Prostatic HyperplasiaPhase 1NCT01495026
A Study Assessing a Range of Formulations of the Fixed Dose Combination Product Containing Dutasteride (0.5mg) and Tamsulosin Hydrochloride (0.2mg) to Find a Formulation Which is Bioequivalent to Harnal-D Tablets (Tamsulosin Hydrochloride, 0.2mg) in Healthy Male Subjects From North East Asia
A Phase 1 study testing Dutasteride (0.5mg, fasted state), Dutasteride (0.5mg, fed state) and Fixed dose combination capsule containing dutasteride 0.5mg and tamsulosin 0.2mg (fasted state) in people with Prostatic Hyperplasia, run by GlaxoSmithKline at 1 site in Australia.
Trial summary
This study is an open-label, randomized, single dose, multi-stage, cross-over study in healthy male subjects of North East Asian ancestry. The aims are to: evaluate the pharmacokinetic parameters of several formulations of a fixed dose combination (FDC) capsule of dutasteride and tamsulosin hydrochloride (0.5 mg/0.2… Read more about this study
- Who is it for?
- Ages 20 to 45 years, men onlyHealthy volunteers can take part
- Conditions the study is for
- Prostatic Hyperplasia
- What is being tested?
- Dutasteride (0.5mg, fasted state), Dutasteride (0.5mg, fed state) and Fixed dose combination capsule containing dutasteride 0.5mg and tamsulosin 0.2mg (fasted state)
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 63 participants
- Where
- 1 siteAustralia
- Study dates
- 6 Nov 2011to 3 Apr 2012
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 20 to 45 years
- Men only
- Healthy volunteers accepted
- Adult
Who may be able to join
- A subject will be eligible for inclusion in this study only if all of the following criteria apply:
- Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. A subject with a clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included only if the Investigator and the GSK Medical Monitor agree that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
- Males between 20 and 45 years of age inclusive, at the time of signing the informed consent form.
- Japanese ancestry defined as being born in Japan, having four ethnic Japanese grandparents, holding a Japanese passport or identity papers and being able to speak Japanese, or Korean ancestry defined as being born in Korea, having four ethnic Korean grandparents, holding a Korean passport or identity papers and being able to speak Korean, or Chinese ancestry defined as being born in China, Hong Kong, Singapore or Taiwan, having four ethnic Chinese grandparents, holding a Chinese passport or identity papers and being able to speak Chinese.
- Japanese, Korean and Chinese subjects should also have lived outside their respective countries for less than 10 years.
- Male subjects with female partners of child-bearing potential must agree to use one of the protocol-approved contraception methods. This criterion must be followed from the time of the first dose of study medication until 45 days after the last dose.
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- BMI within the range 18 -28 kg/m2 (inclusive).
- Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
- Single QTc < 450 msec; or QTc < 480 msec in subjects with Bundle Branch Block.
- AST, ALT, alkaline phosphatase and bilirubin less than or equal to 1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
Who cannot join
- A subject will not be eligible for inclusion in this study if any of the following criteria apply:
- Medical Condition Exclusions:
- Poor metabolizer for CYP2D6 substrates as determined by genotyping of selected CYP2D6 variants at screening.
- 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.
- 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.
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- A positive test for HIV antibody.
- Medical Exclusions:
- Subjects must be able and willing to refrain from use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's Wort, Black Khosh, Dong Quai, Milk Thistle, licorice) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study procedures or compromise subject safety.
- History of sensitivity to tamsulosin HCl or dutasteride, components thereof or drugs of this class or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation.
- A history of sensitivity to heparin or heparin-induced thrombocytopenia
- The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
- Exposure to more than four new chemical entities within 12 months prior to the first dosing day.
- Lifestyle Exclusions:
- A positive pre-study drug/alcohol screen. A minimum list of drugs that will be screened for include amphetamines, barbiturates, cocaine, opiates, cannabinoids and benzodiazepines.
- History of regular alcohol consumption within 6 months of the screening visit defined by the following Australian guidelines:
- Males: An average weekly intake greater than 21 units or an average daily intake greater than 3 units. One unit is equivalent to 270 mL of full strength beer, 470 mL of light beer, 30 mL of spirits and 100 mL of wine.
- Subjects must be able and willing to abstain from beverages and foods containing alcohol 24 hours prior to and during the dosing day.
- Consumption of red wine, grapefruit juice, grapefruit and related hybrids from 7 days prior to the first dose of study medication.
- Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: An Open-label, Randomized, Single Dose, Multi-stage, Cross-over Study to Determine the Relative Bioavailability of Fixed Dose Combination Products Containing a 3-oblong Dutasteride Soft Gel Capsule and Tamsulosin (0.5 mg Dutasteride /0.2 mg Tamsulosin HCl) Pellets Having a Range of Tamsulosin Release Rates Produced by Different Mixtures of Enteric Coated and Uncoated Pellets Relative to Harnal-D Tablets, in Healthy Male Subjects of North East Asian Ancestry.
