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    Clinical Trial Results:
    A Multicenter, Randomized, Open-label, Phase 3 Trial Comparing Selpercatinib to Physicians Choice of Cabozantinib or Vandetanib in Patients with Progressive, Advanced, Kinase Inhibitor Naïve, RET-Mutant Medullary Thyroid Cancer (LIBRETTO-531)

    Summary
    EudraCT number
    		 2019-001978-28
    Trial protocol
    		 CZ   GB   PL   DE   ES   NL   GR   BE   FR   IT  
    Global end of trial date

    Results information
    Results version number
    		 v2(current)
    This version publication date
    27 Feb 2025
    First version publication date
    05 Jun 2024
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Removed crossover arm in AE section.

    Trial information

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    Trial identification
    Sponsor protocol code
    J2G-MC-JZJB
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04211337
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Trial Number: 17478
    Sponsors
    Sponsor organisation name
    Eli Lilly and Company
    Sponsor organisation address
    Lilly Corporate Center, Indianapolis, United States, 46285
    Public contact
    Available Mon - Fri 9 AM - 5 PM EST, Eli Lilly and Company, 1 877‐CTLilly,
    Scientific contact
    Available Mon - Fri 9 AM - 5 PM EST, Eli Lilly and Company, 1 8005955979,
    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
    Interim
    Date of interim/final analysis
    22 May 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 May 2023
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    To compare PFS of patients with progressive, advanced, kinase inhibitor naïve, RET-mutant MTC treated with selpercatinib versus cabozantinib or vandetanib.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonization (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which a study is conducted.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Feb 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 9
    Country: Number of subjects enrolled
    Poland: 25
    Country: Number of subjects enrolled
    Spain: 12
    Country: Number of subjects enrolled
    United Kingdom: 12
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Czechia: 6
    Country: Number of subjects enrolled
    France: 42
    Country: Number of subjects enrolled
    Germany: 13
    Country: Number of subjects enrolled
    Greece: 4
    Country: Number of subjects enrolled
    Italy: 20
    Country: Number of subjects enrolled
    United States: 15
    Country: Number of subjects enrolled
    Japan: 6
    Country: Number of subjects enrolled
    India: 11
    Country: Number of subjects enrolled
    Russian Federation: 21
    Country: Number of subjects enrolled
    Canada: 2
    Country: Number of subjects enrolled
    Korea, Republic of: 12
    Country: Number of subjects enrolled
    China: 30
    Country: Number of subjects enrolled
    Taiwan: 5
    Country: Number of subjects enrolled
    Brazil: 33
    Country: Number of subjects enrolled
    Israel: 1
    Country: Number of subjects enrolled
    Australia: 11
    Worldwide total number of subjects
    291
    EEA total number of subjects
    132
    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)
    1
    Adults (18-64 years)
    215
    From 65 to 84 years
    75
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 If a participant has a recorded death on study, or is alive and being followed but off treatment, then the participant can be considered to be study completer.

    Pre-assignment
    Screening details
    		 Participants randomized to the Cabozantinib or Vandetanib arm will be allowed to crossover to receive the investigational product at the time of Blinded Independent Committee Review (BICR> confirmed radiographic progression.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Selpercatinib
    Arm description
    		 160 milligrams (mg) Selpercatinib administered orally (PO) twice daily (BID). Adolescent Dose: 92 milligrams per square meter (mg/m2) BID (not to exceed 160 mg BID).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Selpercatinib
    Investigational medicinal product code
    LY3527723
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    160 mg Selpercatinib administered orally (PO) twice daily (BID). Adolescent Dose: 92 mg/m2 BID (not to exceed 160 mg BID).

    Arm title
    		 Cabozantinib or Vandetanib
    Arm description
    		 140 mg Cabozantinib administered orally daily (QD) or 300 mg Vandetanib administered orally QD per physician choice. Cabozantinib Adolescent Dose: 40 mg/m2. Vandetanib Adolescent Dose: • 0.7 - <0.9 – 100 mg every other day (QOD) • 0.9 - <1.2 – 100 mg QD • 1.2 - <1.6 - 7-day schedule 100 mg - 200 mg - 100 mg - 200 mg - 100 mg - 200 mg - 100 mg • ≥1.6 - 200 QD
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Cabozantinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    140 mg Cabozantinib administered orally daily (QD) Cabozantinib Adolescent Dose: 40 mg/m2.

