Efficacy and Safety of Pembrolizumab (MK-3475) in Combination With Chemoradiotherapy (CRT) Versus CRT Alone in Muscle-invasive Bladder Cancer (MIBC) (MK-3475-992/KEYNOTE-992)

Urinary Bladder Neoplasms Clinical Trial

Official title:

A Phase 3, Randomized, Double-blind, Placebo-controlled Clinical Trial to Study the Efficacy and Safety of Pembrolizumab (MK-3475) in Combination With Chemoradiotherapy (CRT) Versus CRT Alone in Participants With Muscle-invasive Bladder Cancer (MIBC) (KEYNOTE-992)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04241185
• Other study ID #: 3475-992
• Secondary ID: MK-3475-99220538
• Status: Recruiting
• Phase: Phase 3
• Start date: May 19, 2020
• Est. completion date: June 10, 2031

Study information

• Verified date: May 2024
• Source: Merck Sharp & Dohme LLC
• Contact: Toll Free Number
• Phone: 1-888-577-8839
• Email: Trialsites[@]merck.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study is designed to assess the antitumor efficacy and safety of pembrolizumab in combination with chemoradiotherapy (CRT) versus CRT alone in participants with muscle-invasive bladder cancer (MIBC). The primary hypothesis is that pembrolizumab + chemoradiotherapy is superior to placebo + chemoradiotherapy with respect to bladder intact event-free survival.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 636
• Est. completion date: June 10, 2031
• Est. primary completion date: June 10, 2029
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Has a histologically confirmed initial diagnosis of muscle-invasive bladder cancer (MIBC) with predominant urothelial histology

• Has clinically nonmetastatic bladder cancer (N0M0)

• Has planned and is eligible to receive chemoradiotherapy (CRT) and one of the protocol-specified radiosensitizing chemotherapy regimens

• Has Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2

• Demonstrates adequate organ function

• Male participants are eligible to participate if they agree to the following during the intervention period and for at least 90 days after the last dose of CRT treatment:

• Refrain from donating sperm

• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent; or must agree to use contraception unless confirmed to be azoospermic

• A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:

• Is not a woman of childbearing potential (WOCBP)

• Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis), during the intervention period and for at least 180 days the time needed to eliminate each study intervention after the last dose of study intervention; and agrees not to donate eggs (ova, oocytes) to others or freeze/store for her own use for the purpose of reproduction during this period. The length of time required to continue contraception for each study intervention is as follows: MK-3475 - 120 days and CRT - 180 days

Exclusion Criteria:

• Has the presence of diffuse carcinoma in situ (CIS) (multiple foci of CIS) throughout the bladder

• Has the presence of urothelial carcinoma (UC) at any site outside of the urinary bladder in the previous 2 years except for Ta stage/T1 stage/CIS of the upper tract if the participant has undergone a complete nephroureterectomy

• Has a known additional malignancy that is progressing or has required active therapy within the past 3 years, except basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer or other carcinoma in situ that has undergone potentially curative therapy

• Has the presence of bilateral hydronephrosis

• Has limited bladder function with frequency of small amounts of urine (< 30 mL), urinary incontinence, or requires self-catheterization or a permanent indwelling catheter

• Has received prior pelvic/local radiation therapy or any antineoplastic treatment for muscle-invasive bladder cancer (MIBC). Treatment for non-muscle invasive bladder cancer (NMIBC) with intravesical instillation therapy that was completed =28 days prior to randomization is allowed. Prior systemic treatment of NMIBC is not permitted.

• Received prior therapy with an anti-PD-1 (programmed cell death protein 1), anti-PD-L1 (programmed death-ligand 1), or anti-PD-L2 (programmed cell death 1 ligand 2), or with an agent directed to another stimulatory or coinhibitory T-cell receptor (e.g., CTLA-4 [cytotoxic T-lymphocyte-associated protein 4], OX 40, or CD137 [cluster of differentiation 137])

• Has received a live vaccine within 30 days before the first dose of study medication

• Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks before the first dose of study medication

• Has known severe hypersensitivity (=Grade 3) to the selected chemotherapy regimen, and/or any of their excipients and excipients of pembrolizumab

• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days before the first dose of study medication

• Has an active autoimmune disease that has required systemic treatment in the past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed

• Has a history of non-infectious pneumonitis that required steroids or has current pneumonitis

• Has an active infection requiring systemic therapy

• Has a known history of human immunodeficiency virus (HIV) infection

• Has a known history of hepatitis B or known active hepatitis C virus infection

• Has a known history of active tuberculosis (TB; Bacillus tuberculosis)

• Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study

• Has had an allogenic tissue/solid organ transplant

Related Conditions & MeSH terms

• Urinary Bladder Neoplasms

Intervention

Drug:
• Pembrolizumab
400 mg of IV (intravenous) pembrolizumab once every 6 weeks.

