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    Clinical Trial Results:
    A Randomized, Controlled, Open-label Study of the Efficacy, Durability, and Safety of UGN-102 With or Without TURBT in Patients with Low Grade Intermediate Risk Non-Muscle Invasive Bladder Cancer (LG IR-NMIBC) (ATLAS)

    Summary
    EudraCT number
    		 2020-003541-11
    Trial protocol
    		 EE   BG   LV   PL  
    Global end of trial date
    28 Nov 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 May 2024
    First version publication date
    23 May 2024
    Other versions
    Summary report(s)
    		 BL006_Clinical Study Report Synopsis

    Trial information

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    Trial identification
    Sponsor protocol code
    BL006
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04688931
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    UroGen Pharma, Ltd.
    Sponsor organisation address
    9 Ha'Ta'asiya Street, Ra'anana , Israel, 4365405
    Public contact
    Veronika Kolesnik, Medical Officer, PSI CRO AG, +7 921948 6516, Veronika.Kolesnik@psi-cro.com
    Scientific contact
    Veronika Kolesnik, Medical Officer, PSI CRO AG, +7 921948 6516, Veronika.Kolesnik@psi-cro.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    28 Nov 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Nov 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Nov 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of UGN-102 with or without transurethral resection of bladder tumor (TURBT) versus TURBT alone with respect to disease-free survival (DFS) in patients with Low Grade Intermediate Risk Non-Muscle Invasive Bladder Cancer (LG IR-NMIBC).
    Protection of trial subjects
    This study was conducted in accordance with the protocol and with the following: - Consensus ethical principles derived from international guidelines including the Declaration of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) International Ethical Guidelines - Applicable International Council for Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines - Applicable laws and regulations
    Background therapy
    		 -
    Evidence for comparator
    		 TURBT is the global standard of care for management of LG IR NMIBC and was designated the comparator because there is no accepted therapeutic alternative to treat this patient population.
    Actual start date of recruitment
    12 Jan 2021
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 21 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Israel: 1
    Country: Number of subjects enrolled
    Russian Federation: 91
    Country: Number of subjects enrolled
    Bulgaria: 63
    Country: Number of subjects enrolled
    Ukraine: 31
    Country: Number of subjects enrolled
    Georgia: 30
    Country: Number of subjects enrolled
    United States: 25
    Country: Number of subjects enrolled
    Estonia: 18
    Country: Number of subjects enrolled
    Latvia: 16
    Country: Number of subjects enrolled
    Serbia: 5
    Country: Number of subjects enrolled
    Poland: 2
    Worldwide total number of subjects
    282
    EEA total number of subjects
    99
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    114
    From 65 to 84 years
    162
    85 years and over
    6

    Subject disposition

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    Recruitment
    Recruitment details
    		 Approximately 632 patients were planned to be enrolled. UroGen stopped study enrollment early after 282 patients were randomized (142 in the UGN‑102 ± TURBT arm and 140 in the TURBT alone arm).

    Pre-assignment
    Screening details
    		 Inclusion criteria: signed informed consent; ≥18 years old; LG NMIBC; negative voiding cytology for high-grade disease within 6 weeks of screening; intermediate risk disease (having 1-2 of the following: multiple tumors, solitary tumor >3 cm, recurrence); adequate organ/bone marrow function; no active UTI; agree to sex/contraception requirements.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 UGN-102 ± TURBT
    Arm description
    		 UGN-102 ± TURBT arm underwent 6 weekly intravesical instillations of UGN-102 followed by TURBT at 3 months only if needed.
    Arm type
    		 Experimental

    Investigational medicinal product name
    mitomycin
    Investigational medicinal product code
    UGN-102
    Other name
    Pharmaceutical forms
    Powder and solvent for intravesical solution
    Routes of administration
    Intravesical use
    Dosage and administration details
    The UGN-102 admixture for intravesical instillations contained mitomycin 75 mg in 56 mL admixture (1.33 mg/mL mitomycin). The UGN-102 admixture was prepared in advance of use by the pharmacy, up to 48 hours before administration. UGN-102 intravesical instillation was an outpatient procedure involving application of an anesthetic lubricant in the urethra, urethral catheterization using a flexible plastic catheter, and instillation of UGN-102 into the bladder over a period of approximately 1 to 2 minutes. The catheter stayed in place for approximately 15 minutes, after which it was removed, and the patient could continue activities of daily living.