    Investigational medicinal product name
    Vandetanib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    300 mg Vandetanib administered orally QD. Vandetanib Adolescent Dose: • 0.7 - <0.9 – 100 mg every other day (QOD) • 0.9 - <1.2 – 100 mg QD • 1.2 - <1.6 - 7-day schedule 100 mg - 200 mg - 100 mg - 200 mg - 100 mg - 200 mg - 100 mg • ≥1.6 - 200 QD

    Number of subjects in period 1
    		Selpercatinib Cabozantinib or Vandetanib
    Started
    193
    98
    Received at Least One Dose of Study Drug
    193
    97
    Completed
    18
    56
    Not completed
    175
    42
         On Treatment
    175
    40
         Withdrawal by Subject
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Selpercatinib
    Reporting group description
    		 160 milligrams (mg) Selpercatinib administered orally (PO) twice daily (BID). Adolescent Dose: 92 milligrams per square meter (mg/m2) BID (not to exceed 160 mg BID).

    Reporting group title
    Cabozantinib or Vandetanib
    Reporting group description
    		 140 mg Cabozantinib administered orally daily (QD) or 300 mg Vandetanib administered orally QD per physician choice. Cabozantinib Adolescent Dose: 40 mg/m2. Vandetanib Adolescent Dose: • 0.7 - <0.9 – 100 mg every other day (QOD) • 0.9 - <1.2 – 100 mg QD • 1.2 - <1.6 - 7-day schedule 100 mg - 200 mg - 100 mg - 200 mg - 100 mg - 200 mg - 100 mg • ≥1.6 - 200 QD

    Reporting group values
    		 Selpercatinib Cabozantinib or Vandetanib Total
    Number of subjects
    		 193 98 291
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 1 0 1
        Adults (18-64 years)
    		 143 72 215
        From 65-84 years
    		 49 26 75
        85 years and over
    		 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 78 30 108
        Male
    		 115 68 183
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 3 1 4
        Not Hispanic or Latino
    		 9 3 12
        Unknown or Not Reported
    		 181 94 275
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 43 24 67
        Black or African American
    		 5 2 7
        White
    		 116 52 168
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 29 20 49
    Region of Enrollment
    Units: Subjects
        Netherlands
    		 6 3 9
        Poland
    		 15 10 25
        Spain
    		 9 3 12
        United Kingdom
    		 9 3 12
        Belgium
    		 1 0 1
        Czechia
    		 6 0 6
        France
    		 24 18 42
        Germany
    		 7 6 13
        Greece
    		 3 1 4
        Italy
    		 14 6 20
        United States
    		 11 4 15
        Japan
    		 5 1 6
        India
    		 9 2 11
        Canada
    		 1 1 2
        Korea, Republic of
    		 10 2 12
        China
    		 14 16 30
        Taiwan
    		 4 1 5
        Brazil
    		 20 13 33
        Israel
    		 1 0 1
        Russian Federation
    		 15 6 21
        Australia
    		 9 2 11

    End points

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    End points reporting groups
    Reporting group title
    Selpercatinib
    Reporting group description
    		 160 milligrams (mg) Selpercatinib administered orally (PO) twice daily (BID). Adolescent Dose: 92 milligrams per square meter (mg/m2) BID (not to exceed 160 mg BID).

    Reporting group title
    Cabozantinib or Vandetanib
    Reporting group description
    		 140 mg Cabozantinib administered orally daily (QD) or 300 mg Vandetanib administered orally QD per physician choice. Cabozantinib Adolescent Dose: 40 mg/m2. Vandetanib Adolescent Dose: • 0.7 - <0.9 – 100 mg every other day (QOD) • 0.9 - <1.2 – 100 mg QD • 1.2 - <1.6 - 7-day schedule 100 mg - 200 mg - 100 mg - 200 mg - 100 mg - 200 mg - 100 mg • ≥1.6 - 200 QD

    Primary: Progression Free Survival (PFS) by Blinded Independent Central Review (BICR)