Radiation:
• Conventional Radiotherapy (Bladder only)
64 Gy of radiation administered to participant's bladder only. Thirty-two fractions will be administered over 6.5 weeks.
• Conventional Radiotherapy (Bladder and pelvic nodes)
64 Gy of radiation administered to participant's bladder and pelvic nodes. Thirty-two fractions will be administered over 6.5 weeks.
• Hypofractionated Radiotherapy (Bladder only)
55 Gy of radiation administered to participant's bladder only. Twenty fractions will be administered over 4 weeks.

Drug:
• Cisplatin
35 mg of cisplatin per cubic meter of body volume, administered once weekly via IV infusion.
• Fluorouracil (5-FU)
5-FU administered via IV infusion at a dose of 500 mg per cubic meter of body volume on Days 1-5 and 22-26.
• Mitomycin C (MMC)
MMC administered via IV infusion at a dose of 12 mg per cubic meter of body volume on Day 1.
• Gemcitabine
Gemcitabine administered via IV infusion at a dose of 27 mg per cubic meter of body volume twice weekly.
• Placebo to Pembrolizumab
Placebo to intravenous (IV) pembrolizumab administered once every 6 weeks.

Locations

Country	Name	City	State
Australia	Monash Medical Centre ( Site 0216)	Clayton	Victoria
Australia	Austin Health ( Site 0218)	Heidelberg	Victoria
Australia	Liverpool Hospital ( Site 0220)	Liverpool	New South Wales
Australia	Sir Charles Gairdner Hospital ( Site 0223)	Nedlands	Western Australia
Australia	GenesisCare North Shore ( Site 0217)	St Leonards	New South Wales
Chile	Bradford Hill Norte ( Site 7052)	Antofagasta
Chile	Bradfordhill-Clinical Area ( Site 7051)	Santiago	Region M. De Santiago
Chile	FALP ( Site 7056)	Santiago	Region M. De Santiago
Chile	Oncocentro Valdivia ( Site 7055)	Valdivia	Los Rios
Chile	ONCOCENTRO APYS-ACEREY ( Site 7054)	Viña del Mar	Valparaiso
Czechia	Fakultni nemocnice Olomouc ( Site 0559)	Olomouc
Czechia	2. LF UK a FN Motol ( Site 0555)	Praha 5
Czechia	Nemocnice Na Bulovce ( Site 0556)	Praha 8
Denmark	Herlev og Gentofte Hospital. ( Site 0401)	Herlev	Hovedstaden
Denmark	Odense Universitetshospital ( Site 0403)	Odense	Syddanmark
Estonia	North Estonia Medical Centre Foundation ( Site 0081)	Tallin	Harjumaa
Estonia	Tartu University Hospital ( Site 0079)	Tartu	Tartumaa
France	CHU Amiens Picardie Site Sud Amiens ( Site 0123)	Amiens	Somme
France	Institut Sainte Catherine ( Site 0121)	Avignon	Provence-Alpes-Cote-d Azur
France	A.P.H. Paris. Hopital Bichat Claude Bernard ( Site 0115)	Paris
France	Institut Curie ( Site 0112)	Paris
Guatemala	Centro de Investigaciones Clinicas de Latinoamerica S.A. - CELAN ( Site 0146)	Guatemala
Guatemala	Grupo Medico Angeles ( Site 0143)	Guatemala
Guatemala	Medi-K Cayala ( Site 0142)	Guatemala
Guatemala	Oncomedica ( Site 0145)	Guatemala
Guatemala	Centro Medico Integral De Cancerología (CEMIC) ( Site 0144)	Quetzaltenango
Hungary	Debreceni Egyetem Klinikai Kozpont ( Site 0097)	Debrecen
Hungary	Petz Aladar Megyei Oktato Korhaz ( Site 0099)	Gyor	Gyor-Moson-Sopron
Hungary	Somogy Megyei Kaposi Mor Oktato Korhaz ( Site 0091)	Kaposvar
Hungary	Bacs-Kiskun Megyei Korhaz-Onkoradiologiai Kozpont ( Site 0095)	Kecskemét	Bacs-Kiskun
Hungary	BAZ Megyei Korhaz. Klinikai Onkologia es Sugarterapias Centrum ( Site 0092)	Miskolc	Borsod-Abauj-Zemplen
Israel	Soroka Medical Center-Oncology ( Site 7031)	Be'er Sheva
Israel	Rambam Health Care Campus-Oncology Division ( Site 0088)	Haifa
Israel	Hadassah Medical Center. Ein Kerem ( Site 0086)	Jerusalem
Israel	Rabin Medical Center ( Site 7032)	Petah Tikva
Israel	Chaim Sheba Medical Center ( Site 0087)	Ramat Gan
Israel	Sourasky Medical Center ( Site 0089)	Tel Aviv
Italy	IRCCS Giovanni Paolo II. Ospedale Oncologico ( Site 0193)	Bari	Puglia
