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    Clinical Trial Results:
    A randomized, double-blind, placebo-controlled, multicenter study of ensovibep (MP0420) in ambulatory adult patients with symptomatic COVID-19

    Summary
    EudraCT number
    		 2021-000890-10
    Trial protocol
    		 HU   NL  
    Global end of trial date
    27 Jan 2022

    Results information
    Results version number
    		 v2(current)
    This version publication date
    18 Jan 2023
    First version publication date
    18 Dec 2022
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Timeframe correction for PK endpoints.

    Trial information

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    Trial identification
    Sponsor protocol code
    MP0420-CP302
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04828161
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 CSKO136A12201J: Novartis protocol identifier
    Sponsors
    Sponsor organisation name
    Molecular Partners AG
    Sponsor organisation address
    Wagistrasse 14, Schlieren, Switzerland, 8952
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, +41 613241111, Novartis.email@Novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, +41 613241111, Novartis.email@Novartis.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
    27 Jan 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Jan 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Part A: To assess the effect of ensovibep, compared to placebo, in reducing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load from Baseline through Day 8.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 May 2021
    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
    Hungary: 3
    Country: Number of subjects enrolled
    India: 49
    Country: Number of subjects enrolled
    Netherlands: 19
    Country: Number of subjects enrolled
    South Africa: 87
    Country: Number of subjects enrolled
    United States: 242
    Worldwide total number of subjects
    400
    EEA total number of subjects
    22
    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)
    388
    From 65 to 84 years
    12
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study consisted of 2 parts, Part A and Part B. The Part A was Phase II proof of efficacy study conducted in ambulatory adult participants with symptomatic coronavirus disease 2019 (COVID-19). The Part B was to be Phase III confirmatory study. Only Part A analysis is reported as Part B of the study was not initiated.

    Pre-assignment
    Screening details
    		 Part A of the study consisted of a screening period (up to 3 days) followed by study treatment on Day 1. Participants were randomized in 1:1:1:1 ratio, stratified by risk for COVID-19 disease progression, to receive 1 of 4 study treatments (Ensovibep 600 mg or 225 mg or 75 mg or Placebo). A total of 400 participants were treated in the study.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer
    Blinding implementation details
    Two patients randomized to ensovibep 225 mg didn't receive treatment they were randomized to: 1 patient received no active drug as infusion was not prepared correctly; 1 patient received lower dose (<75 mg) as infusion was interrupted. For Safety set, these 2 were reported in placebo and ensovibep 75 mg arms, respectively.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ensovibep 600 mg
    Arm description
    		 Participants received single intravenous (IV) infusion of ensovibep 600 milligram (mg) on Day 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ensovibep
    Investigational medicinal product code
    MP0420, SKO136
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Single IV infusion of ensovibep 600 mg was administered for over 60 minutes on Day 1.

    Arm title
    		 Ensovibep 225 mg
    Arm description
    		 Participants received single IV infusion of ensovibep 225 mg on Day 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ensovibep
    Investigational medicinal product code
    MP0420, SKO136
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Single IV infusion of ensovibep 225 mg was administered for over 60 minutes on Day 1.

    Arm title
    		 Ensovibep 75 mg
    Arm description
    		 Participants received single IV infusion of ensovibep 75 mg on Day 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ensovibep
    Investigational medicinal product code
    MP0420, SKO136
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Single IV infusion of ensovibep 75 mg was administered for over 60 minutes on Day 1.

    Arm title
    		 Placebo
    Arm description
    		 Participants received single IV infusion of placebo matching with ensovibep on Day 1.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Single IV infusion of placebo matching with ensovibep was administered for over 60 minutes on Day 1.

    Number of subjects in period 1
    		Ensovibep 600 mg Ensovibep 225 mg Ensovibep 75 mg Placebo
    Started
    100
    100
    101
    99
    Completed
    97
    95
    96
    94
    Not completed
    3
    5
    5
    5
         Consent withdrawn by subject
    -
    1
    2
    1
         Death
    -
    -
    -
    2
         Unspecified
    2
    -
    1
    -
         Lost to follow-up
    1
    4
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ensovibep 600 mg
    Reporting group description
    		 Participants received single intravenous (IV) infusion of ensovibep 600 milligram (mg) on Day 1.

