 and =109, or for diabetic subjects, mean sDBP =85 and =109 (see Section 15. 1, Appendix 1). If newly diagnosed, must have qualifying blood pressure confirmed on two consecutive visits with the mean sDBP value not differing more than 8 mmHg. (Previously untreated subjects include subjects who have not been treated for hypertension in the last two months.).

- At Baseline:

DAY BEFORE RANDOMIZATION: Prior to having the baseline ABPM equipment placed, subject has mean sitting cuff DBP that is ≥93 and ≤111 mmHg (or for diabetic subjects, ≥83 and ≤111 mmHg). Subjects who were taking antihypertensive medication at Screening and do not meet this criterion after one week (or 5 half-lives, whichever is longer), can return in one week ±1day and have his/her blood pressure evaluated again for this inclusion criterion. AND RANDOMIZATON DAY: After completion of the ABPM assessment, subject meets the following ABPM (both 12 hr and 24 hr) criteria (see Section 15. 1, Appendix 1):

- Mean 12-hour daytime (9 AM to 9 PM) DBP ≥90 and ≤109mmHg (or for diabetic subjects,

≥80 and ≤109mmHg)

- At least 75% of the programmed readings properly recorded over 24-hour monitoring

period

- No more than two non-consecutive hours with less than two successful readings per

hour while awake, and no more than two consecutive hours with less than one successful reading per hour during the sleep period over the 24-hour monitoring period

- At least two successful readings per hour for three of the last four hours of

recording (trough period i. e., 20-24 hour during which subjects must be awake) with a total of at least 7 successful readings over this period. Exclusion Criteria:

- Subject is taking ≥3 antihypertensive medications. (NOTE: A combination drug

containing two antihypertensive agents represents two antihypertensive medications [e. g., Hyzaar is losartan potassium AND hydrochlorothiazide, therefore, counts as two antihypertensive medications].)

- Subject has DBP =90 mmHg (or for diabetic subjects, DBP =80 mmHg) on two

antihypertensive medications.

- Subject has any known contraindication to ACE inhibitors (e. g., ACE-induced cough,

angioedema or negative renal effects), or blocker treatment.

- Hyperkalemia or history of hyperkalemia resulting from either Type IV RTA (renal

tubular acidosis) or previous ACEi therapy.

- Is female of childbearing potential. NOTE: Female subjects who are postmenopausal

(i. e., no menstrual period for a minimum of 12 months prior to Screening) or surgically sterilized are eligible for the study. If judged appropriate, a postmenopausal woman may be required to have a documented negative urine pregnancy test.

- Subject has malignant (accelerated) hypertension, history of malignant hypertension,

or secondary forms of hypertension.

- Subject has mean sitting SBP =180 mmHg.

- Subject has advanced hypertensive retinopathy (Keith Wagner Grade IV).

- Subject has Type 1 diabetes mellitus, or those with Type 2 having HbA1c ≥9% at

Screening.

- Subject has uncorrected primary obstructive or severe regurgitative valvular disease,

nondilated (restrictive) or hypertrophic cardiomyopathies.

- Subject has any of the following conditions:

uncontrollable or symptomatic arrhythmias unstable angina or angina treated with a beta-blocker sick sinus syndrome or second or third degree heart block (unless treated with a permanent, functioning pacemaker) bradycardia (sitting heart rate <55 bpm) history of myocardial infarction stroke within 3 months of Screening

- Subject is in atrial fibrillation.

- Subject has Congestive Heart Failure NYHA (New York Heart Association) class II-IV

[The Criteria Committee of the New York Heart Association, 1994].

- Current clinical evidence of asthma or chronic obstructive pulmonary disease (e. g.,

severe emphysema or chronic bronchitis) requiring long term use of inhaled oral bronchodilator or steroid drug therapy; also subjects with a history of bronchospastic disease not undergoing active therapy in whom, in the investigator's opinion, treatment with the study medication could provoke bronchospasm; or requirement for or anticipated treatment with beta-2 agonist therapy (e. g., albuterol [Ventolin, Proventil], metaproterenol [Alupent], pirbuterol [Maxair], terbutaline [Brethaire], isoetharine [Bronkosol], and Levalbuterol [Xopenex]).

- Subject has evidence of any of the following clinically significant diseases that

could impair the absorption, metabolism, or excretion of orally-administered medication: renal disease defined as estimated Glomerular Filtration Rate (eGFR) <30mL/min per 1. 73 m2 hepatic disease (i. e., ALT or AST levels greater than three times the upper limit of normal range, history of hepatic impairment, or by clinical assessment) chronic biliary disorders gastric bypass surgery

- Subject has endocrine disorders that affect blood pressure (e. g., pheochromocytoma,

active and untreated hypo- or hyperthyroidism).

- Subject has systemic disease, including cancer, with reduced (<12 months) life

expectancy.

- Subject has used an investigational drug within 30 days or 5 half-lives (whichever is

longer) preceding Screening.

- Subject has a history of a psychological illness/condition that would interfere with

their ability to understand or complete the requirements of the study.