Italy	AOU Careggi ( Site 0191)	Firenze
Italy	Ospedale Civile di Macerata ( Site 0190)	Macerata
Italy	Fondazione IRCCS Istituto Nazionale dei Tumori di Milano ( Site 0186)	Milano
Italy	Ospedale San Raffaele ( Site 0194)	Milano	Lombardia
Italy	Azienda Ospedaliero - Universitaria Policlinico di Modena ( Site 0188)	Modena
Italy	Istituto Nazionale Tumori IRCCS Fondazione Pascale ( Site 0192)	Napoli
Italy	Fondazione Policlinico Universitario Campus Bio-Medico-Radiation Oncology ( Site 7041)	Roma	Lazio
Japan	Hirosaki University Hospital ( Site 0602)	Hirosaki	Aomori
Japan	Nagasaki University Hospital ( Site 0600)	Nagasaki
Japan	Osaka Medical and Pharmaceutical University Hospital ( Site 0604)	Takatsuki	Osaka
Japan	Tokyo Medical and Dental University Hospital ( Site 0601)	Tokyo
Japan	Tokyo Metropolitan Komagome Hospital ( Site 0606)	Tokyo
Japan	University of Tsukuba Hospital ( Site 0605)	Tsukuba	Ibaraki
Korea, Republic of	Chungnam National University Hospital ( Site 0203)	Daejeon	Taejon-Kwangyokshi
Korea, Republic of	National Cancer Center ( Site 0202)	Gyeonggi-do	Kyonggi-do
Korea, Republic of	Seoul National University Bundang Hospital ( Site 0204)	Seongnam-si	Kyonggi-do
Korea, Republic of	Korea University Anam Hospital ( Site 0205)	Seoul
Korea, Republic of	Severance Hospital Yonsei University Health System ( Site 0201)	Seoul
Korea, Republic of	Asan Medical Center ( Site 0200)	Songpagu	Seoul
Latvia	Pauls Stradins Clinical University Hospital ( Site 0073)	Riga
Malaysia	Hospital Kuala Lumpur ( Site 0238)	Kuala Lumpur
Malaysia	University Malaya Medical Centre ( Site 0236)	Kuala Lumpur
Malaysia	Hospital Universiti Sains Malaysia ( Site 0237)	Kubang Kerian	Kelantan
Malaysia	Hospital Pulau Pinang ( Site 0239)	Penang	Pulau Pinang
Netherlands	Netherlands Cancer Institute (NKI) ( Site 0183)	Amsterdam	Noord-Holland
Netherlands	Erasmus MC ( Site 0182)	Rotterdam	Zuid-Holland
Poland	Szpital Wojewodzki im. Mikolaja Kopernika ( Site 0152)	Koszalin	Zachodniopomorskie
Poland	Szpital Specjalistyczny im. Ludwika Rydygiera w Krakowie ( Site 0153)	Krakow	Malopolskie
Poland	Mazowiecki Szpital Wojewódzki w Siedlcach ( Site 0154)	Siedlce	Mazowieckie
Portugal	Centro Hospitalar e Universitario de Coimbra ( Site 0306)	Coimbra
Portugal	Centro Hospitalar Lisboa Norte EPE - Hospital de Santa Maria ( Site 0305)	Lisboa
Portugal	CHLO, EPE - Hospital de Sao Francisco Xavier ( Site 0302)	Lisboa
Portugal	Hospital Beatriz Angelo ( Site 0303)	Loures	Lisboa
Puerto Rico	Advance Urology and Laparoscopic Center ( Site 0281)	Ponce
Puerto Rico	PAN American Center Oncologic ( Site 0280)	San Juan, Rio Piedras
Romania	S.C.Focus Lab Plus S.R.L ( Site 0253)	Bucuresti
Romania	Institutul Oncologic-Oncologie Medicala ( Site 0256)	Cluj
Romania	Institutul Oncologic Prof.Dr. Ion Chiricuta Cluj-Napoca ( Site 0249)	Cluj Napoca	Cluj
Romania	S.C. Radiotherapy Center Cluj S.R.L ( Site 0252)	Cluj-Napoca	Cluj
Romania	S.C. Centrul de Oncologie Sf. Nectarie SRL ( Site 0248)	Craiova	Dolj
Romania	Institutul Regional de Oncologie Iasi ( Site 0255)	Iasi
Romania	Policlinica Oncomed SRL ( Site 0254)	Timisoara	Timis
Spain	Instituto Catalan de Oncologia - ICO ( Site 0103)	L Hospitalet De Llobregat	Barcelona
Spain	HOSPITAL UNIVERSITARIO VIRGEN DEL ROCIO-Medical Oncology ( Site 0106)	Sevilla
Spain	Hospital La Fe de Valencia ( Site 0105)	Valencia	Valenciana, Comunitat
Taiwan	Kaohsiung Chang Gung Memorial Hospital ( Site 0209)	Kaohsiung
Taiwan	Taichung Veterans General Hospital ( Site 0213)	Taichung
Taiwan	National Cheng Kung University Hospital ( Site 0208)	Tainan
Taiwan	Chi Mei Medical Center ( Site 0215)	Tainan City	Tainan
Taiwan	National Taiwan University Hospital ( Site 0210)	Taipei
