Study to Investigate Dose Proportionality of the Fixed Dose Combination of COREG CR and Lisinopril.

Study Overview
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Brief Summary
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This will be an open-label, single-dose, non-randomized, five-period crossover study in healthy volunteers. The duration of the study will last up to eleven weeks from screening to follow-up. PK samples will be taken.

Official Title
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A Non-randomized, Open-label, Single-dose, Crossover Study to Evaluate the Dose Proportionality of the Final Fixed Dose Combination Formulation of COREG CR™ and Lisinopril.

Conditions
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Hypertension

Intervention / Treatment
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* Drug: COREG CR and lisinopril (FDC)


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Healthy volunteer Adult males and females of non-child bearing potential who are between 18 to 55 years of age, inclusively Body weight > 60 kg (132 lbs) and body mass index (BMI) between 19 and 33 Exclusion criteria: Any clinically relevant abnormality identified on the screening history, physical or laboratory examination, or any other medical condition or circumstance making the volunteer unsuitable for participation in the study. Subjects who metabolize carvedilol poorly based on CYP2D6 genotyping as determined at screening. Treatment with any prescription or non-prescription drugs (including vitamins, herbal and dietary supplements, as well as grapefruit-containing products) within 7 days or 5 half-lives (whichever is longer) prior to first dose of study medication and until the end of the study. Treatment with any CYP2D6 inhibitors such as but not limited to quinidine, fluoxetine, paroxetine, duloxetine, and terbinofine at least 14 days or 5 half-lives (whichever is longer) prior to Day 1 of Session 1 and until the end of the study. Treatment with an investigational drug within 30 days or 5 half-lives (whichever is longer) preceding Day 1 of Session 1 Exposure to more than four new chemical entities within 12 months prior to the first dosing day. History of regular alcohol consumption exceeding 7 drinks/week for women or 14 drinks/week for men (1 drink = 5 ounces of wine or 12 ounces of beer or 1.5 ounces of hard liquor) within 6 months of screening. Positive urine drug screen (UDS) including alcohol at screening. A minimum list of drugs that will be screened for include amphetamines, barbiturates, cocaine, opiates, cannabinoids and benzodiazepines. Urine Na/creatinine ratio < 0.1 meq/mg. Positive for Hepatitis B surface antigen, or HIV. Women of child-bearing potential. Resting heart rate of >/ 50 beats per minute (bpm) at screening. Abnormalities on 12-lead ECG during screening Documented history of low blood pressure (average SBP ≤ 110 mm Hg and/or DBP ≤ 50 mm Hg) or blood pressure below these values at time of screening. Orthostatic hypotension diagnosed at screening (orthostatic hypotension will be defined as a reduction in systolic blood pressure of 20 mmHg or more and/or a reduction in diastolic blood pressure of 10 mmHg or more for standing vs. supine measurements. Donation of blood in excess of 500 mL within a 56 day period including the estimated 550 mL of blood to be drawn during this study. History of asthma, COPD and/or hypersensitivity to β-adrenergic blocking agents. History of sensitivity to heparin, heparin-induced thrombocytopenia, or sensitivity to any of the study medications or components thereof. History of anaphylaxis or anaphalactoid reactions or severe allergic responses to drugs. History of angioedema. History of sensitivity to carvedilol, lisinopril, alpha-blockers, beta-blockers or ACE inhibitors Unwillingness or inability to follow the procedures outlined in the protocol or inability to provide written informed consent.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: COREG CR and lisinopril (FDC)|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of dose proportionality by comparison of PK parameters across dosing range Blood sampling over up to a 120 hour period post dose in all dosing sessions |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Characterization of PK, safety and tolerability Safety and tolerability will be assessed by clinical data from spontaneous Adverse Event reporting, nurse/physician observations, vital sign assessment, ECGs, and clinical laboratory tests |  |  | 
| The pharmacokinetic parameters to be evaluated are the Tmax and t1/2 of carvedilol [R(+) and S(-)enantiomers] and Tmax and t1/2 of lisinopril |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COREG CR,, lisinopril,, hypertension,, dose proportionality,, fixed dose combination (FDC)