    Reporting group title
    Ensovibep 225 mg
    Reporting group description
    		 Participants received single IV infusion of ensovibep 225 mg on Day 1.

    Reporting group title
    Ensovibep 75 mg
    Reporting group description
    		 Participants received single IV infusion of ensovibep 75 mg on Day 1.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received single IV infusion of placebo matching with ensovibep on Day 1.

    Reporting group values
    		 Ensovibep 600 mg Ensovibep 225 mg Ensovibep 75 mg Placebo Total
    Number of subjects
    		 100 100 101 99 400
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 40.6 ( 11.50 ) 40.2 ( 12.90 ) 41.5 ( 12.84 ) 42.3 ( 13.75 ) -
    Gender categorical
    Units: Subjects
        Female
    		 47 54 60 57 218
        Male
    		 53 46 41 42 182
    Race and Ethnicity
    Units: Subjects
        White
    		 59 63 62 63 247
        Asian
    		 14 14 13 16 57
        Black or African American
    		 16 11 14 11 52
        Multiple
    		 5 4 6 8 23
        Not reported
    		 1 4 3 1 9
        Native Hawaiian or Other Pacific Islander
    		 1 1 2 0 4
        American Indian or Alaska Native
    		 3 0 1 0 4
        Unknown
    		 1 3 0 0 4

    End points

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    End points reporting groups
    Reporting group title
    Ensovibep 600 mg
    Reporting group description
    		 Participants received single intravenous (IV) infusion of ensovibep 600 milligram (mg) on Day 1.

    Reporting group title
    Ensovibep 225 mg
    Reporting group description
    		 Participants received single IV infusion of ensovibep 225 mg on Day 1.

    Reporting group title
    Ensovibep 75 mg
    Reporting group description
    		 Participants received single IV infusion of ensovibep 75 mg on Day 1.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received single IV infusion of placebo matching with ensovibep on Day 1.

    Subject analysis set title
    Phase 3/Part B: Ensovibep 75 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Phase 3/Part B: ensovibep active treatment. Part B was not initiated.

    Subject analysis set title
    Phase 3/Part B: Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Phase 3/Part B: Placebo. Part B was not initiated.

    Primary: Part A: Time-Weighted Change From Baseline in Log10 SARSCoV- 2 Viral Load Through Day 8

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    End point title
    		 Part A: Time-Weighted Change From Baseline in Log10 SARSCoV- 2 Viral Load Through Day 8
    End point description
    The SARS-CoV-2 viral load was measured by means of a nasopharyngeal swab, followed by quantitative reverse transcription-polymerase chain reaction assay at a central laboratory. The multiple comparison procedure-modeling methodology was used. Time-weighted change from baseline was used as viral loads were measured at multiple time points. The full analysis set (FAS) included all participants in the randomized set for whom IV infusion of study treatment was administered. Only participants included in the analysis are reported.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) and Days 3, 5 and 8
    End point values
    		 Ensovibep 600 mg Ensovibep 225 mg Ensovibep 75 mg Placebo
    Number of subjects analysed
    89
    97
    97
    87
    Units: log10 copies/milliliter (mL)
        least squares mean (standard error)
    -1.99 ( 0.097 )
    -1.73 ( 0.093 )
    -1.81 ( 0.093 )
    -1.40 ( 0.098 )
    Statistical analysis title
    		 Treatment difference in SARSCoV- 2 Viral Load - 1
    Comparison groups
    Ensovibep 600 mg v Placebo
    Number of subjects included in analysis
    176
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Least square (LS) mean difference
    Point estimate
    -0.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.86
         upper limit
    		 -0.32
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.138
    Statistical analysis title
    		 Treatment difference in SARSCoV- 2 Viral Load - 2
    Comparison groups
    Ensovibep 225 mg v Placebo
    Number of subjects included in analysis
    184
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.014
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -0.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.6
         upper limit
    		 -0.07
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.135
    Statistical analysis title
    		 Treatment difference in SARSCoV- 2 Viral Load - 3
    Comparison groups
    Ensovibep 75 mg v Placebo
    Number of subjects included in analysis
    184
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference
    Point estimate
    -0.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.68
         upper limit
    		 -0.15
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.135

    Primary: Part B: Percentage of Participants With Hospitalizations and/or Emergency Room (ER) Visits Related to COVID-19 or Death From Any Cause

