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

Study Overview
=================
Brief Summary
-----------------
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.

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

Official Title
-----------------
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

Conditions
-----------------
Hypertension

Intervention / Treatment
-----------------
* Drug: lisinopril
* Drug: carvedilol controlled release formulation


Participation Criteria
=================
Eligibility 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 All subjects must be able to be safely withdrawn from all antihypertensive treatment during the Washout/Placebo Run-in phase.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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: lisinopril<br>lisinopril | Drug: lisinopril<br> <br> |
| Experimental: carvedilol<br>carvedilol controlled release formulation | Drug: carvedilol controlled release formulation<br> <br> * Other names: lisinopril;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 6 in 24 Hour (hr) Mean Diastolic Blood Pressure | Ambulatory blood pressure monitoring (ABPM) was completed at Baseline and at the end of treatment/Week 6 or early withdrawal by standard electronic ABPM equipment worn by the subject for 24-hr of ambulatory activity. The 24 hr assessment period started at the time of the first reading and ended exactly 24 hr later on the following day. Data collected included mean diastolic blood pressure (DBP). | Baseline, Week 6. | 
| Change From Baseline to Week 6 in Trough Diastolic Blood Pressure | Trough ABPM was the average across 20-24 hr after dosing for each subject. | Baseline, Week 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 6 in 24 Hour Mean Systolic Blood Pressure | Ambulatory blood pressure monitoring (ABPM) was completed at Baseline and at the end of treatment/Week 6 or early withdrawal by standard electronic ABPM equipment worn by the subject for 24-hr of ambulatory activity. The 24 hr assessment period started at the time of the first reading and ended exactly 24 hr later on the following day. Data collected included mean systolic blood pressure (SBP). | Baseline, Week 6 | 
| Change From Baseline to Week 6 in Trough Systolic Blood Pressure | Trough ABPM was the average across 20-24 hr after dosing for each subject. | Baseline, Week 6 | 
| Dose-response Treatment Estimates: Change From Baseline to Week 6 in 24 Hour Mean DBP by ABPM (Ambulatory Blood Pressure Monitoring) | Evaluation of the dose-response relationship between incremental doses of carvedilol CR and lisinopril and mean 24-hr ABPM DBP. | Baseline, Week 6 | 
| Change From Baseline to Week 6 in Trough to Peak Ratios of DBP by 24 Hour ABPM (Ambulatory Blood Pressure Monitoring) | Trough (20-24 hr) to peak (3-7 hr) ratios of DBP were examined in order to evaluate the extent to which once-daily criteria were met (ie trough:peak > 50%). Trough to peak ratios were calculated from change trough mean/change peak mean x 100. | Baseline, Week 6 | 
| Overall Description of Safety in Each Treatment Group Using Adverse Events, Laboratory Evaluations, ECG Changes, Vital Sign Changes, and Withdrawal Rates. | Refer to Adverse Event section for safety information. | Weeks 1 through 48 | 
| Change From Baseline to Week 6 in Mean SBP and DBP Measured in Morning by 24 Hour ABPM | Mean changes from Baseline to Week 6 in DBP and SBP measured by 24hr ABPM at the end of up-titration recorded in the morning. The morning assessment period started at or after 6 am and ended immediately before 12 noon. | Morning BP, Baseline, Week 6 | 
| Change From Baseline to Week 6 in Mean SBP and DBP Measured in Afternoon by 24hr ABPM | Mean changes from Baseline to Week 6 in SBP and DBP measured by 24hr ABPM at the end of up-titration recorded in the afternoon. The afternoon assessment period started at or after 12 noon and ended immediately before 6 pm. | Afternoon BP, Baseline, Week 6 | 
| Change From Baseline to Week 6 in Mean SBP and DBP Measured at Night by 24hr ABPM | Mean changes from Baseline to Week 6 in DBP and SBP measured by 24hr ABPM at the end of up-titration recorded in the night. The night-time assessment period started at the time of the first reading at or after 6 pm and ended immediately before 6 am on the following day. | Night BP, Baseline, Week 6 | 
| Change From Baseline to Week 6 in Mean Trough Sitting SBP and Sitting DBP by Cuff Assessment | Analysis of Change from Baseline to Week 6 in Mean sSBP and sDBP by Cuff Assessments at Drug Trough (20-24 hr) at End of Treatment Titration | Baseline, Week 6 | 
| 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) |  | Week 6 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
carvedilol, hypertension, lisinopril, factorial