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    End point title
    		 Progression Free Survival (PFS) by Blinded Independent Central Review (BICR)
    End point description
    PFS is defined as the time from randomization until the occurrence of documented disease progression by the BICR, per Response Evaluation Criteria in Solid Tumors (RECIST 1.1) criteria, or death from any cause in the absence of BICR-documented progressive disease. Progressive Disease (PD) was at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. Analysis Population Description (APD): All randomized participants, even if a participant did not take the assigned treatment, did not receive the correct treatment, or otherwise did not follow the protocol. Censored participants: Selpercatinib - 167; Cabozantinib or Vandetanib - 66
    End point type
    Primary
    End point timeframe
    Baseline to Progressive Disease or Death from Any Cause Up to 39 Months
    End point values
    		 Selpercatinib Cabozantinib or Vandetanib
    Number of subjects analysed
    193 [1]
    98
    Units: Months
        median (confidence interval 95%)
    9999 (9999 to 9999)
    16.76 (12.22 to 25.10)
    Notes
    [1] - 9999 = Data unavailable due to high censoring.
    Statistical analysis title
    		 Selpercatinib, Cabozantinib or Vandetanib
    Comparison groups
    Cabozantinib or Vandetanib v Selpercatinib
    Number of subjects included in analysis
    291
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [2]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.165
         upper limit
    		 0.475
    Notes
    [2] - Stratified by RET mutation type (M918T vs. Others) and intended treatment if randomized to Arm B (Vandetanib vs. Cabozantinib).

    Secondary: Treatment Failure-Free Survival (TFFS) by Blinded Independent Committee Review (BICR)

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    End point title
    		 Treatment Failure-Free Survival (TFFS) by Blinded Independent Committee Review (BICR)
    End point description
    TFFS by BICR is defined as the time from randomization to the first occurrence of documented radiographic disease progression per RECIST 1.1 as assessed by BICR; or unacceptable toxicity leading to treatment discontinuation as assessed by the investigator. Progressive Disease (PD) was at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. To qualify as an event, the toxicity must be from an intolerable AE (defined as any study drug-related AE that meets protocol guidance for treatment discontinuation, with the exception of alopecia); or death (due to any cause). APD: All randomized participants, even if a participant did not take the assigned treatment.
    End point type
    Secondary
    End point timeframe
    Baseline to Progressive Disease, Unacceptable Toxicity or Death from Any Cause Up to 39 Months
    End point values
    		 Selpercatinib Cabozantinib or Vandetanib
    Number of subjects analysed
    193 [3]
    98
    Units: Months
        median (confidence interval 95%)
    9999 (9999 to 9999)
    13.93 (11.27 to 25.10)
    Notes
    [3] - 9999 = Data not available due to high censoring.
    Statistical analysis title
    		 Selpercatinib, Cabozantinib or Vandetanib
    Comparison groups
    Selpercatinib v Cabozantinib or Vandetanib
    Number of subjects included in analysis
    291
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [4]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.254
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.153
         upper limit
    		 0.423
    Notes
    [4] - Stratified by RET mutation type (M918T vs. Others) and intended treatment if randomized to Arm B (Vandetanib vs. Cabozantinib).

    Secondary: Overall Response Rate (ORR): Percentage of Participants With Complete Response (CR) or Partial Response (PR) by BICR

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    End point title
    		 Overall Response Rate (ORR): Percentage of Participants With Complete Response (CR) or Partial Response (PR) by BICR
    End point description
    ORR is defined as the number of participants who achieved the best overall response (BOR) of CR or PR divided by the total number of participants randomized to each treatment arm. ORR per RECIST 1.1 as assessed by BICR. APD: All randomized participants, even if a participant did not take the assigned treatment, did not receive the correct treatment, or otherwise did not follow the protocol.
    End point type
    Secondary
    End point timeframe
    Baseline through Disease Progression or Death up to 39 Months
    End point values
    		 Selpercatinib Cabozantinib or Vandetanib
    Number of subjects analysed
    193
    98
    Units: Percentage of participants
        number (confidence interval 95%)
    69.4 (62.4 to 75.8)
    38.8 (29.1 to 49.2)
    Statistical analysis title
    		 Selpercatinib, Cabozantinib or Vandetanib
    Comparison groups
    Selpercatinib v Cabozantinib or Vandetanib
    Number of subjects included in analysis
    291
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [5]
    Method
    		 Clopper-Pearson Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.2
         upper limit
    		 6.3
    Notes
    [5] - Stratified by RET mutation type (M918T vs. Others) and intended treatment if randomized to Arm B (Vandetanib vs. Cabozantinib).