This study is an open-label, randomized, single dose, multi-stage, cross-over study in healthy male subjects of North East Asian ancestry. The aims are to:
- evaluate the pharmacokinetic parameters of several formulations of a fixed dose combination (FDC) capsule of dutasteride and tamsulosin hydrochloride (0.5 mg/0.2 mg) relative to co-administration of dutasteride 0.5 mg capsules and tamsulosin hydrochloride 0.2 mg tablets in the fasted state in order to define a formulation which is bioequivalent to a 0.2 mg orally disintegrating tamsulosin tablet, (Harnal-D Tablets)
- determine the effect of food on the relative bioavailability of tamsulosin in the FDC product which is assessed to be bioequivalent to Harnal-D Tablets in the fasted state
- assess the effect of water on the relative bioavailability of tamsulosin in Harnal-D Tablets in the fasted state
- assess the safety and tolerability of dosing with the different FDC capsule formulations Subjects will receive single oral doses in at least one treatment period; treatment periods will be separated by a 5-10 day washout period. Blood samples for pharmacokinetic analysis will be taken at regular intervals after dosing. Safety will be assessed by measurement of blood pressure, heart rate and review of adverse events. Each stage of the study will enrol 18 subjects to ensure 16 complete. Subjects may consent to participate in more than one stage.
Read the detailed description
This study is an open-label, randomized, single dose, multi-stage, cross-over study in healthy male subjects of North East Asian ancestry. The aims are to:
- evaluate the pharmacokinetic parameters of several formulations of a fixed dose combination (FDC) capsule of dutasteride and tamsulosin hydrochloride (0.5 mg/0.2 mg) relative to co-administration of dutasteride 0.5 mg capsules and tamsulosin hydrochloride 0.2 mg tablets in the fasted state in order to define a formulation which is bioequivalent to a 0.2 mg orally disintegrating tamsulosin tablet, (Harnal-D Tablets)
- determine the effect of food on the relative bioavailability of tamsulosin in the FDC product which is assessed to be bioequivalent to Harnal-D Tablets in the fasted state
- assess the effect of water on the relative bioavailability of tamsulosin in Harnal-D Tablets in the fasted state
- assess the safety and tolerability of dosing with the different FDC capsule formulations Subjects will receive single oral doses in at least one treatment period; treatment periods will be separated by a 5-10 day washout period. Blood samples for pharmacokinetic analysis will be taken at regular intervals after dosing. Safety will be assessed by measurement of blood pressure, heart rate and review of adverse events. Each stage of the study will enrol 18 subjects to ensure 16 complete. Subjects may consent to participate in more than one stage.
BACKGROUND:
Dutasteride:
Dutasteride (AVODART ™) is an approved potent 5-alpha-reductase inhibitor indicated for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate to improve symptoms, reduce the risk of acute urinary retention and reduce the risk of the need for BPH-related surgery [AVODART Package Insert, 2009]. In humans, dutasteride is well-tolerated in single doses up to 40mg/day, multiple doses up to 40mg/day administered for 7 days, and 5 mg/day administered for 24 weeks. In single dose clinical studies, the overall incidence and type of adverse events (AEs) was similar across the dutasteride, placebo, and finasteride treatment groups.
Tamsulosin:
Tamsulosin (Harnal, Harnal D, Flomax) is an alpha-1-adrenoceptor blocking agent approved for the treatment of signs and symptoms of benign prostatic hyperplasia. Tamsulosin HCl is extensively metabolized, with less than 10% of the dose excreted in the urine unchanged [Harnal, 2009; Harnal, 2011; Flomax, 2011]. In human liver microsomes and human lymphoblastoid cells expressing CYP cDNAs in vitro, tamsulosin HCl is metabolized by both CYP3A4 and CYP2D6 [Matsushima, 1998].
Dutasteride and Tamsulosin:
Clinical data exist to support that tamsulosin (an alpha-1-adrenoceptor antagonist), when used in combination with dutasteride (a 5-alpha reductase inhibitor), offers a more effective treatment for the symptoms of benign prostatic hyperplasia than either drug used alone [GSK study ARI40005, GlaxoSmithKline document number HM2002/00171/01]. In addition, data from a large, multi-centre National Institutes of Health-sponsored Medical Therapy of Prostatic Symptoms (MTOPS) study revealed greater benefits of combination alpha-1-adreoceptor antagonist and 5-alpha-reductase inhibitor therapy compared with either monotherapy in males with BPH [McConnell, 2002]. Clinical drug interaction studies have shown no pharmacokinetic or pharmacodynamic interactions between dutasteride and tamsulosin. Dutasteride may be administered with or without food. Tamsulosin should be administered with food.
Food effect PK data exists for co-administration of dutasteride and tamsulosin given in a fixed dose combination (FDC) capsule formulation relative to the co-administration of the two components, dutasteride and tamsulosin HCl; GSK studies ARI109882, [GlaxoSmithKline document number ZM2007/00022/00], and ARI114694, [GlaxoSmithKline document number ZM2010/00028/00]. In the latter study, the dose of tamsulosin HCl administered was 0.2 mg versus 0.4mg administered in ARI109882. The dose of dutasteride was the same in both studies (0.5mg). In ARI109882, the GSK combination capsule was found to be bioequivalent (under both fed and fasted conditions) to the marketed products administered separately. ARI114694 demonstrated bioequivalence for dutasteride but not for tamsulosin when administered as an FDC product (of dutasteride 0.5 mg and tamsulosin 0.2 mg) relative to co-administration of separate commercial formulations of dutasteride (0.5 mg) and tamsulosin (0.2 mg) in the fed and fasted stage in different North East Asian ethnic groups.