    Arm title
    		 TURBT Alone
    Arm description
    		 Participants in the TURBT Alone arm underwent TURBT only, followed by repeat TURBT at 3 months if needed.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    transurethral resection of bladder tumor
    Investigational medicinal product code
    Other name
    TURBT
    Pharmaceutical forms
    Pharmaceutical dose form not applicable
    Routes of administration
    Other use
    Dosage and administration details
    TURBT is the current standard of care for low-grade intermediate-risk non-muscle invasive bladder cancer (LG IR NMIBC).

    Number of subjects in period 1
    		UGN-102 ± TURBT TURBT Alone
    Started
    142
    140
    Completed
    123
    106
    Not completed
    19
    34
         Randomization error
    3
    -
         Consent withdrawn by subject
    5
    16
         Physician decision
    3
    5
         Patient decision
    -
    1
         Disease progression
    -
    2
         Not eligible
    1
    3
         Adverse event
    4
    1
         Sponsor requirement
    1
    1
         Lost to follow-up
    1
    3
         New lesion, but biopsy could not be done
    -
    1
         Independently applied to another medical center
    1
    -
         Protocol deviation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    UGN-102 ± TURBT
    Reporting group description
    		 UGN-102 ± TURBT arm underwent 6 weekly intravesical instillations of UGN-102 followed by TURBT at 3 months only if needed.

    Reporting group title
    TURBT Alone
    Reporting group description
    		 Participants in the TURBT Alone arm underwent TURBT only, followed by repeat TURBT at 3 months if needed.

    Reporting group values
    		 UGN-102 ± TURBT TURBT Alone Total
    Number of subjects
    		 142 140 282
    Age categorical
    Units: Subjects
        < 65 years
    		 51 63 114
        ≥ 65 to < 75 years
    		 59 47 106
        ≥ 75 to < 85 years
    		 29 27 56
        ≥ 85 years
    		 3 3 6
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 66.7 ( 10.59 ) 66.3 ( 10.50 ) -
    Gender categorical
    Units: Subjects
        Female
    		 37 47 84
        Male
    		 105 93 198
    Race
    Units: Subjects
        American Indian or Alaskan Native
    		 0 0 0
        Asian
    		 1 1 2
        Black or African American
    		 0 0 0
        Native Hawaiian or other Pacific Islander
    		 0 0 0
        White
    		 140 139 279
        Not reported
    		 1 0 1
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 2 1 3
        Not Hispanic or Latino
    		 140 137 277
        Not reported
    		 0 2 2
    BMI - Mean
    Body mass index (BMI) was taken from screening evaluations. Number of patients who reported BMI: UGN-102 ± TURBT arm = 138; TURBT Alone arm = 131.
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 27.76 ( 5.005 ) 27.31 ( 4.666 ) -
    BMI - Median
    Units: kg/m2
        median (full range (min-max))
    		 26.85 (18.2 to 47.0) 26.69 (17.3 to 41.9) -

    End points

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    End points reporting groups
    Reporting group title
    UGN-102 ± TURBT
    Reporting group description
    		 UGN-102 ± TURBT arm underwent 6 weekly intravesical instillations of UGN-102 followed by TURBT at 3 months only if needed.

    Reporting group title
    TURBT Alone
    Reporting group description
    		 Participants in the TURBT Alone arm underwent TURBT only, followed by repeat TURBT at 3 months if needed.

    Primary: Disease-Free Survival (DFS)

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    End point title
    		 Disease-Free Survival (DFS)
    End point description
    DFS was defined as the time from randomization until the earliest date of any of the following events: - Failure to be rendered free of local disease at the Month 3 assessment after the TURBT procedure. - Recurrence of low-grade (LG) disease after the Month 3 assessment - Progression to high-grade (HG) disease - Death due to any cause DFS was based on the ITT population. Following early study enrollment closure to pursue an alternative development strategy for UGN-102, formal hypothesis testing was removed from the Statistical Analysis Plan assuming the study would be underpowered. In the UGN-102 ± TURBT arm, 37 patients (26.1%) had DFS events, and 105 (73.9%) were censored. In the TURBT Alone arm, 55 patients (39.3%) had DFS events, and 85 (60.7%) were censored.
    End point type
    Primary
    End point timeframe
    See endpoint description.
    End point values
    		 UGN-102 ± TURBT TURBT Alone
    Number of subjects analysed
    142 [1]
    140 [2]
    Units: month
        median (confidence interval 95%)
    9999 (9999 to 9999)
    14.85 (8.94 to 9999)
    Attachments
    		 Kaplan-Meier Plot of Disease-Free Survival
    Notes
    [1] - 9999 = Value not estimable
    [2] - 9999 = Value not estimable
    Statistical analysis title
    		 Hazard Ratio (HR)
    Statistical analysis description
    HR was estimated using a stratified Cox regression model. Confidence intervals (CIs) were computed using the Brookmeyer-Crowley method.
    Comparison groups
    UGN-102 ± TURBT v TURBT Alone
    Number of subjects included in analysis
    282
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.29
         upper limit
    		 0.68
    Notes
    [3] - Descriptive