    Secondary: Duration of Response (DoR) by BICR

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    End point title
    		 Duration of Response (DoR) by BICR
    End point description
    DoR by BICR is defined as the time from the date that measurement criteria for complete response (CR) or partial response (PR) (whichever is first recorded) are first met by the BICR or investigator assessment, as applicable, until the first date that disease is recurrent or documented disease progression is observed, per RECIST 1.1 criteria, or the date of death from any cause in the absence of documented disease progression or recurrence. Progressive Disease (PD) was at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. APD: All randomized participants, even if a participant did not take the assigned treatment, did not receive the correct treatment, or otherwise did not follow the protocol. Censored participants: Selpercatinib - 119, Cabozantinib or Vandetanib - 25
    End point type
    Secondary
    End point timeframe
    Date of CR or PR to Date of Disease Progression or Death Due to Any Cause Up to 39 Months
    End point values
    		 Selpercatinib Cabozantinib or Vandetanib
    Number of subjects analysed
    134 [6]
    38 [7]
    Units: Months
        median (confidence interval 95%)
    9999 (9999 to 9999)
    16.56 (10.41 to 9999)
    Notes
    [6] - 9999 = Data not available due to high censoring.
    [7] - 9999 = Data not available due to high censoring.
    Statistical analysis title
    		 Selpercatinib, Cabozantinib or Vandetanib
    Comparison groups
    Selpercatinib v Cabozantinib or Vandetanib
    Number of subjects included in analysis
    172
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0004 [8]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.275
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.129
         upper limit
    		 0.587
    Notes
    [8] - Stratified by RET mutation type (M918T vs. Others) and intended treatment if randomized to Arm B (Vandetanib vs. Cabozantinib).

    Secondary: Comparative Tolerability: Number of Weeks With High Side Effect Bother Based Score of 3 or 4 on the Functional Assessment of Cancer Therapy Item GP5 (FACT-GP5)

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    End point title
    		 Comparative Tolerability: Number of Weeks With High Side Effect Bother Based Score of 3 or 4 on the Functional Assessment of Cancer Therapy Item GP5 (FACT-GP5)
    End point description
    Comparative tolerability defined as a comparison of the proportion of time on treatment with high side effect bother as assessed by the FACT-GP5. The FACT-GP5 is a single question used to assess the overall bother of the treatment side effects. It is scored using a 5-point rating scale (0 = not at all; 1 = a little bit; 2 = somewhat; 3 = quite a bit; and 4 = very much), where lower scores reflect less bother from treatment side effects. Time with high side effect bother (i.e.) score of 3 or 4 is reported here and was derived as follows: cumulative amount of time, in weeks, during which a participant reports high side effect bother divided by the total duration of therapy (weeks), derived as (date of last study treatment dose - date of first study treatment dose + 1) divided by 7. APD: All participants who received the first dose of study treatment prior to the interim efficacy analysis and at least 6 months prior to the data cutoff date.
    End point type
    Secondary
    End point timeframe
    Baseline to Progressive Disease, Unacceptable Toxicity or Death from Any Cause Up to 39 Months
    End point values
    		 Selpercatinib Cabozantinib or Vandetanib
    Number of subjects analysed
    145
    77
    Units: Weeks
        arithmetic mean (standard deviation)
    0.08 ( 0.169 )
    0.24 ( 0.304 )
    Statistical analysis title
    		 Selpercatinib, Cabozantinib or Vandetanib
    Comparison groups
    Selpercatinib v Cabozantinib or Vandetanib
    Number of subjects included in analysis
    222
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [9]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.23
         upper limit
    		 -0.1
    Notes
    [9] - Stratified by RET mutation type (M918T vs. Others) and intended treatment if randomized to Arm B (Vandetanib vs. Cabozantinib).

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to 39 Months
    Adverse event reporting additional description
    All randomized participants who received at least 1 dose (including a partial dose) of study treatment. Gender specific events occurring only in male or female participants have had the number of participants At Risk adjusted accordingly.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Selpercatinib - Treatment (TRT A)
    Reporting group description
    		 160 milligrams Selpercatinib administered orally (PO) twice daily (BID). Adolescent Dose: 92 milligrams per square meter (mg/m2) BID (not to exceed 160 mg BID).