A subsequent GSK study, ARI115707, therefore investigated the relative bioavailability of tamsulosin (0.2mg tamsulosin HCl) only in the FDC product. Two different enteric-coated formulations of tamsulosin were administered with a 3-oblong dutasteride soft gel (0.5 mg) as a FDC capsule relative to co-administration of Harnal Capsules or Harnal-D Tablets with unbranded AVODART (0.5mg dutasteride). The two FDC formulations consisted of: 10% (weight gain) enteric coated tamsulosin pellets with a 3-oblong dutasteride soft gel and 15% (weight gain) enteric coated tamsulosin pellets with a 3-oblong dutasteride soft gel. Specifically, the study aimed to investigate the relative bioavailability of the following:
- FDC (with 10% enteric coated tamsulosin pellets) to a commercial formulation of dutasteride plus tamsulosin (Harnal-D Tablet)
- FDC (with 10% enteric coated tamsulosin pellets) to a commercial formulation of dutasteride plus tamsulosin (Harnal Capsule)
- FDC (with 15% enteric coated tamsulosin pellets) to a commercial formulation of dutasteride plus tamsulosin (Harnal-D Tablet) (also investigated in ARI114694)
- FDC (with 15% enteric coated tamsulosin pellets) to a commercial formulation of dutasteride plus tamsulosin (Harnal Capsule).
ARI115707 results showed that the GSK combination capsule with 10% enteric coated tamsulosin pellets was bioequivalent to the Harnal Capsule. None of the two GSK formulations was found to be bioequivalent to the Harnal-D Tablet.
In this study ARI115708, the relative bioavailability of tamsulosin (0.2mg tamsulosin HCl) is further investigated in several different formulations administered with a 3-oblong dutasteride soft gel as a FDC capsule relative to co-administration of Harnal-D Tablets (0.2 mg) with unbranded AVODART (dutasteride, 0.5mg). All formulations will be administered in the fasted state except in the last stage where the effect of food on the FDC will be assessed as well as the effect of water on the administration of Harnal-D Tablets. As Harnal Capsules are not available in Korea or Japan, bioequivalence to Harnal-D Tablets would allow the FDC to be registered in China, Korea, Taiwan and Japan, where Harnal-D Tablets are approved. Therefore, in ARI115708, only Harnal-D Tablets are used as the comparator.
- Conditions
- Prostatic Hyperplasia
- Being tested
- Dutasteride (0.5mg, fasted state), Dutasteride (0.5mg, fed state), Fixed dose combination capsule containing dutasteride 0.5mg and tamsulosin 0.2mg (fasted state), Fixed dose combination capsule containing dutasteride 0.5mg and tamsulosin 0.2mg (fed state), Harnal-D Tablets with water (fasted state)
- Keywords
- Healthy male subjects, North-East Asian ancestry, Bioequivalence, Food effect, Tamsulosin hydrochloride, Cross-over design, Pilot bioequivalence, Dutasteride (GI198745)
- Medical subject headings
- Prostatic Hyperplasia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Dutasteride (0.5mg, fasted state)Drug
Open-label, randomized, single dose, multi-stage, cross-over study
Dutasteride (0.5mg, fed state)Drug
Commercial formulation of Dutasteride 0.5mg
Fixed dose combination capsule containing dutasteride 0.5mg and tamsulosin 0.2mg (fasted state)Drug
FDC with 85%, 65% and 0% of the dose as enteric-coated pellets and with X and/or Y% of the dose as enteric-coated pellets (X and Y to be determined from PK results from Stage 1)
Fixed dose combination capsule containing dutasteride 0.5mg and tamsulosin 0.2mg (fasted state)Drug
FDC containing faster-release enteric-coated pellets
Fixed dose combination capsule containing dutasteride 0.5mg and tamsulosin 0.2mg (fasted state)Drug
FDC bioequivalent to Harnal-D tablets
Fixed dose combination capsule containing dutasteride 0.5mg and tamsulosin 0.2mg (fed state)Drug
FDC bioequivalent to Harnal-D tablets
Harnal-D Tablets with water (fasted state)Drug
Commercial formulation of Harnal-D Tablets
Harnal-D Tablets with water (fed state)Drug
Commercial formulation of Harnal-D Tablets
Harnal-D tablets without water (fasted state)Drug
Commercial formulation of Harnal-D Tablets
| Study group | Role | What they receive |
|---|---|---|
| Fixed dose combination product | Experimental | Fixed dose combination capsule containing dutasteride 0.5mg and tamsulosin 0.2mg Receives: Drug: Dutasteride (0.5mg, fasted state); Drug: Dutasteride (0.5mg, fed state); Drug: Harnal-D Tablets with water (fasted state); Drug: Harnal-D Tablets with water (fed state); Drug: Harnal-D tablets without water (fasted state) |
| Dutasteride | Experimental | Commercial formulation of Dutasteride 0.5mg Receives: Drug: Fixed dose combination capsule containing dutasteride 0.5mg and tamsulosin 0.2mg (fasted state); Drug: Fixed dose combination capsule containing dutasteride 0.5mg and tamsulosin 0.2mg (fed state) |