- Subject has any condition that, in the opinion of the Investigator and/or the GSK

Medical Monitor, places the subject at an unacceptable risk as a participant in this trial.

- Subject is receiving ongoing treatment or is anticipated to receive treatment with

any of the following medications during treatment with double blind study medication: any antihypertensive medication except for assigned study medication. This would include alpha blockers or other medications that may be used to treat hypertension and other conditions unrelated to hypertension; monoamine oxidase (MAO) inhibitors; any Class I or III antiarrhythmic; beta-2-agonists.

GSK Investigational Site, Anniston, Alabama 36207, United States

GSK Investigational Site, Birmingham, Alabama 35216, United States

GSK Investigational Site, Birmingham, Alabama 35235, United States

GSK Investigational Site, Birmingham, Alabama 35242, United States

GSK Investigational Site, Birmingham, Alabama 35215, United States

GSK Investigational Site, Haleyville, Alabama 35565, United States

GSK Investigational Site, Mobile, Alabama 36617, United States

GSK Investigational Site, Muscle Shoals, Alabama 35662, United States

GSK Investigational Site, Chandler, Arizona 85225, United States

GSK Investigational Site, Gilbert, Arizona 85296, United States

GSK Investigational Site, Glendale, Arizona 85308, United States

GSK Investigational Site, Mesa, Arizona 85206, United States

GSK Investigational Site, Phoenix, Arizona, Arizona 86106, United States

GSK Investigational Site, Phoenix, Arizona 85023, United States

GSK Investigational Site, Phoenix, Arizona 85032, United States

GSK Investigational Site, Scottsdale, Arizona 85251, United States

GSK Investigational Site, Scottsdale, Arizona 85260, United States

GSK Investigational Site, Sun City, Arizona 85351, United States

GSK Investigational Site, Tucson, Arizona 85712, United States

GSK Investigational Site, Tucson, Arizona 85741, United States

GSK Investigational Site, Little Rock, Arkansas 72204, United States

GSK Investigational Site, Searcy, Arkansas 72143, United States

GSK Investigational Site, Beuna Park, California 90620, United States

GSK Investigational Site, Beverly Hills, California 90211, United States

GSK Investigational Site, Burbank, California 91505, United States

GSK Investigational Site, Carlsbad, California 92008, United States

GSK Investigational Site, Fountain Valley, California 92708, United States

GSK Investigational Site, Fresno, California 93703, United States

GSK Investigational Site, Loma Linda, California 92354, United States

GSK Investigational Site, Mission Viejo, California 92691, United States

GSK Investigational Site, Pico Rivera, California 90660, United States

GSK Investigational Site, Rancho Cordova, California 95670, United States

GSK Investigational Site, San Diego, California 92117, United States

GSK Investigational Site, San Diego, California 92128, United States

GSK Investigational Site, Santa Ana, California 92705, United States

GSK Investigational Site, Vista, California 92084, United States

GSK Investigational Site, Walnut Creek, California 94598, United States

GSK Investigational Site, Colorado Springs, Colorado 80904, United States

GSK Investigational Site, Wilmington, Delaware 19805, United States

GSK Investigational Site, Washington, District of Columbia 20017, United States

GSK Investigational Site, Coral Gables, Florida 33134, United States

GSK Investigational Site, Hialeah, Florida 33013, United States

GSK Investigational Site, Hollywood, Florida 33023, United States

GSK Investigational Site, Jacksonville Beach, Florida 32250, United States

GSK Investigational Site, Jacksonville, Florida 32205, United States

GSK Investigational Site, Miami, Florida 33156, United States

GSK Investigational Site, Miami, Florida 33169, United States

GSK Investigational Site, Palm Harbor, Florida 34684, United States

GSK Investigational Site, Pembroke Pines, Florida 33024, United States

GSK Investigational Site, Pembroke Pines, Florida 33027, United States

GSK Investigational Site, Sarasota, Florida 34239, United States

GSK Investigational Site, West Palm Beach, Florida 33409, United States

GSK Investigational Site, Gainesville, Georgia 30501, United States

GSK Investigational Site, Marietta, Georgia 30066, United States

GSK Investigational Site, Savannah, Georgia 31406, United States

GSK Investigational Site, Aurora, Illinois 60504, United States

GSK Investigational Site, Chicago, Illinois 60607, United States

GSK Investigational Site, Chicago, Illinois 60610, United States

GSK Investigational Site, Melrose Park, Illinois 60160, United States

GSK Investigational Site, Avon, Indiana 46123, United States

GSK Investigational Site, Bloomington, Indiana 47102, United States

GSK Investigational Site, Fort Wayne, Indiana 46804, United States

GSK Investigational Site, Indianapolis, Indiana 46250, United States

GSK Investigational Site, Ames, Iowa 50010, United States

GSK Investigational Site, Wichita, Kansas 67205, United States

GSK Investigational Site, Slidell, Louisiana 70458, United States

GSK Investigational Site, Springfield, Massachusetts 01103, United States