    Reporting group title
    Cabozantinib or Vandetanib - Treatment B (TRT B)
    Reporting group description
    		 140 mg Cabozantinib administered orally daily (QD) or 300 mg Vandetanib administered orally QD per physician choice. Cabozantinib Adolescent Dose: 40 mg/m2. Vandetanib Adolescent Dose: 0.7 - <0.9 - 100 mg every other day (QOD) 0.9 - <1.2 - 100 mg QD 1.2 - <1.6 - 7-day schedule 100 mg - 200 mg - 100 mg - 200 mg - 100 mg - 200 mg - 100 mg ≥1.6 - 200 QD

    Serious adverse events
    		 Selpercatinib - Treatment (TRT A) Cabozantinib or Vandetanib - Treatment B (TRT B)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    43 / 193 (22.28%)
    27 / 97 (27.84%)
         number of deaths (all causes)
    8
    10
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    adenocarcinoma of colon
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    prostate cancer
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed [1]
    1 / 115 (0.87%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    rectosigmoid cancer
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    squamous cell carcinoma
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    aortic stenosis
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    haemorrhage
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    hypertension
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    2 / 193 (1.04%)
    4 / 97 (4.12%)
         occurrences causally related to treatment / all
    1 / 2
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    orthostatic hypotension
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    colporrhaphy
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed [2]
    1 / 78 (1.28%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    inguinal hernia repair
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hip arthroplasty
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    proctectomy
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    general physical health deterioration
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    fatigue
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    complication associated with device
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pain
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    mucosal inflammation
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    multiple organ dysfunction syndrome
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    pyrexia
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    3 / 193 (1.55%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    sudden death
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Reproductive system and breast disorders
    pelvic organ prolapse
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ovarian cyst
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed [3]
    1 / 78 (1.28%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    chronic obstructive pulmonary disease
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    bronchostenosis
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    dyspnoea
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hiccups
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    lung disorder
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pleural effusion
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    suicidal ideation
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    device occlusion
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    blood sodium decreased
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    blood bilirubin increased
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    fibrin d dimer increased
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    lipase increased
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    liver function test increased
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    femur fracture
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    head injury
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    cardiac failure
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    myocardial infarction
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    intracranial pressure increased
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ischaemic stroke
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    lumbar radiculopathy
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    motor dysfunction
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    posterior reversible encephalopathy syndrome
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    seizure
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    transient ischaemic attack
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    polycythaemia
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    vertigo
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    retinopathy
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    colitis
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    anal cyst
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    gastritis
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    enteritis
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    diarrhoea
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    haemorrhoidal haemorrhage
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    inguinal hernia
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    large intestinal obstruction
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pancreatitis
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 193 (0.00%)
    2 / 97 (2.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    nausea
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    oesophagitis
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    vomiting
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    cholecystitis acute
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    cholangitis
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    drug-induced liver injury
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    jaundice
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    liver injury