    Secondary: Time to Recurrence (TTR)

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    End point title
    		 Time to Recurrence (TTR)
    End point description
    TTR was based on the ITT population. TTR analysis was the same as DFS, except death was not considered an event in the TTR analysis. In the UGN-102 ± TURBT arm, 37 patients (26.1%) had events, and 105 (73.9%) were censored. In the TURBT Alone arm, 54 patients (38.6%) had events, and 86 (61.4%) were censored. The Kaplan-Meier median TTR was not estimable (NE) in either arm.
    End point type
    Secondary
    End point timeframe
    See endpoint description.
    End point values
    		 UGN-102 ± TURBT TURBT Alone
    Number of subjects analysed
    142 [4]
    140 [5]
    Units: months
        median (confidence interval 95%)
    9999 (9999 to 9999)
    9999 (9.03 to 9999)
    Notes
    [4] - 9999 = Value not estimable
    [5] - 9999 = Value not estimable
    Statistical analysis title
    		 Hazard Ratio
    Statistical analysis description
    HR was estimated using a stratified Cox regression model. CIs were computed using the Brookmeyer-Crowley method.
    Comparison groups
    UGN-102 ± TURBT v TURBT Alone
    Number of subjects included in analysis
    282
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3
         upper limit
    		 0.7
    Notes
    [6] - Descriptive

    Secondary: Complete Response Rate (CRR) at Month 3 Assessment

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    End point title
    		 Complete Response Rate (CRR) at Month 3 Assessment
    End point description
    CRR was defined as the proportion of patients who achieved complete response at the Month 3 disease assessment. CRR was based on the ITT analysis set.
    End point type
    Secondary
    End point timeframe
    CRR was measured 3 months after the start of treatment.
    End point values
    		 UGN-102 ± TURBT TURBT Alone
    Number of subjects analysed
    142 [7]
    140 [8]
    Units: percent
        number (confidence interval 95%)
    64.8 (56.3 to 72.6)
    63.6 (55.0 to 71.5)
    Notes
    [7] - Patients with CR = 92 Patients with non-CR = 50
    [8] - Patients with CR = 89 Patients with non-CR = 51
    No statistical analyses for this end point

    Secondary: Observed CRR at Scheduled Disease Assessment Time Points

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    End point title
    		 Observed CRR at Scheduled Disease Assessment Time Points
    End point description
    Observed CRR at scheduled disease assessment time points was defined as the proportion of patients who had CR at the Month 3 disease assessment and maintained CR up to that particular follow-up disease assessment. This endpoint was summarized for patients who achieved CR at the Month 3 Visit.
    End point type
    Secondary
    End point timeframe
    Visit level CRR during follow-up was measured every 3 months until the end of study.
    End point values
    		 UGN-102 ± TURBT TURBT Alone
    Number of subjects analysed
    92
    89
    Units: percent
    number (confidence interval 95%)
        Month 6
    92.4 (84.9 to 96.9)
    71.9 (61.4 to 80.9)
        Month 9
    80.4 (70.9 to 88.0)
    62.9 (52.0 to 72.9)
        Month 12
    75.0 (64.9 to 83.4)
    57.3 (46.4 to 67.7)
        Month 15
    71.7 (61.4 to 80.6)
    55.1 (44.1 to 65.6)
        Month 18
    34.8 (25.1 to 45.4)
    25.8 (17.1 to 36.2)
        Month 21
    7.6 (3.1 to 15.1)
    4.5 (1.2 to 11.1)
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR)

