Study to Compare the Efficacy and Safety of Combination Treatment With Dutasteride and Tamsulosin With Tamsulosin Monotherapy, in Men With Moderate to Severe Benign Prostatic Hyperplasia

GlaxoSmithKline (GSK)

Status and phase: Completed; Phase 3

Conditions: Prostatic Hyperplasia

Treatments: Drug: Tamsulosin 0.2mg tablets; Drug: Dutasteride 0.5mg capsules; Drug: Dutasteride placebo capsules; Drug: Disintegrating placebo tamsulosin tablet

Study type: Interventional

Funder types: Industry

Identifiers

NCT02058368

114265

Details and patient eligibility

About

This is a multicentre, randomised, double-blind, parallel group study in Asian subjects. The aim of the study is to investigate whether combination therapy with dutasteride and tamsulosin is more effective than tamsulosin monotherapy for the improvement of symptoms and health outcomes in an at risk population of benign prostatic hyperplasia (BPH) clinical progression including older men (>=50 years), with moderate-severe symptoms of BPH, enlarged prostates (>=30 cubicentimeter [cc]) and prostate specific antigen (PSA) >= 1.5 nanograms per milliliter (ng/mL). Each subject who met the eligibility criteria at screening will enter a four-week single-blind, placebo run-in period following which each subject will be randomised into a 2 year double-blind treatment phase. The total study duration for each subject will be up to 110 weeks.

Enrollment: 607 patients

Sex: Male

Ages: 50+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• 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 >=30cc (by TRUS)
• Total serum Prostate Specific Antigen (PSA) >=1.5ng/mL and <= 10 ng/mL at Screening
• Maximum urinary flow rate (Qmax) >5mL/sec and 15mL/sec and minimum voided volume of >=125 milliliter (mL) at Screening
• Asparate aminotransferase (AST) and Alanine aminotransferase (ALT) < 2x upper limit of normal (ULN); alkaline phosphatase and bilirubin <= 1.5xULN (isolated bilirubin > 1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%)
• Fluent and literate in local language with the ability to comprehend and record information on the IPSS, BPH-related Health Status (BHS), BPH Impact Index (BII), and Problem Assessment Scale Sexual Function Inventory (PAS- SFI) questionnaires
• Men with a female partner of childbearing potential must agree to use a condom up to 6 months after the last dose (applies only to countries where the local product monograph for dutasteride mandates condom use for men with a female partner of childbearing potential)

Exclusion criteria

• History or evidence of prostate cancer (e.g. positive biopsy or ultrasound, suspicious Digital Rectal Examination [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, including consideration of prostate biopsy.

• Previous prostatic surgery (including TURP, laser, transrectal high intensity focused ultrasounds(HIFU), thermotherapy, transurethral needle ablation (TUNA), balloon dilatation, 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. Catheterisation (<10F) 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 conditions other than BPH, which may in the judgment 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).

• Unstable liver disease (chronic stable hepatitis B and C are acceptable if subject meets entry criteria).

• History of renal insufficiency, or serum creatinine >1.5 times the upper limit of normal at Screening.

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

  1. 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.
  2. 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.
  3. Any serious and/or unstable pre-existing medical, psychiatric disorder, or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to study procedures in the opinion of the investigator or GSK medical monitor. Investigator may consult with GSK Medical Monitor if condition could interfere with subject's safety
  4. History of breast cancer or clinical breast examination finding suggestive of malignancy.
  5. History of malignancy within the past five years, except for basal cell carcinoma of the skin. Subjects with a priori malignancy who have had no evidence of disease for at least the past 5 years are eligible.

• Current or Previous Use of the following medications:

  1. Use of any 5-alpha-reductase inhibitor (e.g. finasteride), any drugs with antiandrogenic properties (e.g. spironolactone, flutamide, bicalutamide, cimetidine, ketoconazole, progestational agents), or other drugs noted for gynaecomastia effects, or that could affect prostate volume, within the 6 months preceding the historical TRUS or Screening Visit and throughout the study (other than as study medication). Previous use of dutasteride should not be within 6 months of the baseline or historical TRUS.
  2. Anabolic steroids (subject must discontinue for 6 months prior to study entry to be eligible) and agree not to take them for the duration of the study.
  3. Phytotherapy for BPH within 2 weeks of Screening Visit and/or predicted to need phytotherapy during the study.
  4. Use of any alpha-adrenoreceptor blockers within 2 weeks of Screening Visit (i.e. indoramin, prazosin, terazosin, tamsulosin, alfuzosin, doxazosin, silodosin) and/or predicted to need any alpha blockers other than the study prescribed tamsulosin.
  5. Use of any alpha-adrenoreceptor agonists (e.g. pseudoephedrine, phenylephedrine, ephedrine) or anticholinergics (e.g. oxybutynin,tolterodine, darifenacin, solifenacin,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.

• Participation in any investigational or marketed drug trial within 30 days (or 5 half-lives of drug, whichever is the longer) preceding the Screening Visit and/or plans to participate in such a trial during the course of this study.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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607 participants in 2 patient groups

Arm 1

Experimental group

Description:

Run-in phase: All subjects qualifying for the study will entered into a placebo run-in phase will receive one soft gelatin placebo capsule (swallowed whole and not chewed) and one oral disintegrating placebo tablet once daily (OD) (dissolved on the tongue then swallowed not chewed), following the first meal each day for four weeks. Randomized treatment phase: Subjects will be instructed to take 1 dutasteride 0.5 milligram (mg) capsule (swallowed whole and not chewed) and one tamsulosin 0.2mg tablet OD (dissolved on the tongue then swallowed not chewed) following the first meal each day for 104 weeks.

Treatment:

Drug: Dutasteride 0.5mg capsules

Drug: Disintegrating placebo tamsulosin tablet

Drug: Tamsulosin 0.2mg tablets

Drug: Dutasteride placebo capsules

Arm 2

Experimental group

Description:

Run-in phase: All subjects qualifying for the study will entered into a placebo run-in phase will receive one soft gelatine placebo capsule (swallowed whole and not chewed) and one oral disintegrating placebo tablet OD (dissolved on the tongue then swallowed not chewed), following the first meal each day for four weeks. Randomized treatment phase: Subjects will be instructed to take 1 placebo dutasteride 0.5mg capsule (swallowed whole and not chewed) and one tamsulosin 0.2mg tablet OD (dissolved on the tongue then swallowed not chewed) following the first meal each day for 104 weeks.

Treatment:

Drug: Disintegrating placebo tamsulosin tablet

Drug: Tamsulosin 0.2mg tablets

Drug: Dutasteride placebo capsules