Benign Prostatic Hyperplasia Trial With Dutasteride And Tamsulosin Combination Treatment

Condition(s) targeted: Prostatic Hyperplasia

Intervention: dutasteride 0.5mg once daily for 4 years (Drug); tamsulosin 0.4mg once daily for 4 years (Drug)

Phase: Phase 3

Status: Completed

Sponsored by: GlaxoSmithKline

Official(s) and/or principal investigator(s):
GSK Clinical Trials, Study Director, Affiliation: GlaxoSmithKline

This study will investigate the efficacy and safety of treatment with dutasteride and tamsulosin, 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 (BPH). Study visits are every 3 months for up to 4 years (18 clinic visits). Transrectal ultrasound (TRUS) is done annually.

Official title: See Detailed Description

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Primary outcome:

Number of Events of Acute Urinary Retention (AUR) or Benign Prostatic Hyperplasia (BPH)-Related Prostatic Surgery at the Indicated Time Periods.

Number of Participants With AUR or BPH-related Surgery

Secondary outcome:

Number of Events of First BPH Clinical Progression at Years 1, 2, 3 and 4

The Number of Participants With Each of the Five Components of BPH Clinical Progression

Number of Events of Symptom Deterioration at the Indicated Time Periods

Number of Participants With an Event of Post-baseline BPH-related Macroscopic Hematuria

Number of Participants With an Event of Post-baseline BPH-related Hematospermia

Adjusted Mean Change From Baseline in International Prostate Symptom Score (IPSS) at Months 12, 24, 36, and 48

Adjusted Mean Change From Baseline in Urinary Flow Rate (Qmax) at Months 12, 24, 36, and 48

Adjusted Mean Percent Change From Baseline in Prostate Volume at Months 12, 24, 36, and 48

Adjusted Mean Change From Baseline in Transition Zone (Portion of the Prostate That Surrounds the Proximal Urethra) Volume at Months 12, 24, 36, and 48

Number of Unscheduled Visits to GP/Urologist Regarding AUR Symptoms Since the Last Study Visit

Number of "Yes" Responses to the Question: "Would the Participant Have Paid a Visit to His GP/Urologist Regarding AUR Symptoms if the Study Visit Had Not Been Planned"?.

Number of Visits to GP/Urologist Regarding BPH-related Surgery Since the Last Study Visit

Number of "Yes" Responses to the Question: "Would the Participant Have Paid a Visit to His GP/Urologist Regarding BPH-related Surgery Since the Last Study Visit?"

Number of Unplanned Visits to GP/Urologist That Would Have Taken Place if a Scheduled Study Visit Had Not Been Planned (Including Visits Resulting From UTI, UI, Macroscopic Haematuria, Etc.)

Number of Unscheduled Visits to GP/Urologist (Outpatient) Planned, Not Relating to the Study (Including Visits Resulting From UTI, UI, Macroscopic Haematuria, Etc.)

Adjusted Mean Change From Baseline in BPH Impact Index (BII) at Months 12, 24, 36, and 48

Adjusted Mean Change From Baseline in BPH-Related Health Status (BHS) at Months 12, 24, 36, and 48

Patient Perception of Study Medication (PPSM): Number of Participants With the Indicated Responses to Question 1 (LOCF)

Patient Perception of Study Medication (PPSM): Number of Participants With the Indicated Responses to Question 2 (LOCF)

Patient Perception of Study Medication (PPSM): Number of Participants With the Indicated Responses to Question 3 (LOCF)

Patient Perception of Study Medication (PPSM): Number of Participants With the Indicated Responses to Question 4 (LOCF)

Patient Perception of Study Medication (PPSM): Number of Participants With the Indicated Responses to Question 5 (LOCF)

Patient Perception of Study Medication (PPSM): Number of Participants With the Indicated Responses to Question 6 (LOCF)

Patient Perception of Study Medication (PPSM): Number of Participants With the Indicated Responses to Question 7 (LOCF)

Patient Perception of Study Medication (PPSM): Number of Participants With the Indicated Responses to Question 8 (LOCF)

Patient Perception of Study Medication (PPSM): Number of Participants With the Indicated Responses to Question 9 (LOCF)

Patient Perception of Study Medication (PPSM): Number of Participants With the Indicated Responses to Question 10 (LOCF)

Patient Perception of Study Medication (PPSM): Number of Participants With the Indicated Responses to Question 11 (LOCF)

Patient Perception of Study Medication (PPSM): Number of Participants With the Indicated Responses to Question 12 (LOCF)

Detailed description: A randomised, double-blind, parallel group study to investigate the efficacy and safety of treatment with Dutasteride (0. 5 mg) and Tamsulosin (0. 4 mg), 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.

Minimum age: 50 Years. Maximum age: N/A. Gender(s): Male.

