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

Prostatic Hyperplasia Clinical Trial

Official title:

A Randomized, Double-blind, Parallel Group Study to Compare the Efficacy and Safety of Combination Treatment With Dutasteride (0.5mg) and Tamsulosin (0.2mg) With Tamsulosin (0.2mg) Monotherapy, Administered Once Daily for 2 Years, on the Improvement of Symptoms and Health Outcomes in Men With Moderate to Severe Benign Prostatic Hyperplasia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02058368
• Other study ID #: 114265
• Status: Completed
• Phase: Phase 3
• Start date: February 10, 2014
• Est. completion date: March 3, 2017

Study information

• Verified date: January 2019
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 607
• Est. completion date: March 3, 2017
• Est. primary completion date: March 3, 2017
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 50 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Hyperplasia
• Prostatic Hyperplasia

Intervention

Drug:
• Dutasteride 0.5mg capsules
Dutasteride 0.5mg capsules will be supplied as plain, oblong, opaque, dull yellow soft gelatin capsules.
• Dutasteride placebo capsules
Dutasteride placebo will be supplied as plain, oblong, opaque, dull yellow soft gelatin capsules.
• Tamsulosin 0.2mg tablets
Commercially available tamsulosin 0.2mg tablets will be supplied.
• Disintegrating placebo tamsulosin tablet
Disintegrating placebo tamsulosin tablet will be supplied for the run-in period.

Locations

Country	Name	City	State
China	GSK Investigational Site	Beijing
China	GSK Investigational Site	Beijing
China	GSK Investigational Site	Beijing
China	GSK Investigational Site	Chongqing
China	GSK Investigational Site	Guangzhou	Guangdong
China	GSK Investigational Site	Hangzhou	Zhejiang
China	GSK Investigational Site	Shanghai
China	GSK Investigational Site	Shanghai
China	GSK Investigational Site	Shanghai
China	GSK Investigational Site	Shanghai
China	GSK Investigational Site	Shanghai
China	GSK Investigational Site	Shenyang	Liaoning
China	GSK Investigational Site	Suzhou	Jiangsu
China	GSK Investigational Site	Wuhan	Hubei
China	GSK Investigational Site	Xiame	Fujian
Japan	GSK Investigational Site	Fukuoka
Japan	GSK Investigational Site	Fukuoka
Japan	GSK Investigational Site	Hyogo
Japan	GSK Investigational Site	Kanagawa
Japan	GSK Investigational Site	Kanagawa
Japan	GSK Investigational Site	Oita
Japan	GSK Investigational Site	Osaka
Japan	GSK Investigational Site	Saitama
Japan	GSK Investigational Site	Tokyo
Japan	GSK Investigational Site	Tokyo
Japan	GSK Investigational Site	Yamanashi
Korea, Republic of	GSK Investigational Site	Busan
Korea, Republic of	GSK Investigational Site	Chonju
Korea, Republic of	GSK Investigational Site	Daegu
Korea, Republic of	GSK Investigational Site	Gwangju
Korea, Republic of	GSK Investigational Site	Incheon
Korea, Republic of	GSK Investigational Site	Seoul
Korea, Republic of	GSK Investigational Site	Seoul
Korea, Republic of	GSK Investigational Site	Seoul
Korea, Republic of	GSK Investigational Site	Seoul
Korea, Republic of	GSK Investigational Site	Seoul
Korea, Republic of	GSK Investigational Site	Seoul
Korea, Republic of	GSK Investigational Site	Seoul
Taiwan	GSK Investigational Site	Chia-Yi
Taiwan	GSK Investigational Site	Hualien
Taiwan	GSK Investigational Site	Kaohsiung
Taiwan	GSK Investigational Site	Kaohsiung Hsien
Taiwan	GSK Investigational Site	New Taipei City
Taiwan	GSK Investigational Site	Tainan
Taiwan	GSK Investigational Site	Tainan
Taiwan	GSK Investigational Site	Tau-Yuan

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Countries where clinical trial is conducted

China,  Japan,  Korea, Republic of,  Taiwan, 

References & Publications (1)

