Clinical trial NCT02757768: A Study to Evaluate the Efficacy, Safety, and Tolerability of Mirabegron in Men With OAB Symptoms While Taking Tamsulosin Hydrochloride for Lower Urinary Tract Symptoms (LUTS) Due to Benign Prostatic Hyperplasia (BPH)
Official title: A Phase 4, Double-Blind, Randomized, Placebo-Controlled, Multi-Center Study to Evaluate the Efficacy, Safety, and Tolerability of Mirabegron in Men With Overactive Bladder (OAB) Symptoms While Taking the Alpha Blocker Tamsulosin Hydrochloride for Lower Urinary Tract Symptoms (LUTS) Due to Benign Prostatic Hyperplasia (BPH)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Benign Prostatic Hyperplasia
Overactive Bladder
Keywords: Myrbetriq
Lower Urinary Tract Symptoms
Benign Prostatic Hyperplasia
Overactive Bladder
Betmiga
Mirabegron
Tamsulosin Hydrochloride
Lead sponsor: Astellas Pharma Inc
Sponsor class: INDUSTRY
First posted: 2016-05-02
Enrollment: 715
Sex: MALE
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of the study was to assess the efficacy, safety, and tolerability of mirabegron versus placebo in men with overactive bladder (OAB) symptoms while taking tamsulosin hydrochloride for lower urinary tract symptoms (LUTS) due to Benign Prostatic Hyperplasia (BPH).

Detailed description: At Screening (Visit 1), participants entered into a 4-week open label tamsulosin hydrochloride 0.4 mg QD run-in period prior to being randomized into the 12-week double-blind treatment period (Visit 2). At conclusion of the 4-week tamsulosin hydrochloride run-in period, participants completed a 3-day diary just prior to Baseline (Visit 2). Approximately 7 days prior to Visit 2 participants received a phone call reminding them about the diary and to answer any questions.

If participants met all entry criteria at the end of the tamsulosin hydrochloride run-in period, participants were randomized to 1 of 2 treatment groups (mirabegron or placebo) for 12 weeks of treatment in addition to the continuation of tamsulosin hydrochloride 0.4 mg QD. Those participants randomized to Mirabegron started at 25 mg and increased to 50 mg after 4 weeks. Those participants randomized to placebo started blinded product matched to the mirabegron 25 mg tablet and increased to blinded product matched to 50 mirabegron after 4 weeks. Once a participant increased dose, the participant remained on that dose for the remainder of the study unless for safety reasons was required to discontinue study drug.

A training diary was completed in the first 2 weeks of the tamsulosin hydrochloride run-in period. During this evaluation period at least one telephone contact took place with the participant. Diaries were completed at home, using the electronic patient-reported outcome (ePRO) device, for 3 consecutive days prior to each visit: Baseline (Visit 2), Week 4 (Visit 3), Week 8 (Visit 4), and Week 12/End of Treatment (Visit 5). Site staff contacted the participant approximately 7 days prior to the scheduled visit to remind the participant to complete the electronic diary, review completion instruction and review changes to concomitant medications and adverse events (if applicable).

Three days before Visits 2 (Baseline), 3 (Week 4), 4 (Week 8), and 5 (Week 12), participants completed a 3-day diary, using the ePRO device in which the participant recorded micturition frequency, urgency (PPIUS), incontinence and volume voided. In addition, the diary captured morning and evening blood pressure and pulse rate measurements via Home Blood Pressure Monitoring (HBPM). At Visit 1, International Prostate Symptom Score (IPSS) was completed. At Visits 2, 3, 4, and 5, participants completed the IPSS, EQ-5D-5L, OAB-q, PPBC, and TS-VAS. Maximum urinary flow (Qmax) was measured at Visit 1 (Screening/tamsulosin hydrochloride run-in) and Visit 5 (Week 12/End of Treatment). Post-void residual volume (PVR) was assessed at Screening/tamsulosin hydrochloride run-in (Visit 1), Baseline (Visit 2) and at Week 4 (Visit 3), Week 8 (Visit 4), and Week 12/End of Treatment (Visit 5). A follow-up phone call (Visit 6) was conducted 4-weeks after End of Treatment (Visit 5). Total study participation was approximately 20 weeks.

