Bioequivalence Study of the Second Generation Dutasteride and Tamsulosin Hydrochloride (HCL) Combination Capsule in Fasted State

Study Overview
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Brief Summary
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The purpose of this study is to assess the bioequivalence of the second generation dutasteride and tamsulosin hydrochloride (HCL) combination capsule versus currently available commercial combination of dutasteride 0.5 milligram (mg) and tamsulosin HCL 0.4 mg capsule in healthy adult male subjects. Subjects in this study will receive either a single oral dose of the second generation dutasteride 0.5 mg and tamsulosin 0.4 mg combination capsule or a single dose of commercially available combination of dutasteride 0.5 mg and tamsulosin HCL 0.4 mg followed by a 28-day washout period both in fasted state. The study will enroll approximately 92 healthy adult male subjects in order to complete approximately 76 evaluable subjects. The total duration of a subject's involvement in this study is anticipated to be approximately 12 weeks.

Official Title
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A Single-Dose, Randomised, Open-Label, Two-Period Crossover Study to Determine the Bioequivalence of the Second Generation Dutasteride and Tamsulosin HCl Combination Capsule in the Fasted State in Healthy Adult Male Subjects

Conditions
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Urologic Diseases

Intervention / Treatment
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* Drug: Commercially available combination of dutasteride 0.5 mg and tamsulosin HCL 0.4 mg
* Drug: Second generation dutasteride 0.5 mg and tamsulosin HCL 0.4 mg combination capsule


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males who are 18 to 50 years of age, inclusive. Weight range 55 to 95 kg (inclusive) and body mass index (BMI) 18 to 30 kilogram/meter^2 (kg/m^2) (inclusive). Healthy subjects defined as individuals who are free from clinically significant illness or disease as determined by the investigator based on their medical history, physical examination, vital signs, laboratory studies, and electrocardiograms (ECGs). Single QT interval corrected (QTc) <450 millisecond (msec) or QTc <480 msec in subjects with Bundle Branch Block, no clinically relevant abnormal finding on the screening ECG. Serum creatinine <1.5 x upper limit of normal (ULN) at screening. Cytochrome P450 enzyme 2D6 (CYP2D6) Extensive Metabolizers only at screening Willing and able to give written informed consent. Able to swallow and retain oral medication. Male subjects with female partners of child-bearing potential must agree to use 1 of the contraception methods. - Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatise (ALP), and bilirubin <=1.5 x ULN (isolated bilirubin >1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%). Exclusion Criteria: History of postural hypotension, dizziness, poor hydration, vertigo, vaso-vagal reactions or any other signs and symptoms of orthostasis, which in the opinion of the investigator could be exacerbated by tamsulosin and result in putting the subject at risk of injury. History of any serious and/or unstable pre-existing medical, psychiatric disorder, or other conditions that could interfere with a subject's safety, or interfere with the subject's ability to follow indications or study procedures, or the interpretation of study results or obtaining informed consent or compliance to study procedures in the opinion of the Investigator or GlaxoSmithKline (GSK) Medical Monitor. History of myocardial infarction, coronary bypass surgery, unstable angina, cardiac arrhythmias, clinically evident congestive heart failure, or cerebrovascular accident prior to Screening visit; or diabetes or peptic ulcer disease which is uncontrolled by medical management. History of breast cancer or clinical breast examination finding suggestive of malignancy, malignancy within the past 5 years, except for basal cell carcinoma of the skin. Subjects with a prior malignancy who have had no evidence of disease for at least the past 5 years are eligible. Prior medical history or evidence of prostate cancer. Subjects with suspicious ultrasound or Digital Rectal Examination (DRE) who have had a negative biopsy within the preceding 6 months and stable prostate specific antigen (PSA) are eligible for the study. Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening. Positive human immunodeficiency virus (HIV) test at screening. Use of prescription or non-prescription drugs. Strong Cytochrome P450 enzyme 3A4 (CYP3A4) inhibitors (e.g. ketoconazole) and/or strong CYP2D6 inhibitors (e.g. paroxetine) usage throughout the study. History of sensitivity to heparin or heparin-induced thrombocytopenia. History of regular alcohol consumption exceeding 21 drinks/week for men (1 unit is equivalent to 8 gram of alcohol: a half-pint (equivalent to 240 millilitre [mL]) of beer, 1 glass (equivalent to 125 mL) of wine or 1 (equivalent to 25 mL) measure of spirits) within 6 months of screening. Subjects must be able and willing to abstain from beverages and foods containing alcohol 24 hours prior to the first dose of study medication and until the completion of the final PK sample during each period. A positive urine drug or alcohol screen result at screening and at Day -1. A minimum list of drugs that will be screened for include amphetamines, barbiturates, cocaine, opiates, cannabinoids, and benzodiazepines. Subjects must be able and willing to stop using of any tobacco or nicotine containing products 24 hours prior to each dose and for the duration of confinement. At the discretion of the Investigator, light smokers (smoking <=10 cigarettes a day) would be considered for the study inclusion. The subject has received an investigational product or participated in any other research trial within 6 months or 5 half-lives, or twice the duration of the biological effect of any drug (whichever is longer) prior to the first dose of current study medication or anytime during the study period, exposure to more than 4 new chemical entities within 12 months prior to the first dosing day. Previous donation of blood or blood products in excess of 500 mL within a 90 day prior to the first dose of investigational products and the subject agrees not to donate blood during this study. History or presence of allergy, intolerance, contraindication or sensitivity to alpha blockers (e.g., tamsulosin), or 5 alpha reductase inhibitors (e.g., dutasteride) or drugs of these therapeutic classes, soya or peanuts, or any ingredients of Combodart, or a history of drug or other allergy (including true sulfonamide allergy) that, in the opinion of the investigator, contraindicates your participation in the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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Male