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    End point title
    		 Part B: Percentage of Participants With Hospitalizations and/or Emergency Room (ER) Visits Related to COVID-19 or Death From Any Cause [1]
    End point description
    Percentage of participants experiencing hospitalizations [>= 24 hour (h) of acute care] and/or ER visits related to COVID-19 or death from any cause up to Day 29. The Part B of the study was not initiated based on regulatory feedback indicating that with evolving treatment options, a placebo controlled design was no longer considered to be appropriate.
    End point type
    Primary
    End point timeframe
    Up to Day 29
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The Part B of the study was not initiated based on regulatory feedback indicating that with evolving treatment options, a placebo controlled design was no longer considered to be appropriate.
    End point values
    		 Phase 3/Part B: Ensovibep 75 mg Phase 3/Part B: Placebo
    Number of subjects analysed
    0 [2]
    0 [3]
    Units: percentage of participants
        number (not applicable)
    Notes
    [2] - Part B was not initiated.
    [3] - Part B was not initiated.
    No statistical analyses for this end point

    Secondary: Part A: Percentage of Participants With Hospitalizations and/or ER Visits Related to COVID-19 or Death From Any Cause

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    End point title
    		 Part A: Percentage of Participants With Hospitalizations and/or ER Visits Related to COVID-19 or Death From Any Cause
    End point description
    Percentage of participants experiencing hospitalizations (>= 24 h of acute care) and/or ER visits related to COVID-19 or death from any cause up to Day 29 were presented along with relative risk to placebo. The FAS included all participants in the randomized set for whom IV infusion of study treatment was administered.
    End point type
    Secondary
    End point timeframe
    Up to Day 29
    End point values
    		 Ensovibep 600 mg Ensovibep 225 mg Ensovibep 75 mg Placebo
    Number of subjects analysed
    100
    100
    101
    99
    Units: percentage of participants
    number (not applicable)
        Any event
    1.0
    3.0
    0.0
    6.1
        Hospitalizations (≥ 24 h of acute care)
    0.0
    2.0
    0.0
    5.1
        ER visits related to COVID-19
    1.0
    1.0
    0.0
    5.1
        Death from any cause
    0.0
    0.0
    0.0
    2.0
    No statistical analyses for this end point

    Secondary: Part A: Time to Sustained Clinical Recovery

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    End point title
    		 Part A: Time to Sustained Clinical Recovery
    End point description
    Sustained clinical recovery was defined as follows; 1. All symptoms from the modified Food and Drug Administration (FDA) COVID-19 questionnaire scored as moderate or severe at baseline were subsequently scored as mild or absent, and 2. All symptoms from the modified FDA COVID-19 questionnaire scored as mild or absent at baseline were subsequently scored as absent, with no subsequent worsening, up to Day 29. The FAS included all participants in the randomized set for whom IV infusion of study treatment was administered. Only participants included in the analysis are reported.
    End point type
    Secondary
    End point timeframe
    Up to Day 29
    End point values
    		 Ensovibep 600 mg Ensovibep 225 mg Ensovibep 75 mg Placebo
    Number of subjects analysed
    63
    66
    74
    70
    Units: days
        median (confidence interval 95%)
    23.0 (14.0 to 29.0)
    15.0 (13.0 to 21.0)
    14.0 (11.0 to 28.0)
    29.0 (21.0 to 32.0)
    No statistical analyses for this end point

    Secondary: Part A: Observed Maximum Serum Concentration (Cmax) of Total and Free Ensovibep

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    End point title
    		 Part A: Observed Maximum Serum Concentration (Cmax) of Total and Free Ensovibep [4]
    End point description
    Blood samples were collected to determine the Cmax of free ensovibep (ensovibep not bound to target) and total ensovibep (sum of ensovibep not bound to and bound to target) concentrations in serum. The Pharmacokinetic (PK) analysis set included all participants with at least 1 available valid (that is, not flagged for exclusion) PK concentration measurement, who received any study treatment and with no protocol deviations that impacted PK data. Here, 'n' is number of participants analyzed for each parameter.
    End point type
    Secondary
    End point timeframe
    Data was summarized from pre-dose and at 15 minutes and 90 minutes after end of study drug infusion on Day 1, and at Days 3, 8, 15, 29, 61 and 91
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only participants who received study treatment were analyzed for this endpoint.
    End point values
    		 Ensovibep 600 mg Ensovibep 225 mg Ensovibep 75 mg
    Number of subjects analysed
    94
    92
    95
    Units: microgram (mcg) per mL
    geometric mean (geometric coefficient of variation)
        Total Ensovibep (n=94, 90, 93)
    187 ( 25.3 )
    70.4 ( 27.5 )
    25.1 ( 38.4 )
        Free Ensovibep (n=94, 92, 95)
    210 ( 26.3 )
    78.1 ( 31.5 )
    29.3 ( 46.4 )
    No statistical analyses for this end point