Eligibility criteria: Inclusion Criteria assessed at Visit 1 (Screening):

* Men ≥40 years of age with history of overactive bladder (OAB) symptoms (frequency of ≥8 micturitions per day and urgency episodes of ≥2 per day) while taking tamsulosin hydrochloride for at least 2 months to treat LUTS due to BPH.
* Subject has symptoms of OAB (urinary frequency and urgency with or without incontinence) for ≥3 months prior to Screening.
* Subject has an International Prostate Symptom Score (IPSS) score ≥8.
* Subject has Prostate-Specific Antigen (PSA) \<4 ng/mL or ≥4 but \< 10 ng/mL with a prostate biopsy that is negative for cancer in the past 2 years.
* Subject is willing and able to complete the 3-day diary (including urine volumes, vital signs measurements), and Quality of Life questionnaires.
* Subject and the subject's spouses/partners who are of childbearing potential must be using a highly effective birth control, which includes established use of oral, injected or implanted hormonal methods of contraception, placement of an intrauterine device (IUD) or intrauterine system (IUS). Birth control must be practiced from Screening and continue throughout the study and for 30 days after the final study drug administration. In addition, sperm donation will not be allowed throughout the study and for 30 days after the final study drug administration.
* Subject agrees not to participate in another interventional study while on treatment.

Inclusion Criteria assessed at Visit 2 (Baseline) based on the 3-day diary:

* Subject continues to meet all inclusion criteria of Visit 1 (Screening).
* Subject must experience an average of 8 or more micturitions per day over the 3-day diary period.
* Subject must experience an average of 2 episodes of urgency per day (grade 3 or 4) over the 3-diary period

Exclusion Criteria assessed at Visit 1 (Screening):