Taiwan	Taipei Veterans General Hospital ( Site 0211)	Taipei
Taiwan	Chang Gung Medical Foundation.Linkou Branch ( Site 0212)	Taoyuan
Turkey	Ankara Universitesi Tip Fakultesi. ( Site 0502)	Ankara
Turkey	University of Health Sciences,Gulhane School of Medicine-Oncology ( Site 0509)	Ankara
Turkey	Göztepe Prof. Dr. Süleyman Yalçin Sehir Hastanesi-oncology ( Site 0504)	Istanbul
Turkey	Istanbul Uni. Cerrahpasa Tip Fakultesi ( Site 0501)	Istanbul
Turkey	T.C. Saglik Bakanligi Turkiye Kamu Hastaneleri Kurumu - Baki-Istanbul Bakirkoy Sadi Konuk Training (	Istanbul
Turkey	Ege University Medical Faculty ( Site 0508)	Izmir
Turkey	Karadeniz Teknik Universitesi Tip Fakultesi ( Site 0503)	Trabzon
Ukraine	Clinical oncology dispensary of Dnipro ( Site 0133)	Dnipro	Dnipropetrovska Oblast
Ukraine	Grigoriev Institute for medical Radiology NAMS of Ukraine ( Site 0139)	Kharkiv	Kharkivska Oblast
Ukraine	MNPE Regional Center of Oncology ( Site 0134)	Kharkiv	Kharkivska Oblast
Ukraine	Ukranian Center of TomoTherapy ( Site 0140)	Kropyvnytskiy	Kirovohradska Oblast
Ukraine	Kyiv City Clinical Oncology Center ( Site 0135)	Kyiv
Ukraine	SNPE National Cancer Institute ( Site 0136)	Kyiv	Kyivska Oblast
United Kingdom	Darlington Memorial Hospital NHS Trust ( Site 0446)	Darlington
United Kingdom	The Royal Marsden NHS Foundation Trust. ( Site 0442)	London	London, City Of
United Kingdom	University College London Hospitals NHS Foundation Trust ( Site 0445)	London	London, City Of
United Kingdom	Nottingham University Hospital NHS Trust ( Site 0250)	Nottingham	Nottinghamshire
United Kingdom	Royal Preston Hospital ( Site 0449)	Preston	Lancashire
United Kingdom	Betsi Cadwaladr University Health Board ( Site 0447)	Rhyl	Denbighshire
United Kingdom	South Devon Healthcare Foundation Trust. Torbay Hospital ( Site 0444)	Torquay	Devon
United States	New York Oncology Hematology P.C ( Site 0024)	Albany	New York
United States	MidLantic urology ( Site 0070)	Bala-Cynwyd	Pennsylvania
United States	Baltimore VA Medical Center ( Site 0054)	Baltimore	Maryland
United States	Bay Pines VA Medical Center ( Site 0055)	Bay Pines	Florida
United States	Roswell Park Cancer Institute ( Site 6009)	Buffalo	New York
United States	West Virginia University - Charleston Area Medical Center ( Site 6003)	Charleston	West Virginia
United States	Cleveland Clinic Main ( Site 0062)	Cleveland	Ohio
United States	Inova Schar Cancer Institute ( Site 6006)	Fairfax	Virginia
United States	Summit Medical Group Cancer Center ( Site 6008)	Florham Park	New Jersey
United States	Saint Francis Cancer Center ( Site 0026)	Greenville	South Carolina
United States	John Theurer Cancer Center at Hackensack University Medical Center ( Site 0005)	Hackensack	New Jersey
United States	Norton Cancer Institute ( Site 0044)	Louisville	Kentucky
United States	Froedtert and Medical College of Wisconsin ( Site 0022)	Milwaukee	Wisconsin
United States	Winthrop University Hospital ( Site 0069)	Mineola	New York
United States	Carolina Urologic Research Center ( Site 0002)	Myrtle Beach	South Carolina
United States	New York University Perlmutter Cancer Center ( Site 0001)	New York	New York
United States	AdventHealth Orlando-AdventHealth Medical Group Hematology & Oncology at Orlando ( Site 0004)	Orlando	Florida
United States	Pikeville Medical Center ( Site 0009)	Pikeville	Kentucky
United States	Washington University ( Site 0003)	Saint Louis	Missouri
United States	Urology San Antonio Research ( Site 6010)	San Antonio	Texas
United States	Washington Cancer Institute at MedStar Washington Hospital Center ( Site 0041)	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Merck Sharp & Dohme LLC