Haque N, Masumori N, Sakamoto S, Ye Z, Yoon SJ, Kuo HC, Brotherton B, Wilson T, Muganurmath C, McLaughlin M, Manyak M. Superiority of dutasteride 0.5 mg and tamsulosin 0.2 mg for the treatment of moderate-to-severe benign prostatic hyperplasia in Asian men. Int J Urol. 2018 Nov;25(11):944-951. doi: 10.1111/iju.13785. Epub 2018 Sep 9. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Baseline in International Prostate Symptom Score (IPSS) by Last Observation Carried Forward (LOCF) Approach at 24 Months	IPSS (also called IPSS total score) is the sum of the seven questions with each score ranging from 0 (best) to 5 (worst). IPSS was self administered at screening, Baseline and each time-point of Month 3, 6, 9, 12, 15, 18, 21 and 24. Seven questions included are incomplete emptying, frequency, intermittency, urgency, weak stream, straining and nocturia. The total IPSS score can range from 0-35 with severity catagories of mild (0 to 7), moderate (8 to 19) or severe (20 to 35). LOCF is defined as carrying forward the last non-missing post-Baseline assessment for participants with missing visit data and/or for participants who discontinued from the study. Baseline value is defined as the latest non-missing assessment of either treatment start date or randomization date. Month 24 is the primary timepoint and earlier timepoints are considered secondary. Change from Baseline defined as difference between Post-Baseline value and Baseline value.	Baseline and 3, 6, 9, 12, 15, 18, 21 and 24 months
Secondary	Percent Change in Prostate Volume From Baseline	Prostate Volume measurements were conducted annually using Transrectal ultrasound (TRUS). The following calculation was utilized to assess the prostate volume (cc): pi/6 (Anteroposterior Width multiplied by Cephalocaudal Width multiplied by Transverse Width). Post-Baseline prostate volume was calculated at 12 and 24 months. Baseline value was defined as the latest non-missing assessment of either treatment start date or randomization date. Change from Baseline was reported based on the LOCF. Change from Baseline defined as difference between Post-Baseline value and Baseline value and reported as a percentage.	Baseline,12 and 24 months
Secondary	Number of Participants With IPSS Improvement From Baseline	Improvement in IPSS was categorized as improvement, no change and worsening. Improvement defined as greater than or equal to 2 points, greater than or equal to 3 points and greater than or equal to 25 percent in participants at months 3,6,9,12,15,18,21 and 24 . Baseline value was defined as the latest non-missing assessment of either treatment start date or randomization date. Change from Baseline was reported based on the LOCF. Change from Baseline defined as difference between Post-Baseline value and Baseline value.	Baseline and 3, 6, 9,12,15,18,21 and 24 months
Secondary	Change From Baseline in Maximum Urine Flow Rate (Qmax) by LOCF Approach	Qmax is defined as maximum urine flow. Qmax was measured with Uroflow meter (Urodyn 1000) at Screening, Baseline, and at Months 6,12,18 and 24. Change from Baseline Qmax at each scheduled post-Baseline assessment was compared in terms of combination treatment (Dut plus Tam) versus tamsulosin treatment using t-tests from a general linear model with effects for treatment, country, and Baseline Qmax. Baseline value was defined as the latest non-missing assessment either treatment start date or randomization date. Change from Baseline defined as difference between Post-Baseline value and Baseline value. Only those participants available at the specified time points (represented by n=X in the category titles) were analyzed.	Baseline, 6, 12, 18 and 24 Months
Secondary	Number of Participants With Qmax Improvement From Baseline by LOCF Approach.	Qmax change from Baseline was presented using six improvement levels: >0 milliliter per second (mL/sec) and >=1 mL/sec through >=5mL/sec. Qmax percentage change from Baseline was presented using six improvement levels: >0%, >=10%, >=20%, >=30%, >=40%, and >=50%. Here, Qmax improvement of >= 3 mL/sec and Qmax percentage of >= 30 % for 24 Months has been summarized. Baseline value is defined as the latest non-missing assessment of either treatment start date or randomization date. Change from Baseline defined as difference between Post-Baseline value and Baseline value. Baseline value is defined as the latest non-missing assessment of either treatment start date or randomization date.	Baseline 6, 12, 18 and 24 Months
Secondary	Number of Participants With Acute Urinary Retention (AUR) or Benign Prostatic Hyperplasia (BPH)-Related Prostatic Surgery	AUR is defined as condition when the participant is unable to urinate and requires bladder catheterization. AUR or BPH-related surgery event details per participant was summarized as first occurring of either AUR or BPH-related surgery.	Up to 24 Months