* Subject has post-void residual volume (PVR) \>200 mL.
* Subject has maximum urinary flow (Qmax) \<5.0 mL/second with a minimum voided volume of 125 mL.
* Subject has hematuria \>3 rbc/hpf that has not been fully evaluated.
* Subject has evidence of Urinary Tract Infection (UTI). Urine culture and sensitivity will be performed for positive leukocytes, nitrites, or turbidity and will be confirmed with a culture greater than 100,000 cfu/mL. If a subject has a UTI, at Screening (Visit 1) the subject may be rescreened after successful treatment of the UTI (confirmed by a laboratory result of negative urine culture).
* Subject has neurogenic bladder (spinal cord injury, multiple sclerosis, Parkinson's, etc.).
* Subject has diabetic neuropathy.
* Previous open, robotic or minimally invasive prostate surgery (including transurethral procedures). Planned (scheduled) pelvic or prostate surgery during the study period.
* Planned (scheduled) cataract surgery.
* Subject with significant stress incontinence
* Subject with clinically significant bladder outlet obstruction.
* Subject has an indwelling catheter or practices intermittent self-catheterization.
* Subject has experienced 3 or more episodes of recurrent urinary tract infection within the last 12 months.
* Subject has a symptomatic urinary tract infection, prostatitis, chronic inflammation such as interstitial cystitis, bladder stones, previous pelvic radiation therapy, or previous or current malignant disease of the pelvic organs (i.e., within the confines of the pelvis including the bladder, prostate and rectum; organs of the lower gastrointestinal tract are not necessarily considered pelvic organs such as the distal ascending colon, the full transverse colon and proximal portion of the descending colon are in the abdomen).
* Subject has received intravesical injection in the past 12 months with botulinum toxin, resiniferatoxin, or capsaicin.
* Subject has ever received electro-stimulation therapy for OAB (e.g. sacral nerve stimulation or Percutaneous Tibial Nerve Stimulation \[PTNS\]).
* Subject began or has changed a bladder training program or pelvic floor exercises less than 30 days prior to Screening.
* Subject has postural hypotension or syncope or postural orthostatic tachycardia.
* Subject has moderate or severe hepatic impairment defined as Child-Pugh Class B or C.
* Subject has severe renal impairment defined as estimated creatinine clearance less than 29 mL/min/1.73 m2 as determined by hospital laboratory calculation of eGFR. A subject with End Stage Renal Disease (ESRD) or undergoing dialysis is also not a candidate for the study.
* Subject has severe uncontrolled hypertension, which is defined as a sitting systolic blood pressure ≥180 mmHg and/or diastolic blood pressure ≥110 mmHg.
* Subject has baseline resting pulse rate \<60 BPM or \>90 BPM.
* Subject has evidence of QT prolongation on Screening (Visit 1) or Baseline (Visit 2) electrocardiogram (ECG) defined as QTcF \>450 msec.
* Subject has any clinically significant ECG abnormality.
* Subject has AST or ALT \>2x upper limit of normal (ULN), or γ-GT \>3x ULN and considered clinically significant.
* Subject has a hypersensitivity to any components of mirabegron, tamsulosin hydrochloride, or any of the inactive ingredients.
* Subject has a history of angioedema.
* Subject has any clinical significant condition which makes the subject unsuitable for study participation.
* Subject has been treated with an experimental device within 28 days or received an investigational agent within 28 days or 5 half-lives, whichever is longer, prior to Screening.
* Subject has a concurrent malignancy or history of any malignancy (within the past 5 years), except non-metastatic basal or squamous cell carcinoma of the skin that has been treated successfully.
* Subject has ongoing alcohol and/or drug abuse.
* Subject is using prohibited medications within 30 days prior to Screening (Visit 1) through Follow-Up Phone Call (Visit 6).
* Subject has stopped, started or changed the dose of a restricted medication within the 30 days prior to Screening (Visit 1) through Follow-Up Phone Call (Visit 6)
* Subject has participated in an interventional trial within 30 days prior to Screening (Visit 1).
* Subject is involved in the conduct of the study as an employee of the Astellas group, third party associated with the study, or the study site team.
* Subject has previously received mirabegron in the 6 months prior to Screening (Visit 1).

Exclusion Criteria assessed at Visit 2 (Baseline):

* Subject was non-compliant during the 4-week tamsulosin hydrochloride run-in period, defined as taking less than 80% or greater than 120% of study medication.
* Subject had an average total daily urine volume \>3000 mL as recorded in the 3-day diary.

