Bioequivalence Study of the Second Generation Dutasteride and Tamsulosin HCl Combination Capsule in Fed State

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 Fed State in Healthy Adult Male Subjects

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 milligrams (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 capsule followed by a 28-day washout period both in fed 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.

Study Overview

• Status: Completed
• Conditions: Urologic Diseases
• Intervention / Treatment: 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

• Study Type: Interventional
• Enrollment (Actual): 77
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Belfast, United Kingdom, BT9 6AD
    • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 46 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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 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.
• 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 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 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 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 commercially available combination of dutasteride 0.5 mg and tamsulosin HCL 0.4 mg, 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sequence AB; 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 fed condition.	Drug: Commercially available combination of dutasteride 0.5 mg and tamsulosin HCL 0.4 mg; Commercially available, orange and brown, hard shell capsule, administered orally as a single dose on Day 1 under fed condition.; Drug: Second generation dutasteride 0.5 mg and tamsulosin HCL 0.4 mg combination capsule; Orange and brown, hard shell capsule, administered orally, as a single-dose on Day 1 under fed condition
Experimental: Sequence BA; 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 fed condition.	Drug: Commercially available combination of dutasteride 0.5 mg and tamsulosin HCL 0.4 mg; Commercially available, orange and brown, hard shell capsule, administered orally as a single dose on Day 1 under fed condition.; Drug: Second generation dutasteride 0.5 mg and tamsulosin HCL 0.4 mg combination capsule; Orange and brown, hard shell capsule, administered orally, as a single-dose on Day 1 under fed condition

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic profile for second generation dutasteride when co-administered with tamsulosin HCL relative to the currently available 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-adminstered with second generation dutasteride relative to the currently available commercial dutasteride 0.5 mg and 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

Collaborators and Investigators

• Sponsor: GlaxoSmithKline

Study record dates

Study Major Dates

• Study Start (Actual): February 11, 2014
• Primary Completion (Actual): January 2, 2015
• Study Completion (Actual): January 2, 2015

Study Registration Dates

• First Submitted: February 6, 2014
• First Submitted That Met QC Criteria: February 6, 2014
• First Posted (Estimate): February 10, 2014

Study Record Updates

• Last Update Posted (Actual): September 13, 2018
• Last Update Submitted That Met QC Criteria: September 11, 2018
• Last Verified: September 1, 2018

More Information

Terms related to this study

• Keywords: bioequivalence; GI198745; dutasteride; Tamsulosin; healthy subject; combination of dutasteride 0.5 mg and tamsulosin HCL 0.4 mg; tamsulosin hydrochloride
• Additional Relevant MeSH Terms: Urologic Diseases; Physiological Effects of Drugs; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Urological Agents; Enzyme Inhibitors; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Steroid Synthesis Inhibitors; Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; 5-alpha Reductase Inhibitors; Tamsulosin; Dutasteride
• Other Study ID Numbers: 116108

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: IPD for this study will be made available via the Clinical Study Data Request site.
• IPD Sharing Time Frame: IPD is available via the Clinical Study Data Request site (click on the link provided below)
• IPD Sharing Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)