Secondary	Number of Subjects With AUR	AUR is defined as condition when the participant is unable to urinate and requires bladder catheterization.	Up to 24 Months
Secondary	Number of Participants With BPH-related Surgery	BPH-related interventions were recorded. BPH-related interventions included adenomectomy, balloon dilatation, electroresection, thermotherapy (microwave or radiofrequency), laser resection, prostatectomy, prostatotomy, transurethral resection of the prostate, transurethral drainage of prostatic abscess, drainage of prostatic cysts, radioactive seeding of the prostate, prostatic urethral stenting, incision of periurethral stricture, ethanol injections into the prostate, transrectal high intensity focussed ultrasound, transurethral needle ablation and transurethral microwave thermotherapy.	Up to 24 Months
Secondary	Change From Baseline in the BPH-related Health Status (BHS) by LOCF Approach	BHS was collected as Question 8 the IPSS questionnaire regarding quality of life due to urinary symptom with scores values ranging from 0 (delightful) to 6 (terrible). Baseline value was defined as the latest non-missing assessment of either treatment start date or randomization date. Change from baseline BHS at each scheduled post-baseline assessment was compared in terms of combination treatment (Dut plus Tam) versus tamsulosin treatment using t-tests from a general linear model with effects for treatment, country, and Baseline BHS.	Baseline, 3, 6, 9, 12, 15, 18, 21 and 24 Months
Secondary	Change From Baseline in BPH Impact Index (BII) by LOCF Approach	The BII consists of four questions and BII total score is the sum of four questions. Total score range is 0 (no problem) to 13 (worst value). Baseline value was defined as the latest non-missing assessment of either treatment start date or randomization date. Change from Baseline BII at each scheduled post-baseline assessment was compared in terms of combination treatment (Dut plus Tam) versus tamsulosin treatment using t-tests from a general linear model with effects for treatment, country, and Baseline BII. Change from Baseline was summarized using LOCF approaches.	Baseline 3, 6, 9, 12, 15, 18, 21 and 24 Months
Secondary	Change From Baseline in Problem Assessment Scale of the Sexual Function Inventory (PAS-SFI)	PAS SFI consists of three questions each with a range of 0 (Big Problem) to 4 (No Problem). PAS SFI was administered at screening, Baseline and at each month 12 and 24. The total PSI is the sum of the three questions; the total score range is 0 to 12. Change from Baseline PAS SFI at each scheduled post-baseline assessment was compared in terms of combination treatment (Dut plus Tam) versus tamsulosin treatment using t-tests from a general linear model with effects for treatment, country, and Baseline PAS SFI. Baseline value was defined as the latest non-missing assessment of either treatment start date or randomization date. Change from Baseline defined as difference between Post-Baseline value and Baseline value. Only those participants available at the specified time points (represented by n=X in the category titles) were analyzed.	Baseline, 12 and 24 Months
Secondary	Number of Hospitalization Days	Duration of hospitalization days due to AUR or BPH-related surgery was recorded.	Up to 24 Months
Secondary	Number of Participants in a Hospital Ward	Details of number of participants in different types of wards was recorded. Types of wards included general ward, recovery, intensive care unit, multiple ward types and others	Up to 24 Months
Secondary	Number of Participants With Hospital Admissions	Details of participants who were admitted to hospitals related to AUR or BPH-Related surgery has been recorded.	Up to 24 Months
Secondary	Number of Participants With Non-serious Adverse Events (AE) and Serious AE (SAE)	An adverse event is defined as any untoward medical occurrence in a subject or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A SAE is defined as resulting in death, life threatening, requires hospitalization or prolongation of hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation that is medically important, All events of possible drug-induced liver injury with hyperbilirubinaemia, male breast cancer and spontaneous abortion of a female partner of a male subject	Up to 24 Months
Secondary	Change From Baseline in Serum Prostate Specific Antigen (PSA)	Total serum PSA concentrations were assessed at pre-screening, month 6, 12 and 24. Change from baseline total PSA was compared in terms of combination treatment (Dut plus Tam) versus tamsulosin treatment at each scheduled post-baseline assessment using a general linear model with effects for treatment and baseline total PSA. Baseline value was defined as the latest non-missing assessment of either treatment start date or randomization date. Change from Baseline defined as difference between Post-Baseline value and Baseline value. Only those participants available at the specified time points (represented by n=X in the category titles) were analyzed.	Baseline 6, 12 and 24 Months