Primary outcomes:
measure: Change From Baseline to End of Treatment (EoT) in Mean Number of Micturitions Per Day
timeFrame: Baseline and Week 12
Secondary outcomes:
measure: Change From Baseline to Week 4, Week 8, and Week 12 in Mean Number of Micturitions Per Day
timeFrame: Baseline and Weeks 4, 8, and 12
measure: Change From Baseline to Week 4, Week 8, Week 12 and EoT in Mean Volume Voided Per Micturition
timeFrame: Baseline and Weeks 4, 8, and 12
measure: Change From Baseline to Week 4, Week 8, Week 12 and EoT in Mean Number of Incontinence Episodes Per Day
timeFrame: Baseline and Weeks 4, 8, and 12
measure: Change From Baseline to Week 4, Week 8, Week 12 and EoT in Mean Number of Urgency Episodes (Grade 3 or 4) Per Day
timeFrame: Baseline and Weeks 4, 8, and 12
measure: Change From Baseline to Week 4, Week 8, Week 12 and EoT in International Prostate Symptom Score (IPSS) Total Score
timeFrame: Baseline and Weeks 4, 8, and 12
measure: Change From Baseline to Week 4, Week 8, Week 12 and EoT in IPSS Subscale Voiding Score
timeFrame: Baseline and Weeks 4, 8, and 12
measure: Change From Baseline to Week 4, Week 8, Week 12, and EoT in IPSS Subscale Storage Score
timeFrame: Baseline and Weeks 4, 8, and 12
measure: Change From Baseline to Week 4, Week 8, Week 12 and EoT in IPSS Subscale Quality of Life (QoL) Score
timeFrame: Baseline and Weeks 4, 8, and 12
measure: Change From Baseline to Week 4, Week 8, Week 12 and EoT in Mean Number of Urgency Incontinence Episodes Per Day
timeFrame: Baseline and Weeks 4, 8 and 12
measure: Change From Baseline to Week 4, Week 8, Week 12 and EoT in Symptom Bother Score
timeFrame: Baseline and Weeks 4, 8, and 12
measure: Change From Baseline to Week 4, Week 8, Week 12 and EoT in Total Health Related Quality of Life (HRQL) Score
timeFrame: Baseline and Weeks 4, 8, and 12
measure: Change From Baseline to Week 4, Week 8, Week 12 and EoT in HRQL Subscale Coping Score
timeFrame: Baseline and Weeks 4, 8, and 12
measure: Change From Baseline to Week 4, Week 8, Week 12 and EoT in HRQL Subscale Concern Score
timeFrame: Baseline and Weeks 4, 8, and 12
measure: Change From Baseline to Week 4, Week 8, Week 12 and EoT in HRQL Subscale Sleep Score
timeFrame: Baseline and Weeks 4, 8 and 12
measure: Change From Baseline to Week 4, Week 8, Week 12 and EoT in HRQL Subscale Social Interaction Score
timeFrame: Baseline and Weeks 4, 8, and 12
measure: Change From Baseline to Week 4, Week 8, Week 12 and EoT in European Quality of Life in 5 Dimensions and 5 Levels (EQ-5D-5L Questionnaire) Utilities
timeFrame: Baseline and Weeks 4, 8, and 12
measure: Change From Baseline to Week 4, Week 8, Week 12 and EoT in Patient Perception of Bladder Condition (PPBC)
timeFrame: Baseline and Weeks 4, 8, and 12
measure: Change From Baseline to Week 4, Week 8, Week 12 and EoT in Total Urgency and Frequency Score (TUFS)
timeFrame: Baseline and Weeks 4, 8 and 12
measure: Change From Baseline to Week 4, Week 8, Week 12 and EoT in Mean Number of Nocturia Episodes Per 24 Hours
timeFrame: Baseline and Weeks 4, 8, and 12
measure: Change From Baseline to Week 4, Week 8, Week 12 and EoT in Treatment Satisfaction Visual Analog Scale (TS-VAS)
timeFrame: Baseline and Weeks 4, 8, and 12
Other outcomes:
Locations:
city: Homewood
country: United States
facility: Site US01009
state: Alabama
city: Huntsville
country: United States
facility: Site US01005
state: Alabama
city: Anchorage
country: United States
facility: Site US01012
state: Alaska
city: Hawaiian Gardens
country: United States
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state: California
city: Los Angeles
country: United States
facility: Site US01081
state: California
city: Murrieta
country: United States
facility: Site US01021
state: California
city: San Diego
country: United States
facility: Site US01068
state: California
city: Valley Village
country: United States
facility: Site US01064
state: California
city: Englewood
country: United States
facility: Site US01097
state: Colorado
city: Pompano Beach
country: United States
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state: Florida
city: Saint Petersburg
country: United States
facility: Site US01025
state: Florida
city: Wellington
country: United States
facility: Site US01027
state: Florida
city: West Des Moines
country: United States
facility: Site US01034
state: Iowa
city: Shreveport