| Harnal-D Tablets | Experimental | Commercial formulation of Harna--D Tablets comprising 0.2mg Tamsulosin Hydrochloride Receives: Drug: Dutasteride (0.5mg, fasted state); Drug: Dutasteride (0.5mg, fed state); Drug: Fixed dose combination capsule containing dutasteride 0.5mg and tamsulosin 0.2mg (fasted state); Drug: Fixed dose combination capsule containing dutasteride 0.5mg and tamsulosin 0.2mg (fed state) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Relative bioavailability of tamsulosin from FDC products (0.5 mg dutasteride /0.2 mg tamsulosin HCl) containing a size 3-oblong dutasteride soft gel capsule and tamsulosin pellets having a range of tamsulosin release rates produced by different mixtures
Measured: 0, 15 min, 30 min, 45 min, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 10 hr, 12 hr, 16 hr, 24 hr, 48 hr, 72 hr
Secondary outcomes (3)
Effect of food on the relative bioavailability of tamsulosin in a selected FDC product in healthy male subjects of North East Asian ancestry
Measured: 0, 15 min, 30 min, 45 min, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 10 hr, 12 hr, 16 hr, 24 hr, 48 hr, 72 hr
Effect of water on the relative bioavailability of tamsulosin in Harnal-D Tablets in the fasted state in healthy male subjects of North East Asian ancestry.
Measured: 0, 15 min, 30 min, 45 min, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 10 hr, 12 hr, 16 hr, 24 hr, 48 hr, 72 hr
Safety and tolerability of dosing with the different FDC capsule formulations in healthy male subjects of North East Asian ancestry
Measured: Vital signs: 0, 2 hr, 4 hr, 6 hr, 10 hr, 24 hr, 48 hr and 72 hr. Adverse events: 5 timepoints from pre-dose to follow-up visit (10-14 days post-dose)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Dec 2011 (estimated)
- Study start6 Nov 2011
- Primary completion3 Apr 2012
- Study completion3 Apr 2012
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (15)Papers the sponsor has linked to this study.
- Other trials for Prostatic HyperplasiaStudies of the same condition, open and under way.
- More trials run by GlaxoSmithKlineThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Enrolment
- 63 participants (actual)
Sponsor and investigators
- Lead sponsor
- GlaxoSmithKline
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- GSK Clinical Trials, Study director, GlaxoSmithKline
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01495026
- Sponsor's protocol ID
- 115708
- Status last verified
- Jun 2018
- First submitted
- 15 Dec 2011
- Last updated
- 19 Jun 2018
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- Yes: Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.
Publications
AVODART (Dutasteride 0.5 mg) Product Information. March 2011.
Cai G, Thiessen JJ, Baidoo CA, Fossler MJ. Operating characteristics of a partial-block randomized crossover bioequivalence study for dutasteride, a drug with a long half-life: investigation through simulation and comparison with final results. J Clin Pharmacol. 2010 Oct;50(10):1142-50. doi: 10.1177/0091270009355155. Epub 2010 Feb 16.
PubMed 20160156FLOMAX (Tamsulosin hydrochloride) Product Information. January, 2011.
Food and Drug Administration (FDA). Guidance for Industry: Handling and Retention of BA and BE Testing Samples. Centre for Drug Evaluation and Research, USA; 2004.
GlaxoSmithKline Document Number HM2002/00171/01 Study ID ARI40005. A randomised, double-blind, parallel group study to investigate the efficacy and safety of treatment with Dutasteride (0.5mg) and Tamsulosin (0.4mg), administered once daily for 4 years, alone and in combination, on the improvement of symptoms and clinical outcome in men with moderate to severe symptomatic benign prostatic hyperplasia;. Report Date 09-Jul-2004.
GlaxoSmithKline Document Number ZM2008/00126/02. Dutasteride Clinical Investigators Brochure v10. Report Date 27 May 2011.
HARNAL (Tamsulosin hydrochloride 0.2 mg) Product Information. , 2011.
HARNAL-D (Tamsulosin hydrochloride 0.2 mg) Product Information. , 2009.
Matsushima H, Kamimura H, Soeishi Y, Watanabe T, Higuchi S, Tsunoo M. Pharmacokinetics and plasma protein binding of tamsulosin hydrochloride in rats, dogs, and humans. Drug Metab Dispos. 1998 Mar;26(3):240-5.
PubMed 9492387McConnell JD. The long term effects of medical therapy on the progression of BPH: Results from the MTOPS Trial (abstract 1042). 167 (4):265, 2002. J. Urology. 2002;167 (4):265.
Schuirmann DJ. A comparison of the two one-sided tests procedure and the power approach for assessing the equivalence of average bioavailability. J Pharmacokinet Biopharm. 1987 Dec;15(6):657-80. doi: 10.1007/BF01068419.