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hepatic function abnormal
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    erythema multiforme
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    acute kidney injury
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hydronephrosis
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    adrenocortical insufficiency acute
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    adrenal insufficiency
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypothyroidism
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    back pain
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    haemarthrosis
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    osteonecrosis of jaw
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    osteonecrosis
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    spinal pain
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    covid-19 pneumonia
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    covid-19
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    gastroenteritis escherichia coli
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    gastroenteritis
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    dengue fever
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hepatitis viral
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pneumonia
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    3 / 193 (1.55%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    peritonitis bacterial
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    urinary tract infection
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    2 / 193 (1.04%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    urosepsis
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    diabetic ketoacidosis
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    dehydration
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypercalcaemia
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypocalcaemia
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypokalaemia
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 193 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: Gender specific events occurring only in male or female participants have had the number of participants At Risk adjusted accordingly.
    [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: Gender specific events occurring only in male or female participants have had the number of participants At Risk adjusted accordingly.
    [3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: Gender specific events occurring only in male or female participants have had the number of participants At Risk adjusted accordingly.
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Selpercatinib - Treatment (TRT A) Cabozantinib or Vandetanib - Treatment B (TRT B)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    184 / 193 (95.34%)
    96 / 97 (98.97%)
    Vascular disorders
    hypertension
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    82 / 193 (42.49%)
    39 / 97 (40.21%)
         occurrences all number
    158
    76
    General disorders and administration site conditions
    face oedema
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    15 / 193 (7.77%)
    2 / 97 (2.06%)
         occurrences all number
    19
    3
    asthenia
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    21 / 193 (10.88%)
    24 / 97 (24.74%)
         occurrences all number
    31
    40
    fatigue
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    36 / 193 (18.65%)
    20 / 97 (20.62%)
         occurrences all number
    61
    43
    mucosal inflammation
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    14 / 193 (7.25%)
    25 / 97 (25.77%)
         occurrences all number
    17
    79
    oedema peripheral
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    32 / 193 (16.58%)
    2 / 97 (2.06%)
         occurrences all number
    42
    2
    pyrexia
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    22 / 193 (11.40%)
    2 / 97 (2.06%)
         occurrences all number
    29
    2
    pain
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    7 / 193 (3.63%)
    6 / 97 (6.19%)
         occurrences all number
    8
    9
    Reproductive system and breast disorders
    erectile dysfunction
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed [4]
    12 / 115 (10.43%)
    0 / 67 (0.00%)
         occurrences all number
    15
    0
    Respiratory, thoracic and mediastinal disorders
    cough
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    18 / 193 (9.33%)
    7 / 97 (7.22%)
         occurrences all number
    25
    8
    dysphonia
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    3 / 193 (1.55%)
    5 / 97 (5.15%)
         occurrences all number
    3
    7
    dyspnoea
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    9 / 193 (4.66%)
    5 / 97 (5.15%)
         occurrences all number
    11
    8
    epistaxis
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    8 / 193 (4.15%)
    5 / 97 (5.15%)
         occurrences all number
    17
    7
    oropharyngeal pain
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    6 / 193 (3.11%)
    6 / 97 (6.19%)
         occurrences all number
    8
    8
    Psychiatric disorders
    insomnia
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    6 / 193 (3.11%)
    5 / 97 (5.15%)
         occurrences all number
    10
    5
    Investigations
    alanine aminotransferase increased
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    51 / 193 (26.42%)
    33 / 97 (34.02%)
         occurrences all number
    139
    57
    electrocardiogram qt prolonged
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    26 / 193 (13.47%)
    13 / 97 (13.40%)
         occurrences all number
    67
    22
    blood thyroid stimulating hormone increased
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    13 / 193 (6.74%)
    13 / 97 (13.40%)
         occurrences all number
    16
    14
    blood lactate dehydrogenase increased
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    9 / 193 (4.66%)