Criteria:

Inclusion criteria:

- A subject will be considered eligible for inclusion in this study only if all of the

following criteria apply:

- males, aged ≥50 years

- clinical diagnosis of BPH by medical history and physical examination, including a

digital rectal examination (DRE)

- International Prostate Symptom Score (IPSS) ≥12 points at Screening

- prostate volume ≥30 cc by transrectal ultrasonography; (TRUS)

- total serum Prostate Specific Antigen (PSA) ≥1. 5ng/mL at Screening

- maximum flow rate (Qmax) >5 mL/sec and ≤15 mL/sec and minimum voided volume of ≥125

mL at Screening (based on two voids)

- willing and able to give written informed consent and comply with study procedures

- fluent and literate in local language with the ability to read, comprehend and record

information on the IPSS, BII and Patient Perception of Study Medication

- able to swallow and retain oral medication

- willing and able to participate in the study for the full 4 years.

Exclusion Criteria: A subject will not be eligible for inclusion in this study if any of the following criteria apply:

- total serum PSA >10. 0ng/mL at Screening

- history or evidence of prostate cancer (e. g. positive biopsy or ultrasound,

suspicious DRE). Patients with suspicious ultrasound or DRE who have had a negative biopsy within the preceding 6 months and stable PSA are eligible for the study. Note: If total serum PSA is >4ng/mL and unless PSA value has been stable for at least the past 2 years, the investigator should make every appropriate effort to exclude the possibility of prostate cancer, e. g. further DRE, review TRUS taken within previous month, consider 8-12 core prostate biopsy in accordance with routine clinical practice.

- previous prostatic surgery (including TURP, balloon dilatation, thermotherapy and

stent replacement) or other invasive procedures to treat BPH.

- history of flexible/rigid cystoscopy or other instrumentation of the urethra within 7

days prior to the Screening Visit. Routine catheterisation is acceptable with no time restriction.

- history of AUR within 3 months prior to Screening Visit.

- post-void residual volume >250mL (suprapubic ultrasound) at Screening.

- any causes other than BPH, which may in the judgement of the investigator, result in

urinary symptoms or changes in flow rate (e. g. neurogenic bladder, bladder neck contracture, urethral stricture, bladder malignancy, acute or chronic prostatitis, or acute or chronic urinary tract infections).

- history of breast cancer or clinical breast examination finding of unclear origin or

suggestive of malignancy.

- use of any 5-alpha-reductase inhibitor (e. g. Proscar®, Propecia®, Avodart®), any

drugs with antiandrogenic properties (e. g. spironolactone, flutamide, bicalutamide, cimetidine, ketoconazole, metronidazole, progestational agents), or other drugs which affect prostate volume, within past 6 months of the Screening Visit and throughout the study (other than as study medication).

- concurrent use of anabolic steroids

- use of phytotherapy for BPH within 2 weeks of Screening Visit and/or predicted to

need phytotherapy during the study.

- use of any alpha-adrenoreceptor blockers (i. e. indoramin, prazosin, terazosin,

tamsulosin, alfuzosin and doxazosin) within 2 weeks of Screening Visit and/or predicted to need any alpha blockers other than tamsulosin during the study. Note: the purpose of this criteria is to be able to standardise baseline symptom severity for all enrolled patients prior to randomisation and not to specifically exclude current alpha-adrenoreceptor blocker users from participation in the study.

- use of any alpha-adrenoreceptor agonists (e. g. pseudoephedrine, phenylephrine,

ephedrine) or anticholinergics (e. g. oxybutynin, propantheline) or cholinergics (e. g. bethanecol chloride) within 48 hours prior to all uroflowmetry assessments.

- hypersensitivity to any alpha-/beta- adrenoreceptor blocker or 5-alpha-reductase

inhibitor, or other chemically-related drugs.

- concurrent use of drugs known or thought to have an interaction with tamsulosin, e. g.

cimetidine and warfarin.

- history of hepatic impairment or abnormal liver function tests at Screening defined

as alanine aminotransferase (ALT), aspartate aminotranferase (AST), and/or alkaline phosphatase >2 times the upper limit of normal, or total bilirubin >1. 5 times the upper limit of normal (unless associated with predominantly indirect bilirubin elevation or Gilbert's syndrome).

- history of renal insufficiency, or serum creatinine >1. 5 times the upper limit of

normal or serum creatinine ≥1. 5 mg/dL at Screening.

- prior history of malignancies other than basal cell carcinoma or squamous cell

carcinoma of the skin within the past 5 years. Subjects with a prior malignancy who have had no evidence of disease for at least the past 5 years are eligible.

- history of any illness that in the opinion of the investigator might confound the

results of the study or poses additional risk to the patient.