PubMed 3450848GlaxoSmithKline Document Number 2011N112801_00 Study ID ARI114694. GlaxoSmithKline studyARI114694: An open-label, randomized, single dose, two-period cross-over study to determine the bioavailability of a fixed dose combination capsule formulation of dutasteride and tamsulosin hydrochloride (0.5 mg/0.2mg) relative to co-administration of dutasteride 0.5mg capsules and tamsulosin hydrochloride 0.2mg tablets in healthy male subjects of north east Asian and non-Asian ancestry;. Report Date 02-May-2011.
GlaxoSmithKline Document Number RM2001/00128/01 Study ID ARI10019. A Double-Blind, Placebo Controlled, Randomized, Parallel Group Study To Investigate The Changes In The Corrected QT Interval Following Repeat Oral Doses Of GI198745 In Healthy Male Volunteers. Report Date 02-Oct-2002.
GlaxoSmithKline Document Number RM2003/00174/01 Study ID ARI10021. An Open-Label, Single Dose, 2-Way Cross-over Study to Investigate the Pharmacokinetics, Safety and Tolerability of oral Flomax (tamsulosin hydrochloride 0.4mg capsule-US) and Omnic (tamsulosin hydrochloride 0.4mg capsule-Germany) in Healthy Male Volunteers. Report Date 04-Sep-2003.
GlaxoSmithKline Document Number ZM2007/00022/00 Study ID ARI109882. An Open-Label, Randomized, Single Dose, Three-Period Cross-over Study to Determine the Bioequivalence and Food Effect of a Combination Capsule Formulation of Dutasteride and Tamsulosin Hydrochloride (0.5mg/0.4mg) Compared to Concomitant Dosing of AVODART 0.5mg and FLOMAX 0.4 mg Commercial Capsules in Healthy Male Subjects. Report Date 30-Aug-2007.
Study at a glance
From the registry record, last updated by the sponsor on 19 Jun 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- An Open-label, Randomized, Single Dose, Multi-stage, Cross-over Study to Determine the Relative Bioavailability of Fixed Dose Combination Products Containing a 3-oblong Dutasteride Soft Gel Capsule and Tamsulosin (0.5 mg Dutasteride /0.2 mg Tamsulosin HCl) Pellets Having a Range of Tamsulosin Release Rates Produced by Different Mixtures of Enteric Coated and Uncoated Pellets Relative to Harnal-D Tablets, in Healthy Male Subjects of North East Asian Ancestry.
- ClinicalTrials.gov ID
- NCT01495026
- Acronym / sponsor ID
- 115708
- Conditions
- Prostatic Hyperplasia
- Keywords
- Healthy male subjects, North-East Asian ancestry, Bioequivalence, Food effect, Tamsulosin hydrochloride, Cross-over design, Pilot bioequivalence, Dutasteride (GI198745)
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 63 participants (actual)
- Lead sponsor
- GlaxoSmithKlineIndustry (pharma, biotech, devices)
- Study start
- 6 Nov 2011 (actual)
- Primary completion
- 3 Apr 2012 (actual)
- Study completion
- 3 Apr 2012 (actual)
- First posted
- 19 Dec 2011 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This study is an open-label, randomized, single dose, multi-stage, cross-over study in healthy male subjects of North East Asian ancestry. The aims are to:
- evaluate the pharmacokinetic parameters of several formulations of a fixed dose combination (FDC) capsule of dutasteride and tamsulosin hydrochloride (0.5 mg/0.2 mg) relative to co-administration of dutasteride 0.5 mg capsules and tamsulosin hydrochloride 0.2 mg tablets in the fasted state in order to define a formulation which is bioequivalent to a 0.2 mg orally disintegrating tamsulosin tablet, (Harnal-D Tablets)
- determine the effect of food on the relative bioavailability of tamsulosin in the FDC product which is assessed to be bioequivalent to Harnal-D Tablets in the fasted state
- assess the effect of water on the relative bioavailability of tamsulosin in Harnal-D Tablets in the fasted state
- assess the safety and tolerability of dosing with the different FDC capsule formulations Subjects will receive single oral doses in at least one treatment period; treatment periods will be separated by a 5-10 day washout period. Blood samples for pharmacokinetic analysis will be taken at regular intervals after dosing. Safety will be assessed by measurement of blood pressure, heart rate and review of adverse events. Each stage of the study will enrol 18 subjects to ensure 16 complete. Subjects may consent to participate in more than one stage.
Detailed description
This study is an open-label, randomized, single dose, multi-stage, cross-over study in healthy male subjects of North East Asian ancestry. The aims are to:
- evaluate the pharmacokinetic parameters of several formulations of a fixed dose combination (FDC) capsule of dutasteride and tamsulosin hydrochloride (0.5 mg/0.2 mg) relative to co-administration of dutasteride 0.5 mg capsules and tamsulosin hydrochloride 0.2 mg tablets in the fasted state in order to define a formulation which is bioequivalent to a 0.2 mg orally disintegrating tamsulosin tablet, (Harnal-D Tablets)
- determine the effect of food on the relative bioavailability of tamsulosin in the FDC product which is assessed to be bioequivalent to Harnal-D Tablets in the fasted state
- assess the effect of water on the relative bioavailability of tamsulosin in Harnal-D Tablets in the fasted state
- assess the safety and tolerability of dosing with the different FDC capsule formulations Subjects will receive single oral doses in at least one treatment period; treatment periods will be separated by a 5-10 day washout period. Blood samples for pharmacokinetic analysis will be taken at regular intervals after dosing. Safety will be assessed by measurement of blood pressure, heart rate and review of adverse events. Each stage of the study will enrol 18 subjects to ensure 16 complete. Subjects may consent to participate in more than one stage.