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: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sequence AB<br>Subjects will receive Treatment A (commercially available combination of dutasteride 0.5 mg and tamsulosin HCL 0.4 mg) in period 1 and Treatment B (combination of second generation dutasteride 0.5 mg and tamsulosin HCl 0.4 mg combination) in period 2 orally once daily under fasted condition. | Drug: Commercially available combination of dutasteride 0.5 mg and tamsulosin HCL 0.4 mg<br>* Commercially available, orange and brown, hard shell capsule, administered orally as a single dose on Day 1 under fasted condition.<br>Drug: Second generation dutasteride 0.5 mg and tamsulosin HCL 0.4 mg combination capsule<br>* Orange and brown, hard shell capsule, administered orally, as a single-dose on Day 1 under fasted condition.<br>|
| Experimental: Sequence BA<br>Subjects will be randomized to receive Treatment B (combination of second generation dutasteride 0.5 mg and tamsulosin HCl 0.4 mg combination) in period 1 and Treatment A (commercially available combination of dutasteride 0.5 mg and tamsulosin HCL 0.4 mg) in period 2 orally once daily under fasted condition.[dutasteride 0.5 mg and tamsulosin HCl 0.4 mg) in period 2 orally once daily under fasted condition. | Drug: Commercially available combination of dutasteride 0.5 mg and tamsulosin HCL 0.4 mg<br>* Commercially available, orange and brown, hard shell capsule, administered orally as a single dose on Day 1 under fasted condition.<br>Drug: Second generation dutasteride 0.5 mg and tamsulosin HCL 0.4 mg combination capsule<br>* Orange and brown, hard shell capsule, administered orally, as a single-dose on Day 1 under fasted condition.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic (PK) profile of second generation dutasteride when co-administered with tamsulosin HCL relative to the commercial combination of dutasteride 0.5 mg and tamsulosin HCL 0.4 mg in the fed state to investigate bioequivalence | PK parameters include: area under the concentration-time curve from time zero to last time of quantifiable concentration within a subject (AUC [0-t]), and maximum observed concentration (Cmax) as data permit | PK blood samples will be collected at pre-dose, 0, 0.25, 0.50, 0.75, 1, 2, 3, 4, 5, 6, 6.5, 7, 7.5, 8, 10, 12, 16, 24, 48, 72 hour post dose in each period. | 
| Composite of PK parameters for tamsulosin HCl when it is co-administered with second generation dutasteride relative to the currently available commercial dutasteride 0.5 mg + tamsulosin HCL 0.4 mg in the fed state to investigate bioequivalence | PK parameters include: AUC[0-t]), area under the concentration-time curve from time zero extrapolated to infinite time (AUC[0-infinity]) [defaulting to AUC(0-t) | PK blood samples will be collected at pre-dose, 0, 0.25, 0.50, 0.75, 1, 2, 3, 4, 5, 6, 6.5, 7, 7.5, 8, 10, 12, 16, 24, 48, 72 hour post dose in each period. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK profile of dutasteride | PK parameters include: time of occurrence of Cmax (tmax), and negative slope of the terminal phase (lambda) as data permit. | PK blood samples will be collected at pre-dose, 0, 0.25, 0.50, 0.75, 1, 2, 3, 4, 5, 6, 6.5, 7, 7.5, 8, 10, 12, 16, 24, 48, 72 hour post dose in each period. | 
| PK profile of tamsulosin HCl | PK parameters include: tmax, lambda, and half life (t1/2) | PK blood samples will be collected at pre-dose, 0, 0.25, 0.50, 0.75, 1, 2, 3, 4, 5, 6, 6.5, 7, 7.5, 8, 10, 12, 16, 24, 48, 72 hour post dose in each period. | 
| Clinically significant changes in Vital signs measurements to assess safety and tolerability | Vital signs will include blood pressure and pulse rate measurements | Baseline (screening) and up to 33 days. | 
| Incidence of adverse events (AEs) | An AE is any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. | Up to 48 days | 
| Clinical laboratory parameter assessment as a measure of safety and tolerability | Laboratory parameters include: hematology, clinical chemistry and urinalysis. | Up to 33 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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dutasteride, tamsulosin, healthy subject, dutasteride and tamsulosin combination, combination capsule of dutasteride 0.5 mg and tamsulosin HCL 0.4 mg