GSK Investigational Site, Taunton, Massachusetts 02780., United States

GSK Investigational Site, Bingham Farms, Michigan 48025, United States

GSK Investigational Site, Brooklyn Center, Minnesota 55430, United States

GSK Investigational Site, Missoula, Montana 59808, United States

GSK Investigational Site, O Fallon, Montana 63366, United States

GSK Investigational Site, Omaha, Nebraska 68131, United States

GSK Investigational Site, Las Vegas, Nevada 89016, United States

GSK Investigational Site, Las Vegas, Nevada 89119, United States

GSK Investigational Site, Las Vegas, Nevada 89128, United States

GSK Investigational Site, Cherry Hill, New Jersey 08034, United States

GSK Investigational Site, Edison, New Jersey 08817, United States

GSK Investigational Site, Ridgewood, New Jersey 7450, United States

GSK Investigational Site, Voorhees, New Jersey 08043, United States

GSK Investigational Site, Albuquerque, New Mexico 87102, United States

GSK Investigational Site, Brooklyn, New York 11203, United States

GSK Investigational Site, Buffalo, New York 14215, United States

GSK Investigational Site, Kingston, New York 12401, United States

GSK Investigational Site, Lewinston, New York 14092, United States

GSK Investigational Site, Asheville, North Carolina 28801, United States

GSK Investigational Site, Charlotte, North Carolina 28211, United States

GSK Investigational Site, High Point, North Carolina 27262, United States

GSK Investigational Site, Raleigh, North Carolina 27615, United States

GSK Investigational Site, Fargo, North Dakota 58103, United States

GSK Investigational Site, Cincinnati, Ohio 45236, United States

GSK Investigational Site, Cincinnati, Ohio 45219, United States

GSK Investigational Site, Cleveland, Ohio 44106, United States

GSK Investigational Site, Cleveland, Ohio 44195, United States

GSK Investigational Site, Dayton, Ohio 45406, United States

GSK Investigational Site, Oklahoma City, Oklahoma 73103, United States

GSK Investigational Site, Oklahoma City, Oklahoma 73112, United States

GSK Investigational Site, Tulsa, Oklahoma 74104, United States

GSK Investigational Site, Eugene, Oregon 97401, United States

GSK Investigational Site, Beaver, Pennsylvania 15009, United States

GSK Investigational Site, Doylestown, Pennsylvania 18901, United States

GSK Investigational Site, Erie, Pennsylvania 16504, United States

GSK Investigational Site, Havertown, Pennsylvania 19083, United States

GSK Investigational Site, Landsdale, Pennsylvania 19446, United States

GSK Investigational Site, Leetsdale, Pennsylvania 15056, United States

GSK Investigational Site, Philadelphia, Pennsylvania 19152, United States

GSK Investigational Site, Philadelphia, Pennsylvania 19154, United States

GSK Investigational Site, Warminster, Pennsylvania 18974, United States

GSK Investigational Site, West Chester, Pennsylvania 19380, United States

GSK Investigational Site, Columbia, South Carolina 29201, United States

GSK Investigational Site, Gaffney, South Carolina 29340, United States

GSK Investigational Site, Greer, South Carolina 29651, United States

GSK Investigational Site, Hilton Head Island, South Carolina 29926, United States

GSK Investigational Site, Manning, South Carolina 29102, United States

GSK Investigational Site, Simpsonville, South Carolina 29681, United States

GSK Investigational Site, Spartanburg, South Carolina 29303, United States

GSK Investigational Site, Taylors, South Carolina 29687, United States

GSK Investigational Site, Union, South Carolina 29309, United States

GSK Investigational Site, Clarksville, Tennessee 37043, United States

GSK Investigational Site, Jackson, Tennessee 38305, United States

GSK Investigational Site, Johnson City, Tennessee 37601, United States

GSK Investigational Site, Nashville, Tennessee 37203, United States

GSK Investigational Site, Arlington, Texas 76014, United States

GSK Investigational Site, Austin, Texas 78705, United States

GSK Investigational Site, Georgetown, Texas 78626, United States

GSK Investigational Site, Grand Prairie/Texas, Texas 5052, United States

GSK Investigational Site, Houston, Texas 77081, United States

GSK Investigational Site, Longview, Texas 75605, United States

GSK Investigational Site, San Antonio, Texas 78224, United States

GSK Investigational Site, San Antonio, Texas 78229, United States

GSK Investigational Site, Sugar Land, Texas 77479, United States

GSK Investigational Site, Temple, Texas 76502, United States

GSK Investigational Site, Salt Lake City, Utah 84102, United States

GSK Investigational Site, Sandy, Utah 84094, United States

GSK Investigational Site, Arlington, Virginia 22205, United States

GSK Investigational Site, Burke, Virginia 22015, United States

GSK Investigational Site, Chester, Virginia 23836, United States

GSK Investigational Site, Fairfax, Virginia 22030, United States

GSK Investigational Site, Manassas, Virginia 20110, United States

GSK Investigational Site, Spokane, Washington 99206, United States

GSK Investigational Site, Tacoma, Washington 98405, United States

GSK Investigational Site, Milwaukee, Wisconsin 53209, United States

Starting date: July 2006
Last updated: April 20, 2015