Countries where clinical trial is conducted

United States,  Australia,  Chile,  Czechia,  Denmark,  Estonia,  France,  Guatemala,  Hungary,  Israel,  Italy,  Japan,  Korea, Republic of,  Latvia,  Malaysia,  Netherlands,  Poland,  Portugal,  Puerto Rico,  Romania,  Spain,  Taiwan,  Turkey,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Bladder Intact Event-Free Survival (BI-EFS)	BI-EFS is defined as the time from randomization to any of the following events: residual/recurrent MIBC post-chemoradiotherapy (CRT), nodal or distant metastases as assessed by computerized tomography (CT) and CT urography (CTU) or magnetic resonance urography (MRU) per blinded independent central review (BICR) and/or biopsy results assessed by central pathology review, radical cystectomy, or death due to any cause. If biopsy is not feasible due to participant safety, the imaging alone will be sufficient. The BI-EFS for all participants will be presented.	Up to approximately 71 months
Secondary	Overall Survival (OS)	Time from randomization to death due to any cause.	Up to approximately 83 months
Secondary	Metastasis-Free Survival (MFS)	MFS is defined as the time from randomization to the first documented occurrence of nodal or distant metastases as assessed by CT and CTU or MRU per BICR and/or biopsy results assessed by central pathology review If biopsy is not feasible due to participant safety, the imaging alone will be sufficient.	Up to approximately 83 months
Secondary	Time to Occurrence of Non-Muscle-Invasive Bladder Cancer (NMIBC)	Time to occurrence of low-grade disease, defined as the time from randomization until the development of NMIBC, will be presented.	Up to approximately 83 months
Secondary	Number of Participants Who Experienced an Adverse Event (AE)	An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants who experience an AE will be presented.	Up to approximately 83 months
Secondary	Number of Participants Who Discontinued Study Intervention Due to an AE	An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants who discontinue study treatment due to an AE will be presented.	Up to approximately 1 year
Secondary	Change from Baseline in the Global Health Status/Quality of Life (Items 29 and 30) Combined Score on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30)	The EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Participant responses to the questions "How would you rate your overall health during the past week?" and "How would you rate your overall quality of life during the past week?" are scored on a 7-point scale (1=Very Poor to 7=Excellent). A higher score indicates a better overall outcome. The change from baseline in Global Health Status/Quality of Life (EORTC QLQ-C30 Items 29 and 30) combined score will be presented.	Baseline and up to approximately 83 months
Secondary	Change from Baseline in Physical Functioning (Items 1-5) Combined Score on the EORTC QLQ-C30	EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Participant responses to 5 questions about their physical functioning are scored on a 4-point scale (1=Not at All to 4=Very Much). A higher score indicates a better quality of life. The change from baseline in Physical Functioning (EORTC QLQ-C30 Items 1-5) combined score will be presented.	Baseline and up to approximately 83 months
Secondary	Change from Baseline in Urinary, Bowel, and Sexual Domains of the Bladder Cancer Index (BCI)	The BCI is a validated, condition-specific health questionnaire assessing quality of life among participants with bladder cancer. The BCI contains 36 items which assess 3 domains (urinary, bowel, and sexual) with function and bother subdomains. Scores range from 0 to 100 with higher scores corresponding to better functioning and health-related quality of life. The change from baseline in the combined scores of the urinary, bowel, and sexual domains of the BCI will be presented.	Baseline and up to approximately 83 months