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    End point title
    		 Duration of Response (DOR)
    End point description
    DOR was defined as the time from first documented CR until the earliest date of recurrence of LG disease, progression to HG disease, or death due to any cause. This endpoint was summarized for CR patients at the Month 3 disease assessment. DOR was based on the ITT population. In the UGN-102 ± TURBT arm, 18 patients (19.6%) had DOR events, and 74 (80.4%) were censored. In the TURBT Alone arm, 24 patients (27.0%) had DOR events, and 65 (73.0%) were censored.
    End point type
    Secondary
    End point timeframe
    See endpoint description.
    End point values
    		 UGN-102 ± TURBT TURBT Alone
    Number of subjects analysed
    92 [9]
    89 [10]
    Units: month
        median (confidence interval 95%)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    Notes
    [9] - 9999 = Value not estimable
    [10] - 9999 = Value not estimable
    Statistical analysis title
    		 Hazard Ratio
    Statistical analysis description
    HR was estimated using a stratified Cox regression model. CIs were computed using the Brookmeyer-Crowley method.
    Comparison groups
    UGN-102 ± TURBT v TURBT Alone
    Number of subjects included in analysis
    181
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.24
         upper limit
    		 0.86
    Notes
    [11] - Descriptive

    Secondary: Patients Who Underwent TURBT for LG IR NMIBC by Month 3 Assessment

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    End point title
    		 Patients Who Underwent TURBT for LG IR NMIBC by Month 3 Assessment
    End point description
    Defined as the proportion of patients receiving a per protocol TURBT in each arm and the average number of per protocol TURBTs per patient in each arm in the Safety Analysis Set. Per protocol TURBTs were defined as the Day 1 TURBT for patients in the TURBT Alone arm and TURBT due to residual LG disease at the Month 3 disease assessment in either arm. Presented here is the number of patients who underwent TURBT by the Month 3 assessment.
    End point type
    Secondary
    End point timeframe
    Timeframe for this endpoint was 3 months after the start of treatment.
    End point values
    		 UGN-102 ± TURBT TURBT Alone
    Number of subjects analysed
    138 [12]
    132 [13]
    Units: percent
        number (not applicable)
    17.4
    100
    Notes
    [12] - Mean (SD) number of per protocol TURBT per patient = 0.2 (0.38)
    [13] - Mean (SD) number of per protocol TURBT per patient = 1.1 (0.34)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AEs) were collected from informed consent to the Month 6 Visit. After the Month 6 Visit, all SAEs (regardless of causality) and non-serious AEs assessed as related to UGN-102, TURBT, or study procedures were reported until the EOS Visit.
    Adverse event reporting additional description
    Patient was counted once per system organ class or preferred term even if ≥1 event was reported.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    UGN-102 ± TURBT Arm - TEAEs
    Reporting group description
    		 The values provided are for TEAEs. A TEAE in the UGN-102 ± TURBT arm was defined as an AE that occurred on or after the day of the first instillation of UGN-102, or a pre-treatment AE that worsened during the study. TEAEs and serious TEAEs are taken from the Safety Analysis Set. For the UGN ± TURBT arm, the Safety Analysis Set includes all patients who received any dose of UGN-102.

    Reporting group title
    TURBT Alone Arm - TEAEs
    Reporting group description
    		 The values provided are for TEAEs. A TEAE in the TURBT Alone arm was defined as an AE that occurred on or after the day of initial TURBT, or a pre-treatment AE that worsened during the study. TEAEs and serious TEAEs are taken from the Safety Analysis Set. For the TURBT Alone arm, the Safety Analysis Set includes all patients who received at least one TURBT intervention.

