NCT02058368 - 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 | Crick

Eligibility

Sex: MALEMin age: 50 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

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.

Time frame: Baseline and 3, 6, 9, 12, 15, 18, 21 and 24 months

Secondary Outcomes

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.

Time frame: Baseline,12 and 24 months

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.

Time frame: Baseline and 3, 6, 9,12,15,18,21 and 24 months

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.

Time frame: Baseline, 6, 12, 18 and 24 Months

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.

Time frame: Baseline 6, 12, 18 and 24 Months

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.

Time frame: Up to 24 Months

Number of Subjects With AUR

AUR is defined as condition when the participant is unable to urinate and requires bladder catheterization.

Time frame: Up to 24 Months

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.

Time frame: Up to 24 Months

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.

Time frame: Baseline, 3, 6, 9, 12, 15, 18, 21 and 24 Months

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.

Time frame: Baseline 3, 6, 9, 12, 15, 18, 21 and 24 Months

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.

Time frame: Baseline, 12 and 24 Months

Number of Hospitalization Days

Duration of hospitalization days due to AUR or BPH-related surgery was recorded.

Time frame: Up to 24 Months

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

Time frame: Up to 24 Months

Number of Participants With Hospital Admissions

Details of participants who were admitted to hospitals related to AUR or BPH-Related surgery has been recorded.

Time frame: Up to 24 Months

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

Time frame: Up to 24 Months

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.

Time frame: Baseline 6, 12 and 24 Months

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).

Time frame: Up to 24 Months

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.

Time frame: Baseline, 6, 12, 18 and 24 Months

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.

Time frame: Up to 24 Months

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.

Time frame: Up to 24 Months

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.

Time frame: 6, 12, 18 , 24 months and final assessment

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.

Time frame: 6, 12, 18 , 24 months and final assessment

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.

Time frame: 6, 12, 18 , 24 months and final assessment

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

Overview

Conditions

Interventions

Eligibility

Locations (46)

Outcomes

Primary Outcomes

Secondary Outcomes