    14 / 97 (14.43%)
         occurrences all number
    11
    17
    blood creatinine increased
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    18 / 193 (9.33%)
    2 / 97 (2.06%)
         occurrences all number
    41
    4
    blood bilirubin increased
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    21 / 193 (10.88%)
    8 / 97 (8.25%)
         occurrences all number
    47
    12
    blood alkaline phosphatase increased
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    19 / 193 (9.84%)
    13 / 97 (13.40%)
         occurrences all number
    37
    16
    aspartate aminotransferase increased
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    46 / 193 (23.83%)
    37 / 97 (38.14%)
         occurrences all number
    105
    60
    neutrophil count decreased
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    10 / 193 (5.18%)
    9 / 97 (9.28%)
         occurrences all number
    24
    22
    white blood cell count decreased
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    17 / 193 (8.81%)
    9 / 97 (9.28%)
         occurrences all number
    33
    21
    platelet count decreased
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    12 / 193 (6.22%)
    7 / 97 (7.22%)
         occurrences all number
    16
    17
    weight decreased
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    10 / 193 (5.18%)
    27 / 97 (27.84%)
         occurrences all number
    10
    49
    weight increased
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    22 / 193 (11.40%)
    2 / 97 (2.06%)
         occurrences all number
    44
    2
    Nervous system disorders
    dizziness
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    11 / 193 (5.70%)
    10 / 97 (10.31%)
         occurrences all number
    13
    15
    dysgeusia
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    10 / 193 (5.18%)
    16 / 97 (16.49%)
         occurrences all number
    10
    19
    headache
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    44 / 193 (22.80%)
    20 / 97 (20.62%)
         occurrences all number
    70
    22
    paraesthesia
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    4 / 193 (2.07%)
    7 / 97 (7.22%)
         occurrences all number
    6
    7
    Blood and lymphatic system disorders
    anaemia
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    11 / 193 (5.70%)
    10 / 97 (10.31%)
         occurrences all number
    12
    16
    leukopenia
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    10 / 193 (5.18%)
    6 / 97 (6.19%)
         occurrences all number
    13
    7
    lymphopenia
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    10 / 193 (5.18%)
    4 / 97 (4.12%)
         occurrences all number
    16
    4
    neutropenia
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    3 / 193 (1.55%)
    8 / 97 (8.25%)
         occurrences all number
    6
    17
    thrombocytopenia
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    4 / 193 (2.07%)
    9 / 97 (9.28%)
         occurrences all number
    5
    10
    Gastrointestinal disorders
    abdominal pain
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    19 / 193 (9.84%)
    14 / 97 (14.43%)
         occurrences all number
    28
    30
    abdominal distension
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    10 / 193 (5.18%)
    2 / 97 (2.06%)
         occurrences all number
    16
    2
    ascites
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    11 / 193 (5.70%)
    0 / 97 (0.00%)
         occurrences all number
    11
    0
    abdominal pain upper
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    16 / 193 (8.29%)
    7 / 97 (7.22%)
         occurrences all number
    19
    12
    constipation
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    31 / 193 (16.06%)
    12 / 97 (12.37%)
         occurrences all number
    58
    14
    diarrhoea
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    51 / 193 (26.42%)
    59 / 97 (60.82%)
         occurrences all number
    116
    195
    dry mouth
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    61 / 193 (31.61%)
    10 / 97 (10.31%)
         occurrences all number
    72
    12
    dyspepsia
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    19 / 193 (9.84%)
    8 / 97 (8.25%)
         occurrences all number
    21
    14
    dysphagia
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    6 / 193 (3.11%)
    6 / 97 (6.19%)
         occurrences all number
    7
    7
    gastrooesophageal reflux disease
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    8 / 193 (4.15%)
    8 / 97 (8.25%)
         occurrences all number
    11
    11
    nausea
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    20 / 193 (10.36%)
    31 / 97 (31.96%)
         occurrences all number
    36
    54
    oral pain
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    3 / 193 (1.55%)
    5 / 97 (5.15%)
         occurrences all number
    3
    11
    stomatitis
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    7 / 193 (3.63%)
    15 / 97 (15.46%)
         occurrences all number
    8
    32
    toothache
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    3 / 193 (1.55%)
    5 / 97 (5.15%)
         occurrences all number
    4
    5
    vomiting
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    15 / 193 (7.77%)
    20 / 97 (20.62%)
         occurrences all number
    20
    25
    Hepatobiliary disorders
    hepatic cytolysis
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    5 / 193 (2.59%)
    5 / 97 (5.15%)
         occurrences all number
    10
    7
    Skin and subcutaneous tissue disorders
    alopecia
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    10 / 193 (5.18%)
    7 / 97 (7.22%)
         occurrences all number
    10
    7
    acne
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    4 / 193 (2.07%)
    6 / 97 (6.19%)
         occurrences all number
    5
    6
    dermatitis acneiform
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    7 / 97 (7.22%)
         occurrences all number
    1
    8
    dry skin
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    13 / 193 (6.74%)