BACKGROUND:
Dutasteride:
Dutasteride (AVODART ™) is an approved potent 5-alpha-reductase inhibitor indicated for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate to improve symptoms, reduce the risk of acute urinary retention and reduce the risk of the need for BPH-related surgery [AVODART Package Insert, 2009]. In humans, dutasteride is well-tolerated in single doses up to 40mg/day, multiple doses up to 40mg/day administered for 7 days, and 5 mg/day administered for 24 weeks. In single dose clinical studies, the overall incidence and type of adverse events (AEs) was similar across the dutasteride, placebo, and finasteride treatment groups.
Tamsulosin:
Tamsulosin (Harnal, Harnal D, Flomax) is an alpha-1-adrenoceptor blocking agent approved for the treatment of signs and symptoms of benign prostatic hyperplasia. Tamsulosin HCl is extensively metabolized, with less than 10% of the dose excreted in the urine unchanged [Harnal, 2009; Harnal, 2011; Flomax, 2011]. In human liver microsomes and human lymphoblastoid cells expressing CYP cDNAs in vitro, tamsulosin HCl is metabolized by both CYP3A4 and CYP2D6 [Matsushima, 1998].
Dutasteride and Tamsulosin:
Clinical data exist to support that tamsulosin (an alpha-1-adrenoceptor antagonist), when used in combination with dutasteride (a 5-alpha reductase inhibitor), offers a more effective treatment for the symptoms of benign prostatic hyperplasia than either drug used alone [GSK study ARI40005, GlaxoSmithKline document number HM2002/00171/01]. In addition, data from a large, multi-centre National Institutes of Health-sponsored Medical Therapy of Prostatic Symptoms (MTOPS) study revealed greater benefits of combination alpha-1-adreoceptor antagonist and 5-alpha-reductase inhibitor therapy compared with either monotherapy in males with BPH [McConnell, 2002]. Clinical drug interaction studies have shown no pharmacokinetic or pharmacodynamic interactions between dutasteride and tamsulosin. Dutasteride may be administered with or without food. Tamsulosin should be administered with food.
Food effect PK data exists for co-administration of dutasteride and tamsulosin given in a fixed dose combination (FDC) capsule formulation relative to the co-administration of the two components, dutasteride and tamsulosin HCl; GSK studies ARI109882, [GlaxoSmithKline document number ZM2007/00022/00], and ARI114694, [GlaxoSmithKline document number ZM2010/00028/00]. In the latter study, the dose of tamsulosin HCl administered was 0.2 mg versus 0.4mg administered in ARI109882. The dose of dutasteride was the same in both studies (0.5mg). In ARI109882, the GSK combination capsule was found to be bioequivalent (under both fed and fasted conditions) to the marketed products administered separately. ARI114694 demonstrated bioequivalence for dutasteride but not for tamsulosin when administered as an FDC product (of dutasteride 0.5 mg and tamsulosin 0.2 mg) relative to co-administration of separate commercial formulations of dutasteride (0.5 mg) and tamsulosin (0.2 mg) in the fed and fasted stage in different North East Asian ethnic groups.
A subsequent GSK study, ARI115707, therefore investigated the relative bioavailability of tamsulosin (0.2mg tamsulosin HCl) only in the FDC product. Two different enteric-coated formulations of tamsulosin were administered with a 3-oblong dutasteride soft gel (0.5 mg) as a FDC capsule relative to co-administration of Harnal Capsules or Harnal-D Tablets with unbranded AVODART (0.5mg dutasteride). The two FDC formulations consisted of: 10% (weight gain) enteric coated tamsulosin pellets with a 3-oblong dutasteride soft gel and 15% (weight gain) enteric coated tamsulosin pellets with a 3-oblong dutasteride soft gel. Specifically, the study aimed to investigate the relative bioavailability of the following:
- FDC (with 10% enteric coated tamsulosin pellets) to a commercial formulation of dutasteride plus tamsulosin (Harnal-D Tablet)
- FDC (with 10% enteric coated tamsulosin pellets) to a commercial formulation of dutasteride plus tamsulosin (Harnal Capsule)
- FDC (with 15% enteric coated tamsulosin pellets) to a commercial formulation of dutasteride plus tamsulosin (Harnal-D Tablet) (also investigated in ARI114694)
- FDC (with 15% enteric coated tamsulosin pellets) to a commercial formulation of dutasteride plus tamsulosin (Harnal Capsule).
ARI115707 results showed that the GSK combination capsule with 10% enteric coated tamsulosin pellets was bioequivalent to the Harnal Capsule. None of the two GSK formulations was found to be bioequivalent to the Harnal-D Tablet.