- any unstable, serious co-existing medical condition(s) including, but not limited to,

myocardial infarction, coronary bypass surgery, unstable angina, cardiac arrhythmias, clinically evident congestive heart failure, or cerebrovascular accident within 6 months prior to Screening visit; uncontrolled diabetes or peptic ulcer disease which is uncontrolled by medical management.

- history of postural hypotension, dizziness, vertigo 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 unsuccessful treatment with tamsulosin or 'first dose' hypotensive episode

on initiation of alpha-1-adrenoreceptor antagonist therapy.

- history of unsuccessful treatment with finasteride or dutasteride

- history or current evidence of drug or alcohol abuse within the previous 12 months.

- participation in any investigational or marketed drug trial within 30 days (or 5

half-lives whichever is the longer) preceding the Screening Visit and/or during the course of this study.

GSK Investigational Site, Buenos Aires 1416, Argentina

GSK Investigational Site, Rio de Janeiro 20 551-030, Brazil

GSK Investigational Site, São Paulo 04262-000, Brazil

GSK Investigational Site, Gif-sur-Yvette 91190, France

GSK Investigational Site, Pontonx Sur Adour 40465, France

GSK Investigational Site, Saint Sebastien de Morsent 27180, France

GSK Investigational Site, Tours 37044, France

GSK Investigational Site, Vourey 38210, France

GSK Investigational Site, Reykjavik 101, Iceland

GSK Investigational Site, Haifa 31048, Israel

GSK Investigational Site, Haifa, Israel

GSK Investigational Site, Holon 58100, Israel

GSK Investigational Site, Kfar Saba 44281, Israel

GSK Investigational Site, Ramat Gan 52621, Israel

GSK Investigational Site, Zrifin 70300, Israel

GSK Investigational Site, Mexico 06700, Mexico

GSK Investigational Site, Manila 1003, Philippines

GSK Investigational Site, Quezon City 1101, Philippines

GSK Investigational Site, Lisboa 1269-098 Lisboa, Portugal

GSK Investigational Site, S. Martinho do Bispo 3040-316 Coimbra, Portugal

GSK Investigational Site, Guadalajara 19002, Spain

GSK Investigational Site, Kaohsiung 813, Taiwan

GSK Investigational Site, Taichung 404, Taiwan

GSK Investigational Site, Tainan 704, Taiwan

GSK Investigational Site, Taipei 100, Taiwan

GSK Investigational Site, Taipei 112, Taiwan

GSK Investigational Site, Taipei 114, Taiwan

GSK Investigational Site, Taoyuan 333, Taiwan

GSK Investigational Site, Clydebank, Glasgow G81 2DR, United Kingdom

GSK Investigational Site, Dundee DD1 9SY, United Kingdom

GSK Investigational Site, Edgbaston, Birmingham B15 2SQ, United Kingdom

GSK Investigational Site, Manchester M15 6SX, United Kingdom

GSK Investigational Site, Waterloo, Liverpool L22 0LG, United Kingdom

GSK Investigational Site, Swansea, Glamorgan SA4 4NU, United Kingdom

GSK Investigational Site, Buckshaw Village, Chorley, Lancashire PR7 7NA, United Kingdom

GSK Investigational Site, Northwood, Middlesex HA6 2RN, United Kingdom

GSK Investigational Site, Belo Horizonte, Minas Gerais 30130-008, Brazil

GSK Investigational Site, Porto Alegre, Rio Grande Do Sul 90035-903, Brazil

GSK Investigational Site, Porto Alegre, Rio Grande Do Sul 90470-340, Brazil

GSK Investigational Site, Porto Alegre, Rio Grande Do Sul 90610-000, Brazil

GSK Investigational Site, Chichester, Sussex West PO19 4SE, United Kingdom

Related publications:

Roehrborn CG, Andriole GL, Wilson TH, Castro R, Rittmaster RS. Effect of dutasteride on prostate biopsy rates and the diagnosis of prostate cancer in men with lower urinary tract symptoms and enlarged prostates in the Combination of Avodart and Tamsulosin trial. Eur Urol. 2011 Feb;59(2):244-9. doi: 10.1016/j.eururo.2010.10.040. Epub 2010 Nov 4.

Black L, Grove A, Morrill B. The psychometric validation of a US English satisfaction measure for patients with benign prostatic hyperplasia and lower urinary tract symptoms. Health Qual Life Outcomes. 2009 Jun 19;7:55. doi: 10.1186/1477-7525-7-55.

Bjerklund Johansen TE, Baker TM, Black LK. Cost-effectiveness of combination therapy for treatment of benign prostatic hyperplasia: a model based on the findings of the Combination of Avodart and Tamsulosin trial. BJU Int. 2012 Mar;109(5):731-8. doi: 10.1111/j.1464-410X.2011.10511.x. Epub 2011 Sep 20.