Secondary	Change from Baseline in the Visual Analog Score (VAS) of the European Quality of Life (EuroQoL)-5 Dimensions, 5-level Questionnaire (EQ-5D-5L)	The EQ-5D-5L VAS records the respondent's self-rated health on a 10 cm vertical, visual analogue scale. It is rated by the respondent on a scale 0 to 100, with 0 being "the worst health you can imagine" and 100 being "the best health you can imagine". The change from baseline in EQ-5D-5L VAS will be presented.	Baseline and up to approximately 83 months
Secondary	Time to Deterioration (TTD) in the Global Health Status/Quality of Life (Items 29 and 30) Combined Score on the EORTC QLQ-C30	The EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Participant responses to the questions "How would you rate your overall health during the past week?" and "How would you rate your overall quality of life during the past week?" are scored on a 7-point scale (1=Very Poor to 7=Excellent). A higher score indicates a better overall outcome. TTD in Global Health Status/Quality of Life is defined as the time from baseline to the first onset of a 10 point or greater decrease from baseline in the Global Health Status/Quality of Life (EORTC QLQ-C30 Items 29 and 30) combined score, with or without subsequent confirmation.	Up to approximately 83 months
Secondary	TTD in Physical Functioning (Items 1-5) Combined Score on the EORTC QLQ-C30	EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Participant responses to 5 questions about their physical functioning are scored on a 4-point scale (1=Not at All to 4=Very Much). A higher score indicates a better quality of life. TTD in Physical Functioning (EORTC QLQ-C30 Items 1-5) combined score is defined as the time from baseline (at randomization) to the first onset of a =10-point decrease with confirmation by the subsequent visit of a =10-point decrease in physical functioning Items 1 to 5 scale scores.	Up to approximately 83 months
Secondary	TTD in Urinary, Bowel, and Sexual Domains of the BCI	The BCI is a validated, condition-specific health questionnaire assessing quality of life among participants with bladder cancer. The BCI contains 36 items which assess 3 domains (urinary, bowel, and sexual) with function and bother subdomains. Scores range from 0 to 100 with higher scores corresponding to better functioning and health-related quality of life. TTD in BCI is defined as a 6, 7, and 7 points or greater worsening from baseline for urinary, bowel, and sexual domains, respectively, with or without subsequent confirmation, under a right-censoring rule.	Up to approximately 83 months
Secondary	TTD in the VAS of the EQ-5D-5L	The EQ-5D-5L VAS records the respondent's self-rated health on a 10 cm vertical, visual analogue scale. It is rated by the respondent on a scale 0 to 100, with 0 being "the worst health you can imagine" and 100 being "the best health you can imagine". TTD in EQ-5D-5L VAS is defined as the time from baseline to the first onset of a 7 point or greater decrease from baseline in EQ-5D-5L VAS, with or without subsequent confirmation, under a right-censoring rule.	Up to approximately 83 months
Secondary	Time to Cystectomy	Time to cystectomy is defined as time from a participant's randomization to date of cystectomy.	Up to approximately 83 months

External Links

•   Merck Clinical Trials Information
•   Plain Language Summary