In this study ARI115708, the relative bioavailability of tamsulosin (0.2mg tamsulosin HCl) is further investigated in several different formulations administered with a 3-oblong dutasteride soft gel as a FDC capsule relative to co-administration of Harnal-D Tablets (0.2 mg) with unbranded AVODART (dutasteride, 0.5mg). All formulations will be administered in the fasted state except in the last stage where the effect of food on the FDC will be assessed as well as the effect of water on the administration of Harnal-D Tablets. As Harnal Capsules are not available in Korea or Japan, bioequivalence to Harnal-D Tablets would allow the FDC to be registered in China, Korea, Taiwan and Japan, where Harnal-D Tablets are approved. Therefore, in ARI115708, only Harnal-D Tablets are used as the comparator.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Fixed dose combination product | Experimental | Drug: Dutasteride (0.5mg, fasted state), Drug: Dutasteride (0.5mg, fed state), Drug: Harnal-D Tablets with water (fasted state), Drug: Harnal-D Tablets with water (fed state), Drug: Harnal-D tablets without water (fasted state)Fixed dose combination capsule containing dutasteride 0.5mg and tamsulosin 0.2mg |
| Dutasteride | Experimental | Drug: Fixed dose combination capsule containing dutasteride 0.5mg and tamsulosin 0.2mg (fasted state), Drug: Fixed dose combination capsule containing dutasteride 0.5mg and tamsulosin 0.2mg (fed state)Commercial formulation of Dutasteride 0.5mg |
| Harnal-D Tablets | Experimental | Drug: Dutasteride (0.5mg, fasted state), Drug: Dutasteride (0.5mg, fed state), Drug: Fixed dose combination capsule containing dutasteride 0.5mg and tamsulosin 0.2mg (fasted state), Drug: Fixed dose combination capsule containing dutasteride 0.5mg and tamsulosin 0.2mg (fed state)Commercial formulation of Harna--D Tablets comprising 0.2mg Tamsulosin Hydrochloride |
Who may qualify
- Ages
- 20 to 45 years
- Sex
- Male only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (10 listed)
- A subject will be eligible for inclusion in this study only if all of the following criteria apply:
- Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. A subject with a clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included only if the Investigator and the GSK Medical Monitor agree that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
- Males between 20 and 45 years of age inclusive, at the time of signing the informed consent form.
- Japanese ancestry defined as being born in Japan, having four ethnic Japanese grandparents, holding a Japanese passport or identity papers and being able to speak Japanese, or Korean ancestry defined as being born in Korea, having four ethnic Korean grandparents, holding a Korean passport or identity papers and being able to speak Korean, or Chinese ancestry defined as being born in China, Hong Kong, Singapore or Taiwan, having four ethnic Chinese grandparents, holding a Chinese passport or identity papers and being able to speak Chinese.
- Japanese, Korean and Chinese subjects should also have lived outside their respective countries for less than 10 years.
Key exclusion criteria (20 listed)
- A subject will not be eligible for inclusion in this study if any of the following criteria apply:
- Poor metabolizer for CYP2D6 substrates as determined by genotyping of selected CYP2D6 variants at screening.
- 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.
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Dutasteride (0.5mg, fasted state)Open-label, randomized, single dose, multi-stage, cross-over study | Drug | Fixed dose combination product, Harnal-D Tablets |
| Dutasteride (0.5mg, fed state)Commercial formulation of Dutasteride 0.5mg | Drug | Fixed dose combination product, Harnal-D Tablets |
| Fixed dose combination capsule containing dutasteride 0.5mg and tamsulosin 0.2mg (fasted state)FDC with 85%, 65% and 0% of the dose as enteric-coated pellets and with X and/or Y% of the dose as enteric-coated pellets (X and Y to be determined from PK results from Stage 1) | Drug | Dutasteride, Harnal-D Tablets |
| Fixed dose combination capsule containing dutasteride 0.5mg and tamsulosin 0.2mg (fasted state)FDC containing faster-release enteric-coated pellets | Drug | Dutasteride, Harnal-D Tablets |
| Fixed dose combination capsule containing dutasteride 0.5mg and tamsulosin 0.2mg (fasted state)FDC bioequivalent to Harnal-D tablets | Drug | Dutasteride, Harnal-D Tablets |
| Fixed dose combination capsule containing dutasteride 0.5mg and tamsulosin 0.2mg (fed state)FDC bioequivalent to Harnal-D tablets | Drug | Dutasteride, Harnal-D Tablets |
| Harnal-D Tablets with water (fasted state)Commercial formulation of Harnal-D Tablets | Drug | Fixed dose combination product |
| Harnal-D Tablets with water (fed state)Commercial formulation of Harnal-D Tablets | Drug | Fixed dose combination product |
| Harnal-D tablets without water (fasted state)Commercial formulation of Harnal-D Tablets | Drug | Fixed dose combination product |
Primary outcome
Relative bioavailability of tamsulosin from FDC products (0.5 mg dutasteride /0.2 mg tamsulosin HCl) containing a size 3-oblong dutasteride soft gel capsule and tamsulosin pellets having a range of tamsulosin release rates produced by different mixtures
Time frame: 0, 15 min, 30 min, 45 min, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 10 hr, 12 hr, 16 hr, 24 hr, 48 hr, 72 hr
3 secondary outcomes
Effect of food on the relative bioavailability of tamsulosin in a selected FDC product in healthy male subjects of North East Asian ancestry
Time frame: 0, 15 min, 30 min, 45 min, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 10 hr, 12 hr, 16 hr, 24 hr, 48 hr, 72 hr
Effect of water on the relative bioavailability of tamsulosin in Harnal-D Tablets in the fasted state in healthy male subjects of North East Asian ancestry.