    11 / 97 (11.34%)
         occurrences all number
    16
    11
    hair colour changes
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 193 (0.00%)
    7 / 97 (7.22%)
         occurrences all number
    0
    10
    palmar-plantar erythrodysaesthesia syndrome
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    7 / 193 (3.63%)
    41 / 97 (42.27%)
         occurrences all number
    7
    93
    pruritus
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    7 / 193 (3.63%)
    5 / 97 (5.15%)
         occurrences all number
    9
    6
    rash
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    28 / 193 (14.51%)
    20 / 97 (20.62%)
         occurrences all number
    36
    39
    Renal and urinary disorders
    haematuria
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    1 / 193 (0.52%)
    8 / 97 (8.25%)
         occurrences all number
    1
    13
    proteinuria
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    3 / 193 (1.55%)
    23 / 97 (23.71%)
         occurrences all number
    3
    44
    Endocrine disorders
    hypothyroidism
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    12 / 193 (6.22%)
    4 / 97 (4.12%)
         occurrences all number
    18
    4
    Musculoskeletal and connective tissue disorders
    arthralgia
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    15 / 193 (7.77%)
    12 / 97 (12.37%)
         occurrences all number
    16
    16
    back pain
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    12 / 193 (6.22%)
    11 / 97 (11.34%)
         occurrences all number
    18
    11
    myalgia
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    7 / 193 (3.63%)
    5 / 97 (5.15%)
         occurrences all number
    8
    8
    neck pain
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    0 / 193 (0.00%)
    8 / 97 (8.25%)
         occurrences all number
    0
    10
    pain in extremity
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    12 / 193 (6.22%)
    5 / 97 (5.15%)
         occurrences all number
    19
    6
    Infections and infestations
    covid-19
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    19 / 193 (9.84%)
    17 / 97 (17.53%)
         occurrences all number
    19
    17
    urinary tract infection
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    11 / 193 (5.70%)
    8 / 97 (8.25%)
         occurrences all number
    13
    11
    Metabolism and nutrition disorders
    decreased appetite
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    23 / 193 (11.92%)
    27 / 97 (27.84%)
         occurrences all number
    29
    45
    hypercalcaemia
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    10 / 193 (5.18%)
    0 / 97 (0.00%)
         occurrences all number
    22
    0
    hyperphosphataemia
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    13 / 193 (6.74%)
    2 / 97 (2.06%)
         occurrences all number
    21
    2
    hypocalcaemia
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    20 / 193 (10.36%)
    25 / 97 (25.77%)
         occurrences all number
    43
    56
    hypokalaemia
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    10 / 193 (5.18%)
    15 / 97 (15.46%)
         occurrences all number
    16
    33
    hypomagnesaemia
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    10 / 193 (5.18%)
    7 / 97 (7.22%)
         occurrences all number
    15
    13
    hyponatraemia
    alternative dictionary used: MedDRA 26.0
         subjects affected / exposed
    10 / 193 (5.18%)
    4 / 97 (4.12%)
         occurrences all number
    24
    5
    Notes
    [4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Gender specific events occurring only in male or female participants have had the number of participants At Risk adjusted accordingly.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Nov 2019
    Amendment (a): Overall rationale for this amendment was to add information for adolescent such as dose and growth plate imaging. Additional information on AE collection and benefit/risk, dose modifications if hypersensitivity occurs. Modifications to inclusion/exclusion criteria per regulatory feedback.
    18 Nov 2019
    Amendment (b): Added the starting dose for the control arm treatment vandetanib for patients with mild to moderate renal impairment is incorporated, in order to maximize patient safety
    10 Jun 2020
    Amendment (c): There are two major changes within this amendment: - Changing of the criteria of events counted toward the primary endpoint of treatment failure free survival (TFFS), and - Aligning the required visit schedule and procedures to better align with standard of care treatment with prolonged use of oral kinase inhibitors
    15 Feb 2021
    Amendment (d): The primary rationale for this amendment was to update information around the comparative tolerability key secondary objective based on regulatory agency feedback. Changes from additional regulatory and investigator feedback and minor corrections are also incorporated
    04 Nov 2021
    Amendment (e): In this amendment, the following changes are incorporated in response to: - Regulatory feedback: Added progression free survival (PFS), as a primary endpoint and removed it as a secondary endpoint; Removed treatment failure free survival (TFFS), as a primary endpoint and added it as a secondary endpoint; - New external data disclosure: The study has been updated to an adaptive design to allow sample size re-estimation based on results at an interim analysis - Site feedback: Updated the cycles to align the visits with the schedule
    06 Apr 2022
    Amendment (f): Overall rationale for this amendment is in response to fluctuating vandetanib availability to ensure participants on control arm remain on active treatment. This amendment provides guidance to allow patients on vandetanib to switch to cabozantinib if necessary.
    11 Aug 2023
    Amendment (i): The primary purpose of this amendment is to update as per the latest Investigator Brochure (IB) and to align with EU Clinical Trial Regulation (EU-CTR) requirements.

    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.
    None reported
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