Barkin J, Roehrborn CG, Siami P, Haillot O, Morrill B, Black L, Montorsi F; CombAT Study Group. Effect of dutasteride, tamsulosin and the combination on patient-reported quality of life and treatment satisfaction in men with moderate-to-severe benign prostatic hyperplasia: 2-year data from the CombAT trial. BJU Int. 2009 Apr;103(7):919-26. doi: 10.1111/j.1464-410X.2009.08196.x. Epub 2009 Feb 23.

Antoñanzas F, Brenes F, Molero JM, Fernández-Pro A, Huerta A, Palencia R, Cozar JM. [Cost-effectiveness of the combination therapy of dutasteride and tamsulosin in the treatment of benign prostatic hyperlasia in Spain]. Actas Urol Esp. 2011 Feb;35(2):65-71. doi: 10.1016/j.acuro.2010.11.008. Epub 2011 Jan 26. Spanish.

Montorsi F, Roehrborn C, Garcia-Penit J, Borre M, Roeleveld TA, Alimi JC, Gagnier P, Wilson TH. The effects of dutasteride or tamsulosin alone and in combination on storage and voiding symptoms in men with lower urinary tract symptoms (LUTS) and benign prostatic hyperplasia (BPH): 4-year data from the Combination of Avodart and Tamsulosin (CombAT) study. BJU Int. 2011 May;107(9):1426-31. doi: 10.1111/j.1464-410X.2011.10129.x. Epub 2011 Feb 23.

Haillot O, Fraga A, Maciukiewicz P, Pushkar D, Tammela T, Höfner K, Chantada V, Gagnier P, Morrill B. The effects of combination therapy with dutasteride plus tamsulosin on clinical outcomes in men with symptomatic BPH: 4-year post hoc analysis of European men in the CombAT study. Prostate Cancer Prostatic Dis. 2011 Dec;14(4):302-6. doi: 10.1038/pcan.2011.13. Epub 2011 Apr 19.

Montorsi F, Henkel T, Geboers A, Mirone V, Arrosagaray P, Morrill B, Black L. Effect of dutasteride, tamsulosin and the combination on patient-reported quality of life and treatment satisfaction in men with moderate-to-severe benign prostatic hyperplasia: 4-year data from the CombAT study. Int J Clin Pract. 2010 Jul;64(8):1042-51. doi: 10.1111/j.1742-1241.2010.02428.x. Epub 2010 May 7.

Becher E, Roehrborn CG, Siami P, Gagnier RP, Wilson TH, Montorsi F. The effects of dutasteride, tamsulosin, and the combination on storage and voiding in men with benign prostatic hyperplasia and prostatic enlargement: 2-year results from the Combination of Avodart and Tamsulosin study. Prostate Cancer Prostatic Dis. 2009;12(4):369-74. doi: 10.1038/pcan.2009.37. Epub 2009 Sep 1.

Roehrborn CG, Wilson TH, Black LK. Quantifying the contribution of symptom improvement to satisfaction of men with moderate to severe benign prostatic hyperplasia: 4-year data from the CombAT trial. J Urol. 2012 May;187(5):1732-8. doi: 10.1016/j.juro.2011.12.083. Epub 2012 Mar 15.

Roehrborn CG, Siami P, Barkin J, Damião R, Major-Walker K, Nandy I, Morrill BB, Gagnier RP, Montorsi F; CombAT Study Group. The effects of combination therapy with dutasteride and tamsulosin on clinical outcomes in men with symptomatic benign prostatic hyperplasia: 4-year results from the CombAT study. Eur Urol. 2010 Jan;57(1):123-31. doi: 10.1016/j.eururo.2009.09.035. Epub 2009 Sep 19. Erratum in: Eur Urol. 2010 Nov;58(5):801.

Chung BH, Roehrborn CG, Siami P, Major-Walker K, Morrill BB, Wilson TH, Montorsi F. Efficacy and safety of dutasteride, tamsulosin and their combination in a subpopulation of the CombAT study: 2-year results in Asian men with moderate-to-severe BPH. Prostate Cancer Prostatic Dis. 2009;12(2):152-9. doi: 10.1038/pcan.2008.49. Epub 2008 Sep 23.

Roehrborn CG, Barkin J, Siami P, Tubaro A, Wilson TH, Morrill BB, Gagnier RP. Clinical outcomes after combined therapy with dutasteride plus tamsulosin or either monotherapy in men with benign prostatic hyperplasia (BPH) by baseline characteristics: 4-year results from the randomized, double-blind Combination of Avodart and Tamsulosin (CombAT) trial. BJU Int. 2011 Mar;107(6):946-54. doi: 10.1111/j.1464-410X.2011.10124.x. Epub 2011 Feb 18.

Starting date: November 2003
Last updated: April 11, 2013