    Serious adverse events
    		 UGN-102 ± TURBT Arm - TEAEs TURBT Alone Arm - TEAEs
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 138 (8.70%)
    7 / 132 (5.30%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung squamous cell carcinoma stage III
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Upper limb fracture
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Intestinal obstruction
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Prostatitis
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urethral stenosis
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 138 (0.00%)
    2 / 132 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    4 / 138 (2.90%)
    2 / 132 (1.52%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 132 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 138 (0.72%)
    2 / 132 (1.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 UGN-102 ± TURBT Arm - TEAEs TURBT Alone Arm - TEAEs
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    102 / 138 (73.91%)
    62 / 132 (46.97%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 138 (4.35%)
    2 / 132 (1.52%)
         occurrences all number
    14
    2
    General disorders and administration site conditions
    Malaise
         subjects affected / exposed
    8 / 138 (5.80%)
    2 / 132 (1.52%)
         occurrences all number
    8
    2
    Fatigue
         subjects affected / exposed
    5 / 138 (3.62%)
    0 / 132 (0.00%)
         occurrences all number
    6
    0
    Pyrexia
         subjects affected / exposed
    5 / 138 (3.62%)
    0 / 132 (0.00%)
         occurrences all number
    5
    0
    Gastrointestinal disorders
    Flatulence
         subjects affected / exposed
    13 / 138 (9.42%)
    4 / 132 (3.03%)
         occurrences all number
    19
    4
    Abdominal distension
         subjects affected / exposed
    6 / 138 (4.35%)
    4 / 132 (3.03%)
         occurrences all number
    7
    4
    Reproductive system and breast disorders
    Erectile dysfunction
         subjects affected / exposed
    9 / 138 (6.52%)
    4 / 132 (3.03%)
         occurrences all number
    9
    4
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    42 / 138 (30.43%)
    6 / 132 (4.55%)
         occurrences all number
    66
    6
    Micturition urgency
         subjects affected / exposed
    25 / 138 (18.12%)
    10 / 132 (7.58%)
         occurrences all number
    29
    10
    Nocturia
         subjects affected / exposed
    25 / 138 (18.12%)
    9 / 132 (6.82%)
         occurrences all number
    30
    10
    Pollakiuria
         subjects affected / exposed
    22 / 138 (15.94%)
    8 / 132 (6.06%)
         occurrences all number
    26
    9
    Haematuria
         subjects affected / exposed
    9 / 138 (6.52%)
    5 / 132 (3.79%)
         occurrences all number
    11
    5
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 138 (0.00%)
    4 / 132 (3.03%)
         occurrences all number
    0
    4
    Infections and infestations
    COVID-19
         subjects affected / exposed
    7 / 138 (5.07%)
    6 / 132 (4.55%)
         occurrences all number
    7
    6
    Cystitis
         subjects affected / exposed
    5 / 138 (3.62%)
    5 / 132 (3.79%)
         occurrences all number
    9
    5
    Urinary tract infection
         subjects affected / exposed
    4 / 138 (2.90%)
    5 / 132 (3.79%)
         occurrences all number
    4
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Dec 2021
    • Added notification of early study enrollment closure (Sponsor pursuing an alternative development path for UGN-102 in patients with LG IR NMIBC.) • Clarified that NCR patients at the Month 3 Visit may have an alternative procedure to address residual disease if a formal TURBT is unnecessary. (Data from Study BL005 suggest some patients with NCR/disease recurrence may be managed with biopsy and/or fulguration.) • Revised statistical plans to reflect that the study is not powered to perform hypothesis testing or statistical comparison, and all analyses will be descriptive. (Smaller sample size due to early enrollment closure.) • Revised definitions of DFS and TTR to start from time of randomization for both CR and NCR patients at the Month 3 Visit. (Feedback from US FDA.) • Deleted exploratory endpoint of other resource utilization. (Reflect data being captured in the eCRF.) • Removed data review committee. (No interim analysis.) • Removed ET Visit from SOA and clarified that patients who discontinue the study should have an EOS Visit performed. (Logistical simplicity.) • Added COVID-19 to study risk assessment. (Feedback from Poland Office for Registration of Medicinal Products, Medical Devices and Biocidal Products.) • Clarified that hospitalization is not a study requirement. (Feedback from the Ministry of Healthcare of the Russian Federation.) • Clarified that access to treatment information by sponsor personnel will be restricted by role. (Maintain trial integrity.) • Clarified that patients with disease progression at the Month 3 Visit or subsequent follow-up visits will be considered to have completed the study at that time. (HG or muscle-invasive disease requires different care.) • Revised Section 8.2.2 and added new Appendix 1 (Guidance on Evaluation of Response). (Clarify evaluation of response at Month 3 Visit and follow-up visits.) • Deleted planned supportive analysis of primary endpoint based on propensity scores. (Feedback from FDA.)

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Sponsor closed enrollment early to pursue alternative development strategy for UGN-102 in patients with LG IR-NMIBC. Study design followed patients up to 24 months after treatment start. Sponsor terminated study after last patient had 15 month Visit.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/37548555
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