Time frame: 0, 15 min, 30 min, 45 min, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 10 hr, 12 hr, 16 hr, 24 hr, 48 hr, 72 hr
Safety and tolerability of dosing with the different FDC capsule formulations in healthy male subjects of North East Asian ancestry
Time frame: Vital signs: 0, 2 hr, 4 hr, 6 hr, 10 hr, 24 hr, 48 hr and 72 hr. Adverse events: 5 timepoints from pre-dose to follow-up visit (10-14 days post-dose)
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Jun 2018.
- BackgroundAVODART (Dutasteride 0.5 mg) Product Information. March 2011.
- Background: PubMed 20160156Cai G, Thiessen JJ, Baidoo CA, Fossler MJ. Operating characteristics of a partial-block randomized crossover bioequivalence study for dutasteride, a drug with a long half-life: investigation through simulation and comparison with final results. J Clin Pharmacol. 2010 Oct;50(10):1142-50. doi: 10.1177/0091270009355155. Epub 2010 Feb 16.
- BackgroundFLOMAX (Tamsulosin hydrochloride) Product Information. January, 2011.
- BackgroundFood and Drug Administration (FDA). Guidance for Industry: Handling and Retention of BA and BE Testing Samples. Centre for Drug Evaluation and Research, USA; 2004.
- BackgroundGlaxoSmithKline Document Number HM2002/00171/01 Study ID ARI40005. A randomised, double-blind, parallel group study to investigate the efficacy and safety of treatment with Dutasteride (0.5mg) and Tamsulosin (0.4mg), administered once daily for 4 years, alone and in combination, on the improvement of symptoms and clinical outcome in men with moderate to severe symptomatic benign prostatic hyperplasia;. Report Date 09-Jul-2004.
- BackgroundGlaxoSmithKline Document Number ZM2008/00126/02. Dutasteride Clinical Investigators Brochure v10. Report Date 27 May 2011.
- BackgroundHARNAL (Tamsulosin hydrochloride 0.2 mg) Product Information. , 2011.
- BackgroundHARNAL-D (Tamsulosin hydrochloride 0.2 mg) Product Information. , 2009.
- Background: PubMed 9492387Matsushima H, Kamimura H, Soeishi Y, Watanabe T, Higuchi S, Tsunoo M. Pharmacokinetics and plasma protein binding of tamsulosin hydrochloride in rats, dogs, and humans. Drug Metab Dispos. 1998 Mar;26(3):240-5.
- BackgroundMcConnell JD. The long term effects of medical therapy on the progression of BPH: Results from the MTOPS Trial (abstract 1042). 167 (4):265, 2002. J. Urology. 2002;167 (4):265.
- Background: PubMed 3450848Schuirmann DJ. A comparison of the two one-sided tests procedure and the power approach for assessing the equivalence of average bioavailability. J Pharmacokinet Biopharm. 1987 Dec;15(6):657-80. doi: 10.1007/BF01068419.
- Results publicationGlaxoSmithKline Document Number 2011N112801_00 Study ID ARI114694. GlaxoSmithKline studyARI114694: An open-label, randomized, single dose, two-period cross-over study to determine the bioavailability of a fixed dose combination capsule formulation of dutasteride and tamsulosin hydrochloride (0.5 mg/0.2mg) relative to co-administration of dutasteride 0.5mg capsules and tamsulosin hydrochloride 0.2mg tablets in healthy male subjects of north east Asian and non-Asian ancestry;. Report Date 02-May-2011.
- Results for study 115708 can be found on the GSK Clinical Study Register.Link provided by the sponsor.
- Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.Link provided by the sponsor.
- Individual participant dataSharing planned: Yes. Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
GSK Clinical Trials study director
GlaxoSmithKline
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Dutasteride (0.5mg, fasted state), Dutasteride (0.5mg, fed state) and Fixed dose combination capsule containing dutasteride 0.5mg and tamsulosin 0.2mg (fasted state) in people with Prostatic Hyperplasia, run by GlaxoSmithKline at 1 site in Australia.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 19 Jun 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Australia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Relative bioavailability of tamsulosin from FDC products (0.5 mg dutasteride /0.2 mg tamsulosin HCl) containing a size 3-oblong dutasteride soft gel capsule and tamsulosin pellets having a range of tamsulosin release rates produced by different mixtures (time frame: 0, 15 min, 30 min, 45 min, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 10 hr, 12 hr, 16 hr, 24 hr, 48 hr, 72 hr). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01495026, which also lists 15 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Jun 2018.