country: United States
facility: Site US01094
state: Louisiana
city: Baltimore
country: United States
facility: Site US01041
state: Maryland
city: Boston
country: United States
facility: Site US01016
state: Massachusetts
city: Watertown
country: United States
facility: Site US01003
state: Massachusetts
city: Kansas City
country: United States
facility: Site US01060
state: Missouri
city: Billings
country: United States
facility: Site US01067
state: Montana
city: Omaha
country: United States
facility: Site US01061
state: Nebraska
city: Edison
country: United States
facility: Site US01029
state: New Jersey
city: Albuquerque
country: United States
facility: Site US01031
state: New Mexico
city: Garden City
country: United States
facility: Site US01015
state: New York
city: Plainview
country: United States
facility: Site US01019
state: New York
city: Cary
country: United States
facility: Site US01069
state: North Carolina
city: Maiden
country: United States
facility: Site US01079
state: North Carolina
city: Bristol
country: United States
facility: Site US01072
state: Tennessee
city: Clarksville
country: United States
facility: Site US01042
state: Tennessee
city: Knoxville
country: United States
facility: Site US01056
state: Tennessee
city: Knoxville
country: United States
facility: Site US01075
state: Tennessee
city: Knoxville
country: United States
facility: Site US01078
state: Tennessee
city: Newport News
country: United States
facility: Site US01063
state: Virginia
city: Calgary
country: Canada
facility: Site CA15008
state: Alberta
city: Barrie
country: Canada
facility: Site CA15003
state: Ontario
city: Brampton
country: Canada
facility: Site CA15001
state: Ontario
city: Toronto
country: Canada
facility: Site CA15005
state: Ontario
city: Quebec City
country: Canada
facility: Site CA15011
state: Quebec
city: Sherbrooke
country: Canada
facility: Site CA15002
state: Quebec
city: Sherbrooke
country: Canada
facility: Site CA15009
state: Quebec
city: Victoriaville
country: Canada
facility: Site CA15014
state: Quebec
city: Benesov
country: Czechia
facility: Site CZ42004
city: Domazlice
country: Czechia
facility: Site CZ42006
city: Prague 10
country: Czechia
facility: Site CZ42005
city: Praha 4
country: Czechia
facility: Site CZ42003
city: Sternberk
country: Czechia
facility: Site CZ42001
city: Colmar Cedex
country: France
facility: Site FR33004
city: Pierre Benite Cedex
country: France
facility: Site FR33002
city: Duisburg
country: Germany
facility: Site DE49002
city: Hagenow
country: Germany
facility: Site DE49001
city: Halle (Saale)
country: Germany
facility: Site DE49006
city: Hamburg
country: Germany
facility: Site DE49004
city: Hettstedt
country: Germany
facility: Site DE49005
city: Lutherstadt Eisleben
country: Germany
facility: Site DE49003
city: Sangerhausen
country: Germany
facility: Site DE49007
city: Avellino
country: Italy
facility: Site IT39002
city: Catanzaro
country: Italy
facility: Site IT39003
city: Chieti
country: Italy
facility: Site IT39010
city: Florence
country: Italy
facility: Site IT39004
city: Latina
country: Italy
facility: Site IT39005
city: Pisa
country: Italy
facility: Site IT39006
city: Treviglio
country: Italy
facility: Site IT39001
city: Vasto
country: Italy
facility: Site IT39008
city: Katowice
country: Poland
facility: Site PL48006
city: Piaseczno
country: Poland
facility: Site PL48001
city: Warszawa
country: Poland
facility: Site PL48004
city: Wroclaw
country: Poland
facility: Site PL48007
city: Wrocław
country: Poland
facility: Site PL48005
city: Barcelona
country: Spain
facility: Site ES34007
city: Lugo
country: Spain
facility: Site ES34009
city: Madrid
country: Spain
facility: Site ES34001
city: Miranda de Ebro
country: Spain
facility: Site ES34003
city: Sevilla
country: Spain
facility: Site ES34002
city: Valencia
country: Spain
facility: Site ES34006
city: Vigo
country: Spain
facility: Site ES34004
city: Bristol
country: United Kingdom
facility: Site GB44005
city: Bristol
country: United Kingdom
facility: Site GB44011
city: Newcastle upon Tyne
country: United Kingdom
facility: Site GB44004
city: Reading
country: United Kingdom
facility: Site GB44002
city: York
country: United Kingdom
facility: Site GB44006
Study officials:
affiliation: Astellas Pharma Global Development, Inc., Medical Affairs, Americas
name: Medical Director
role: STUDY_DIRECTOR
References: