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    Clinical Trial Results:
    A Randomized Phase 4 Study Comparing 2 Intravenous Temsirolimus (TEMSR) Regimens in Subjects With Relapsed, Refractory Mantle Cell Lymphoma (MCL)

    Summary
    EudraCT number
    		 2009-015498-11
    Trial protocol
    		 BE   FR   HU   DE   IT   BG   CZ  
    Global end of trial date
    28 Jun 2018

    Results information
    Results version number
    		 v3(current)
    This version publication date
    09 Jun 2019
    First version publication date
    26 Nov 2016
    Other versions
    		 v1 , v2
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    B1771007 (3066K1-4438)
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01180049
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pfizer Inc.
    Sponsor organisation address
    235 East 42nd Street, New York, United States, 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 18007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 18007181021, ClinicalTrials.gov_Inquiries@pfizer.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
    08 Oct 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Jun 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Estimate independently assessed PFS in subjects with relapsed, refractory MCL.
    Protection of trial subjects
    This study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. In addition, all local regulatory requirements were followed; in particular, those affording greater protection to the safety of study subjects.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Mar 2011
    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
    Australia: 23
    Country: Number of subjects enrolled
    Czech Republic: 12
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Italy: 12
    Country: Number of subjects enrolled
    Korea, Republic of: 5
    Country: Number of subjects enrolled
    Poland: 27
    Country: Number of subjects enrolled
    Romania: 6
    Country: Number of subjects enrolled
    Russian Federation: 7
    Country: Number of subjects enrolled
    Serbia: 1
    Country: Number of subjects enrolled
    United States: 4
    Worldwide total number of subjects
    101
    EEA total number of subjects
    61
    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)
    40
    From 65 to 84 years
    58
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 The study was conducted at multiple centers from 10 Mar 2011 to 28 Jun 2018.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    The study was not blinded.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 TEMSR 175/75 mg
    Arm description
    		 Subjects had received desipramine 50 mg one week prior to the first dose of temsirolimus (TEMSR). An additional desipramine 50 mg was administered again approximately 30 min prior to every first dose of TEMSR on Day 1. Subjects then received 175 mg intravenously (IV) once weekly for the first 3 weeks and followed by 75 mg once weekly thereafter.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Temsirolimus (TEMSR)
    Investigational medicinal product code
    PF-05208748
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Treatment was administered once weekly (IV dosing). In the test group, TEMSR was administered as 175 mg IV once weekly for the first 3 weeks followed by 75 mg once weekly thereafter. In the comparator group, TEMSR was administered as 75 mg IV once weekly.

    Arm title
    		 TEMSR 75 mg
    Arm description
    		 Subjects had received desipramine 50 mg one week prior to the first dose of TEMSR. An additional desipramine 50 mg was administered again approximately 30 min prior to every first dose of TEMSR on Day 1. Subjects then received TEMSR 75 mg IV once weekly.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Temsirolimus (TEMSR)
    Investigational medicinal product code
    PF-05208748
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Treatment was administered once weekly (IV dosing). TEMSR was administered as 75 mg once weekly.

    Number of subjects in period 1
    		TEMSR 175/75 mg TEMSR 75 mg
    Started
    53
    48
    Completed
    0
    0
    Not completed
    53
    48
         Death
    36
    35
         Unspecified
    9
    7
         Lost to follow-up
    8
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    TEMSR 175/75 mg
    Reporting group description
    		 Subjects had received desipramine 50 mg one week prior to the first dose of temsirolimus (TEMSR). An additional desipramine 50 mg was administered again approximately 30 min prior to every first dose of TEMSR on Day 1. Subjects then received 175 mg intravenously (IV) once weekly for the first 3 weeks and followed by 75 mg once weekly thereafter.

    Reporting group title
    TEMSR 75 mg
    Reporting group description
    		 Subjects had received desipramine 50 mg one week prior to the first dose of TEMSR. An additional desipramine 50 mg was administered again approximately 30 min prior to every first dose of TEMSR on Day 1. Subjects then received TEMSR 75 mg IV once weekly.

    Reporting group values
    		 TEMSR 175/75 mg TEMSR 75 mg Total
    Number of subjects
    		 53 48 101
    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)
    		 0 0 0
        Adults (18-64 years)
    		 22 18 40
        From 65-84 years
    		 29 29 58
        85 years and over
    		 2 1 3
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 67.2 ± 9.11 66.3 ± 8.36 -
    Gender, Male/Female
    Units: Participants
        Female
    		 15 8 23
        Male
    		 38 40 78

    End points

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    End points reporting groups
    Reporting group title
    TEMSR 175/75 mg
    Reporting group description
    		 Subjects had received desipramine 50 mg one week prior to the first dose of temsirolimus (TEMSR). An additional desipramine 50 mg was administered again approximately 30 min prior to every first dose of TEMSR on Day 1. Subjects then received 175 mg intravenously (IV) once weekly for the first 3 weeks and followed by 75 mg once weekly thereafter.

    Reporting group title
    TEMSR 75 mg
    Reporting group description
    		 Subjects had received desipramine 50 mg one week prior to the first dose of TEMSR. An additional desipramine 50 mg was administered again approximately 30 min prior to every first dose of TEMSR on Day 1. Subjects then received TEMSR 75 mg IV once weekly.

    Subject analysis set title
    Intention to treat (ITT) population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The analysis was done on ITT population which included all subjects who were randomized, with study drug assignment designated according to initial randomization, regardless of whether subjects received study drug or received a different drug dose from that to which they were randomized.

    Subject analysis set title
    Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Analysis was done on safety population which included any subject who received at least 1 dose of TEMSR was included in the evaluation for safety.

    Primary: Independently assessed Progression-free survival (PFS)

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    End point title
    		 Independently assessed Progression-free survival (PFS)
    End point description
    PFS is defined as the time from randomization to first documentation of disease progression by the independent assessor or to death due to any cause, whichever occurred first. PFS = (earliest date of progression or death due to any cause- randomization date+1)/30.4. Subjects who were alive and progression-free at the time of analysis were censored on the date of last assessment; subjects without adequate baseline assessment or without post-baseline assessments were censored on the randomization date; subjects who died or progressed after 2 or more missed visits were censored on the date of last tumor assessment prior to the missing visit; and subjects who started new anti-cancer therapy prior to death or progression were censored on the date of last tumor assessment prior to the start of anti-tumor treatment.
    End point type
    Primary
    End point timeframe
    From randomization date to the date of first documentation of progression or death (average follow up done for 15 months)
    End point values
    		 TEMSR 175/75 mg TEMSR 75 mg
    Number of subjects analysed
    47
    43
    Units: Months
        median (confidence interval 80%)
    4.3 (3.3 to 6.4)
    4.5 (2.7 to 4.9)
    Statistical analysis title
    		 TEMSR 175/75 group vs. TEMSR 75 group
    Statistical analysis description
    Hazard ratio of TEMSR 175/75 mg vs. TEMSR 75 mg with 80% CI is estimated in unstratified Cox regression model.
    Comparison groups
    TEMSR 175/75 mg v TEMSR 75 mg
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.731
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 1.027

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS is defined as the time from the date of randomization to the date of death due to any cause. The analysis was done on ITT population which included all subjects who were randomized, with study drug assignment designated according to initial randomization, regardless of whether subjects received study drug or received a different drug dose from that to which they were randomized. Here, "Overall Number of Subjects Analyzed" signifies subjects who were evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    From randomization date until death due to any cause (average follow up done for 56.1 months)
    End point values
    		 TEMSR 175/75 mg TEMSR 75 mg
    Number of subjects analysed
    53
    48
    Units: Months
        median (confidence interval 80%)
    10.9 (7.0 to 19.7)
    11.2 (6.6 to 18.1)
    Statistical analysis title
    		 TEMSR 175/75 mg vs. TEMSR 75 mg
    Statistical analysis description
    Hazard ratio of TEMSR 175/75 mg vs. TEMSR 75 mg with 80% CI was estimated in unstratified Cox regression model.
    Comparison groups
    TEMSR 175/75 mg v TEMSR 75 mg
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.778
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.568
         upper limit
    		 1.064

    Secondary: Independent assessment - Objective Response Rate (ORR = CR + PR)

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    End point title
    		 Independent assessment - Objective Response Rate (ORR = CR + PR)
    End point description
    ORR is defined as the percentage of subjects with confirmed complete response (CR) or confirmed partial response (PR) according to the Cheson Criteria relative to all randomized subjects. Subjects who did not have on-study radiographic tumor re-evaluation or who died, progressed or dropped out for any reason prior to reaching a CR or PR were counted as non--responders in the assessment of ORR.
    End point type
    Secondary
    End point timeframe
    From randomization date until end of treatment (average follow up done for 15 months)
    End point values
    		 TEMSR 175/75 mg TEMSR 75 mg
    Number of subjects analysed
    47
    43
    Units: Percentage of subjects
        number (confidence interval 80%)
    27.7 (19.1 to 37.7)
    20.9 (13.0 to 31.0)
    Statistical analysis title
    		 TEMSR 175/75 mg vs. TEMSR 75 mg
    Statistical analysis description
    Independent assessment- Difference (%) TEMSR 175/75 mg – TEMSR 75 mg (80% CI)
    Comparison groups
    TEMSR 175/75 mg v TEMSR 75 mg
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Difference in arms
    Point estimate
    6.7
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -6.9
         upper limit
    		 20.3

    Secondary: Investigator’s assessment ORR (ORR = CR + PR)

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    End point title
    		 Investigator’s assessment ORR (ORR = CR + PR)
    End point description
    ORR is defined as the percentage of subjects with confirmed CR or PR according to the Cheson Criteria relative to all randomized subjects. Subjects who did not have on-study radiographic tumor re-evaluation or who died, progressed or dropped out for any reason prior to reaching a CR or PR were counted as non-responders in the assessment of ORR.
    End point type
    Secondary
    End point timeframe
    From randomization date until end of treatment (average follow up done for 15 months)
    End point values
    		 TEMSR 175/75 mg TEMSR 75 mg
    Number of subjects analysed
    47
    43
    Units: Percentage of subjects
        number (confidence interval 80%)
    31.9 (22.9 to 42.2)
    18.6 (11.1 to 28.5)
    Statistical analysis title
    		 TEMSR 175/75 mg vs. TEMSR 75 mg
    Statistical analysis description
    Investigator’s assessment- Difference (%)TEMSR 175/75 mg – TEMSR 75 mg (80% CI)
    Comparison groups
    TEMSR 175/75 mg v TEMSR 75 mg
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Difference between arms
    Point estimate
    13.3
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.4
         upper limit
    		 26.7

    Secondary: Investigator assessed PFS

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    End point title
    		 Investigator assessed PFS
    End point description
    PFS is defined as the time from randomization to first documentation of disease progression by the independent assessor or to death due to any cause, whichever occurred first. PFS = (earliest date of progression or death due to any cause- randomization date+1)/30.4. Subjects who were alive and progression-free at the time of analysis were censored on the date of last assessment; subjects without adequate baseline assessment or without post-baseline assessments were censored on the randomization date; subjects who died or progressed after 2 or more missed visits were censored on the date of last tumor assessment prior to the missing visit; and subjects who started new anti-cancer therapy prior to death or progression were censored on the date of last tumor assessment prior to the start of anti-tumor treatment.
    End point type
    Secondary
    End point timeframe
    From randomization date to the date of first documentation of progression or death (average follow up done for 15 months)
    End point values
    		 TEMSR 175/75 mg TEMSR 75 mg
    Number of subjects analysed
    47
    43
    Units: Percentage of subjects
        median (confidence interval 80%)
    4.7 (2.7 to 8.3)
    3.9 (2.8 to 4.7)
    Statistical analysis title
    		 TEMSR 175/75 mg vs. TEMSR 75 mg
    Statistical analysis description
    Hazard ratio of TEMSR 175/75 mg vs. TEMSR 75 mg with 80% CI was estimated in unstratified Cox regression model.
    Comparison groups
    TEMSR 175/75 mg v TEMSR 75 mg
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.646
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.453
         upper limit
    		 0.922

    Secondary: Percentage of Subjects With Treatment-Emergent Infection- Related Adverse Events (AEs) With Grade 2 or Higher as per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE)

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    End point title
    		 Percentage of Subjects With Treatment-Emergent Infection- Related Adverse Events (AEs) With Grade 2 or Higher as per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE)
    End point description
    AE was any untoward medical occurrence in subject who received study drug without regard to possibility of causal relationship. Treatment emergent adverse event=as an event that emerged during treatment period that was absent before treatment, or worsened during treatment period relative to pretreatment state. Treatment-emergent infection-related AEs included events: pneumonia, bronchitis, infection, herpes simplex, oral candidiasis and sepsis. Grading by NCI CTCAE Version 3.0.: Grade 1= mild; Grade 2= moderate; Grade 3= severe; Grade 4= life-threatening; urgent intervention indicated; Grade 5= death. Analysis was done on safety population which included any subject who received at least 1 dose of TEMSR.
    End point type
    Secondary
    End point timeframe
    From screening up to a maximum of 57.1 months
    End point values
    		 TEMSR 175/75 mg TEMSR 75 mg
    Number of subjects analysed
    53
    47
    Units: Percentage of subjects
    number (not applicable)
        Pneumonia
    17.0
    21.3
        Bronchitis
    7.5
    2.1
        Infection
    5.7
    2.1
        Herpes simplex
    3.8
    2.1
        Oral candidiasis
    3.8
    0
        Sepsis
    0
    2.1
        Cellulitis
    1.9
    0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Treatment-Emergent Bleeding-Related AEs With Grade 2 or Higher as per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE)

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    End point title
    		 Percentage of Subjects With Treatment-Emergent Bleeding-Related AEs With Grade 2 or Higher as per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE)
    End point description
    An AE was any untoward medical occurrence in subject who received study drug without regard to possibility of causal relationship. Treatment emergent adverse event=as an event that emerged during treatment period that was absent before treatment, or worsened during treatment period relative to pretreatment state. Treatment-emergent bleeding related AEs included events: epistaxis and ecchymosis. AE were assessed according to maximum severity grading based on NCI CTCAE Version 4.03.Grade 1=mild; Grade 2=moderate; within normal limits. Grade 3=severe or medically significant but not immediately life-threatening; Grade 4=life-threatening or disabling; urgent intervention indicated; Grade 5=death. Analysis was done on safety population which included any subject who received at least 1 dose of TEMSR.
    End point type
    Secondary
    End point timeframe
    From screening up to a maximum of 57.1 months
    End point values
    		 TEMSR 175/75 mg TEMSR 75 mg
    Number of subjects analysed
    53
    47
    Units: Percentage of subjects
    number (not applicable)
        Epistaxis
    13.2
    2.1
        Ecchymosis
    1.9
    0
    No statistical analyses for this end point

    Secondary: Quantify the potential effect of TEMSR on AUC and Cmax

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    End point title
    		 Quantify the potential effect of TEMSR on AUC and Cmax
    End point description
    Potential TEMSR effects were investigated by calculating the ratio of AUCs with and without concomitant TEMSR from the model-estimated effect of TEMSR on apparent clearance (CL/F) values and using individual ratios of observed Cmax values with and without concomitant temsirolimus, for both parent and metabolite. The AUC mean ratio was calculated as 1 / mean shift on apparent clearance from TEMSR, and the 90% CI of the AUC ratios was calculated as 1 / 90% CI of the shift on apparent clearance from TEMSR. AUC: Area under plasma concentration-time curve from time zero to infinity Cmax: Characterization of maximum observed plasma concentration
    End point type
    Secondary
    End point timeframe
    From one week predose (Day -7, -4hr, -8hr, -48hr) upto 2 weeks post dose (4hr, 8hr, 48hr and Day 8)
    End point values
    		 TEMSR 175/75 mg TEMSR 75 mg
    Number of subjects analysed
    47
    43
    Units: Ratio
    arithmetic mean (confidence interval 90%)
        AUC
    1.00 (0.965 to 1.11)
    0.980 (0.870 to 1.12)
        Cmax
    0.828 (0.758 to 0.898)
    0.779 (0.7005 to 0.857)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From screening up to a maximum of 57.1 months
    Adverse event reporting additional description
    Same event may appear as both an AE and SAE.However,what is presented are distinct events. An event may be categorized as serious in 1 subject and as non-serious in another, or a subject may have experienced both a serious and non-serious event. Analysis was done on safety population which included any subject who received at least 1 dose of TEMSR.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    TEMSR 75 mg
    Reporting group description
    		 Subjects had received desipramine 50 mg one week prior to the first dose of TEMSR. An additional desipramine 50 mg was administered again approximately 30 min prior to every first dose of TEMSR on Day 1. Subjects then received TEMSR 75 mg IV once weekly.

    Reporting group title
    TEMSR 175/75 mg
    Reporting group description
    		 Subjects had received desipramine 50 mg one week prior to the first dose of temsirolimus (TEMSR). An additional desipramine 50 mg was administered again approximately 30 min prior to every first dose of TEMSR on Day 1. Subjects then received 175 mg intravenously (IV) once weekly for the first 3 weeks and followed by 75 mg once weekly thereafter.

    Serious adverse events
    		 TEMSR 75 mg TEMSR 175/75 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    34 / 47 (72.34%)
    35 / 53 (66.04%)
         number of deaths (all causes)
    35
    36
         number of deaths resulting from adverse events
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 53 (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
    Death
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Disease progression
         subjects affected / exposed
    9 / 47 (19.15%)
    10 / 53 (18.87%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 10
         deaths causally related to treatment / all
    0 / 12
    0 / 9
    Mucosal inflammation
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pyrexia
         subjects affected / exposed
    1 / 47 (2.13%)
    4 / 53 (7.55%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hiccups
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    3 / 47 (6.38%)
    2 / 53 (3.77%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 47 (4.26%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    2 / 47 (4.26%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    1 / 47 (2.13%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Hallucination
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Eastern Cooperative Oncology Group performance status worsened
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoglobin
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcus test positive
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Human rhinovirus test positive
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 53 (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
    Toxicity to various agents
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    2 / 47 (4.26%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 47 (0.00%)
    2 / 53 (3.77%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Agranulocytosis
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    1 / 47 (2.13%)
    2 / 53 (3.77%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    2 / 47 (4.26%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    3 / 3
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute abdomen
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric disorder
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incarcerated inguinal hernia
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 53 (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
    Chondrocalcinosis pyrophosphate
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 53 (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
    Atypical pneumonia
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 47 (0.00%)
    2 / 53 (3.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fungal infection
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Listeria sepsis
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    9 / 47 (19.15%)
    7 / 53 (13.21%)
         occurrences causally related to treatment / all
    4 / 11
    5 / 11
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Pneumonia pseudomonal
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia streptococcal
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 53 (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 / 47 (2.13%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 47 (0.00%)
    2 / 53 (3.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 47 (4.26%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varicella zoster virus infection
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral skin infection
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Acidosis
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    3 / 47 (6.38%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertriglyceridaemia
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 TEMSR 75 mg TEMSR 175/75 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    46 / 47 (97.87%)
    51 / 53 (96.23%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 47 (0.00%)
    3 / 53 (5.66%)
         occurrences all number
    0
    3
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    7 / 47 (14.89%)
    7 / 53 (13.21%)
         occurrences all number
    11
    9
    Chest discomfort
         subjects affected / exposed
    4 / 47 (8.51%)
    1 / 53 (1.89%)
         occurrences all number
    4
    2
    Fatigue
         subjects affected / exposed
    13 / 47 (27.66%)
    11 / 53 (20.75%)
         occurrences all number
    19
    24
    Oedema peripheral
         subjects affected / exposed
    8 / 47 (17.02%)
    9 / 53 (16.98%)
         occurrences all number
    25
    15
    Pyrexia
         subjects affected / exposed
    11 / 47 (23.40%)
    13 / 53 (24.53%)
         occurrences all number
    12
    18
    Mucosal inflammation
         subjects affected / exposed
    5 / 47 (10.64%)
    3 / 53 (5.66%)
         occurrences all number
    8
    4
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    9 / 47 (19.15%)
    8 / 53 (15.09%)
         occurrences all number
    12
    17
    Dyspnoea
         subjects affected / exposed
    13 / 47 (27.66%)
    10 / 53 (18.87%)
         occurrences all number
    17
    10
    Dyspnoea exertional
         subjects affected / exposed
    5 / 47 (10.64%)
    3 / 53 (5.66%)
         occurrences all number
    5
    4
    Epistaxis
         subjects affected / exposed
    9 / 47 (19.15%)
    14 / 53 (26.42%)
         occurrences all number
    13
    20
    Oropharyngeal pain
         subjects affected / exposed
    3 / 47 (6.38%)
    1 / 53 (1.89%)
         occurrences all number
    3
    1
    Pneumonitis
         subjects affected / exposed
    2 / 47 (4.26%)
    4 / 53 (7.55%)
         occurrences all number
    3
    6
    Psychiatric disorders
    Initial insomnia
         subjects affected / exposed
    3 / 47 (6.38%)
    0 / 53 (0.00%)
         occurrences all number
    3
    0
    Insomnia
         subjects affected / exposed
    0 / 47 (0.00%)
    4 / 53 (7.55%)
         occurrences all number
    0
    8
    Investigations
    Blood pressure increased
         subjects affected / exposed
    0 / 47 (0.00%)
    3 / 53 (5.66%)
         occurrences all number
    0
    3
    Platelet count decreased
         subjects affected / exposed
    2 / 47 (4.26%)
    6 / 53 (11.32%)
         occurrences all number
    6
    12
    Weight decreased
         subjects affected / exposed
    6 / 47 (12.77%)
    6 / 53 (11.32%)
         occurrences all number
    7
    7
    Blood cholesterol increased
         subjects affected / exposed
    0 / 47 (0.00%)
    3 / 53 (5.66%)
         occurrences all number
    0
    6
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    3 / 47 (6.38%)
    0 / 53 (0.00%)
         occurrences all number
    3
    0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    4 / 47 (8.51%)
    0 / 53 (0.00%)
         occurrences all number
    6
    0
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    4 / 47 (8.51%)
    2 / 53 (3.77%)
         occurrences all number
    4
    3
    Headache
         subjects affected / exposed
    3 / 47 (6.38%)
    5 / 53 (9.43%)
         occurrences all number
    4
    8
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    13 / 47 (27.66%)
    14 / 53 (26.42%)
         occurrences all number
    37
    32
    Leukopenia
         subjects affected / exposed
    2 / 47 (4.26%)
    5 / 53 (9.43%)
         occurrences all number
    4
    18
    Neutropenia
         subjects affected / exposed
    11 / 47 (23.40%)
    18 / 53 (33.96%)
         occurrences all number
    39
    34
    Thrombocytopenia
         subjects affected / exposed
    28 / 47 (59.57%)
    37 / 53 (69.81%)
         occurrences all number
    182
    178
    Leukocytosis
         subjects affected / exposed
    1 / 47 (2.13%)
    3 / 53 (5.66%)
         occurrences all number
    1
    3
    Lymphadenopathy
         subjects affected / exposed
    1 / 47 (2.13%)
    3 / 53 (5.66%)
         occurrences all number
    1
    5
    Lymphopenia
         subjects affected / exposed
    3 / 47 (6.38%)
    2 / 53 (3.77%)
         occurrences all number
    15
    13
    Eye disorders
    Dry eye
         subjects affected / exposed
    3 / 47 (6.38%)
    0 / 53 (0.00%)
         occurrences all number
    3
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    6 / 47 (12.77%)
    3 / 53 (5.66%)
         occurrences all number
    6
    3
    Constipation
         subjects affected / exposed
    5 / 47 (10.64%)
    6 / 53 (11.32%)
         occurrences all number
    5
    6
    Diarrhoea
         subjects affected / exposed
    14 / 47 (29.79%)
    19 / 53 (35.85%)
         occurrences all number
    32
    24
    Mouth ulceration
         subjects affected / exposed
    3 / 47 (6.38%)
    3 / 53 (5.66%)
         occurrences all number
    3
    3
    Nausea
         subjects affected / exposed
    9 / 47 (19.15%)
    6 / 53 (11.32%)
         occurrences all number
    12
    7
    Stomatitis
         subjects affected / exposed
    4 / 47 (8.51%)
    7 / 53 (13.21%)
         occurrences all number
    5
    8
    Vomiting
         subjects affected / exposed
    3 / 47 (6.38%)
    2 / 53 (3.77%)
         occurrences all number
    3
    2
    Aphthous ulcer
         subjects affected / exposed
    4 / 47 (8.51%)
    1 / 53 (1.89%)
         occurrences all number
    4
    3
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    5 / 47 (10.64%)
    5 / 53 (9.43%)
         occurrences all number
    10
    7
    Erythema
         subjects affected / exposed
    4 / 47 (8.51%)
    0 / 53 (0.00%)
         occurrences all number
    5
    0
    Night sweats
         subjects affected / exposed
    5 / 47 (10.64%)
    0 / 53 (0.00%)
         occurrences all number
    6
    0
    Onychoclasis
         subjects affected / exposed
    1 / 47 (2.13%)
    4 / 53 (7.55%)
         occurrences all number
    2
    5
    Pruritus
         subjects affected / exposed
    3 / 47 (6.38%)
    3 / 53 (5.66%)
         occurrences all number
    4
    3
    Rash
         subjects affected / exposed
    8 / 47 (17.02%)
    10 / 53 (18.87%)
         occurrences all number
    13
    12
    Skin lesion
         subjects affected / exposed
    3 / 47 (6.38%)
    1 / 53 (1.89%)
         occurrences all number
    8
    1
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    0 / 47 (0.00%)
    3 / 53 (5.66%)
         occurrences all number
    0
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 47 (2.13%)
    3 / 53 (5.66%)
         occurrences all number
    1
    4
    Pain in extremity
         subjects affected / exposed
    3 / 47 (6.38%)
    1 / 53 (1.89%)
         occurrences all number
    3
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 47 (2.13%)
    4 / 53 (7.55%)
         occurrences all number
    1
    8
    Herpes simplex
         subjects affected / exposed
    2 / 47 (4.26%)
    4 / 53 (7.55%)
         occurrences all number
    2
    4
    Infection
         subjects affected / exposed
    1 / 47 (2.13%)
    3 / 53 (5.66%)
         occurrences all number
    1
    3
    Nasopharyngitis
         subjects affected / exposed
    1 / 47 (2.13%)
    3 / 53 (5.66%)
         occurrences all number
    1
    13
    Pneumonia
         subjects affected / exposed
    4 / 47 (8.51%)
    3 / 53 (5.66%)
         occurrences all number
    4
    4
    Rhinitis
         subjects affected / exposed
    1 / 47 (2.13%)
    4 / 53 (7.55%)
         occurrences all number
    1
    5
    Skin infection
         subjects affected / exposed
    1 / 47 (2.13%)
    3 / 53 (5.66%)
         occurrences all number
    2
    3
    Upper respiratory tract infection
         subjects affected / exposed
    10 / 47 (21.28%)
    10 / 53 (18.87%)
         occurrences all number
    14
    28
    Urinary tract infection
         subjects affected / exposed
    3 / 47 (6.38%)
    3 / 53 (5.66%)
         occurrences all number
    6
    3
    Oral candidiasis
         subjects affected / exposed
    2 / 47 (4.26%)
    3 / 53 (5.66%)
         occurrences all number
    2
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    8 / 47 (17.02%)
    6 / 53 (11.32%)
         occurrences all number
    9
    8
    Diabetes mellitus
         subjects affected / exposed
    5 / 47 (10.64%)
    2 / 53 (3.77%)
         occurrences all number
    5
    2
    Hypercholesterolaemia
         subjects affected / exposed
    5 / 47 (10.64%)
    3 / 53 (5.66%)
         occurrences all number
    6
    5
    Hyperglycaemia
         subjects affected / exposed
    5 / 47 (10.64%)
    4 / 53 (7.55%)
         occurrences all number
    5
    7
    Hypertriglyceridaemia
         subjects affected / exposed
    5 / 47 (10.64%)
    6 / 53 (11.32%)
         occurrences all number
    6
    15
    Hypoalbuminaemia
         subjects affected / exposed
    4 / 47 (8.51%)
    2 / 53 (3.77%)
         occurrences all number
    4
    2
    Hypokalaemia
         subjects affected / exposed
    8 / 47 (17.02%)
    8 / 53 (15.09%)
         occurrences all number
    10
    14
    Hypophosphataemia
         subjects affected / exposed
    3 / 47 (6.38%)
    3 / 53 (5.66%)
         occurrences all number
    4
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Jun 2010
    Introduction of additional exclusion criteria regarding significant medical illness and abnormal laboratory findings, hypersensitivity to TEMSR and its metabolites, hypersensitivity to polysorbate 80 or other components of TEMSR formulation, hypersensitivity to antihistamines, and subjects who cannot receive antihistamines for other medical reasons.
    20 Mar 2012
    • Incorporation of updated Pfizer protocol template language from legacy Wyeth; • Clarifications to eligibility criteria, concomitant medications, and AEs of interest; • Modification of required procedures.
    30 Sep 2014
    • Modification of inclusion criteria value for total bilirubin and addition of a dose modification guideline to account for subjects with mild hepatic impairment per the updated Investigator Drug Brochure in September 2014; • Removal of the requirement for desipramine substudy and supporting PK sample collection, including CYP2D6 screening genotype sample, based on feedback from EMA in September 2014 confirming that results of interim PK analysis were acceptable and no further PK sampling was required; • Minor additions and modifications to align with the sponsor’s standard protocol template and standard policies.
    08 Jun 2017
    Terminated long-term follow-up.

    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.
    Overall Survival was not collected for the intended duration as planned initially, no long term follow up was conducted according to amendment in protocol. Hence overall survival results were limited.
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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