Secondary	Number of Participants With Vital Signs Exceeding Threshold Values	Vital signs included assessment of systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate. Threshold ranges for SBP ranged from < 80 mmHg (millimeter of mercury) (lower) to > 165 mmHg (upper); for DBP ranged from < 40 mmHg (lower) to > 105 mmHg (upper) and heart rate < 40 beats per minute (bpm) (lower) to > 100 bpm (upper).	Up to 24 Months
Secondary	Change From Baseline in Post Void Residual Volume	Post void residual volume was measured suprapubically by ultrasound (immediately following the urinary flow measurement). Post void residual volume change from Baseline distribution at each scheduled post-Baseline assessment was compared with combination treatment (Dut plus Tam) versus tamsulosin treatment using a nonparametric van Elteren test. Baseline value was defined as the latest non-missing assessment of either treatment start date or randomization date. Change from Baseline defined as difference between Post-Baseline value and Baseline value. Only those participants available at the specified time points (represented by n=X in the category titles) were analyzed.	Baseline, 6, 12, 18 and 24 Months
Secondary	Number of Participants With Threshold Hematology Value.	The threshold laboratory values are defined in terms of a multiplicative factor of the testing laboratory's normal range. A laboratory value that is above the upper limit factor multiplied by the upper limit of the normal (ULN) range is considered a high threshold value. A laboratory value that is below the lower limit factor multiplied by the lower limit of the normal (LLN) range is considered a low threshold value. Hematology laboratory parameters assessed included hemoglobin (Hgb), platelet count, white blood cell count (WBC) and red blood cell (RBC) count. Threshold factors are in the below table. Only those participants available at the specified time points (represented by n=X in the category titles) were analyzed.	Up to 24 Months
Secondary	Number of Participants With Threshold Clinical Chemistry Value.	Clinical chemistry laboratory parameters assessed included albumin, alanine aminotransferase (ALT), alkaline phosphatase (ALP), aspartate aminotransferase (AST), creatinine, glucose, potassium, sodium, total bilirubin, total protein and urea/blood urea nitrogen (BUN). Threshold factors are in the below table. Only those participants available at the specified time points (represented by n=X in the category titles) were analyzed.	Up to 24 Months
Secondary	Number of Participants With Digital Rectal Examination (DRE)	DRE evaluation was carried out from normal/diffusely enlarged at Baseline to focal abnormalities at any time post-Baseline. DRE was assessed at screening visit, Month 6, 12, 18 , 24 and final assessment is the latest post-Baseline evaluation that was available. Here, participants with focal abnormalities are summarized. Only those participants available at the specified time points (represented by n=X in the category titles) were analyzed.	6, 12, 18 , 24 months and final assessment
Secondary	Number of Participants With Clinically Significant Qualitative Breast Examination	Qualitative breast examination included palpable breast tissue and nipple tenderness. Here, participants with clinically significant abnormalities for palpable breast tissue and nipple tenderness are summarized. Qualitative breast examination was done at screening visit, Month 6, 12, 18 , 24 and final assessment (latest post-Baseline evaluation that was available). Only those participants available at the specified time points (represented by n=X in the category titles) were analyzed.	6, 12, 18 , 24 months and final assessment
Secondary	Number of Participants With Suicidal Ideation and Suicidal Behavior	Suicidality was assessed utilizing the Columbia Suicide Severity Rating Scale (C-SSRS). It included tabular summaries of suicidal ideation and suicidal behavior questions that were administered. Assessments were carried out at Screening, Month 6, Month 12, and Month 24 (or end of treatment) visits. C-SSRS included Question1-2 were for suicidal ideation Question 1: Passive: wish to be dead, Question 2: Active: Non-specific (no method, intent or plan). Questions 6-10 were for suicidal behavior, Question 6: Preparatory Acts or Behavior, Question 7: any aborted attempt, Question 8: Any interrupted attempts, Question 9: Any non-fatal actual suicide attempt, Question 10: Completed suicide. Only those participants available at the specified time points (represented by n=X in the category titles) were analyzed.	6, 12, 18 , 24 months and final assessment

External Links

•   IPD for this study will be made available via the Clinical Study Data Request site.