    Secondary: Part A: Area Under the Concentration-Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Total and Free Ensovibep

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    End point title
    		 Part A: Area Under the Concentration-Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Total and Free Ensovibep [5]
    End point description
    Blood samples were collected to determine the AUClast of free ensovibep (ensovibep not bound to target) and total ensovibep (sum of ensovibep not bound to and bound to target) concentrations in serum. The PK analysis set included all participants with at least 1 available valid (that is, not flagged for exclusion) PK concentration measurement, who received any study treatment and with no protocol deviations that impacted PK data. Here, 'n' is number of participants analyzed for each parameter.
    End point type
    Secondary
    End point timeframe
    Data was summarized from pre-dose and at 15 minutes and 90 minutes after end of study drug infusion on Day 1, and at Days 3, 8, 15, 29, 61 and 91
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only participants who received study treatment were analyzed for this endpoint.
    End point values
    		 Ensovibep 600 mg Ensovibep 225 mg Ensovibep 75 mg
    Number of subjects analysed
    94
    91
    95
    Units: h*mcg/mL
    geometric mean (geometric coefficient of variation)
        Total Ensovibep (n=94, 88, 95)
    63300 ( 87.6 )
    21100 ( 122.0 )
    7950 ( 67.1 )
        Free Ensovibep (n=94, 91, 95)
    68200 ( 84.4 )
    22500 ( 126.9 )
    8380 ( 67.9 )
    No statistical analyses for this end point

    Secondary: Part A: Area Under the Concentration-Time Curve From Time Zero to 48 Hours (AUC 0-48h) of Total and Free Ensovibep

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    End point title
    		 Part A: Area Under the Concentration-Time Curve From Time Zero to 48 Hours (AUC 0-48h) of Total and Free Ensovibep [6]
    End point description
    Blood samples were collected to determine the AUC 0-48h of free ensovibep (ensovibep not bound to target) and total ensovibep (sum of ensovibep not bound to and bound to target) concentrations in serum. The PK analysis set included all participants with at least 1 available valid (that is, not flagged for exclusion) PK concentration measurement, who received any study treatment and with no protocol deviations that impacted PK data. Here, 'n' is number of participants analyzed for each parameter.
    End point type
    Secondary
    End point timeframe
    Data was summarized from pre-dose and at 15 minutes and 90 minutes after end of study drug infusion on Day 1, and at Day 3
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only participants who received study treatment were analyzed for this endpoint.
    End point values
    		 Ensovibep 600 mg Ensovibep 225 mg Ensovibep 75 mg
    Number of subjects analysed
    95
    90
    95
    Units: h*mcg/mL
    geometric mean (geometric coefficient of variation)
        Total Ensovibep (n=93, 89, 95)
    7520 ( 35.3 )
    2830 ( 35.7 )
    999 ( 34.4 )
        Free Ensovibep (n=95, 90, 95)
    8290 ( 32.1 )
    2800 ( 156.2 )
    1120 ( 36.7 )
    No statistical analyses for this end point

    Secondary: Part A: Area Under the Concentration-Time Curve From Time Zero to 168 Hours (AUC 0-168h) of Total and Free Ensovibep

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    End point title
    		 Part A: Area Under the Concentration-Time Curve From Time Zero to 168 Hours (AUC 0-168h) of Total and Free Ensovibep [7]
    End point description
    Blood samples were collected to determine the AUC 0-168h of free ensovibep (ensovibep not bound to target) and total ensovibep (sum of ensovibep not bound to and bound to target) concentrations in serum. The PK analysis set included all participants with at least 1 available valid (that is, not flagged for exclusion) PK concentration measurement, who received any study treatment and with no protocol deviations that impacted PK data. Here, 'n' is number of participants analyzed for each parameter.
    End point type
    Secondary
    End point timeframe
    Data was summarized from pre-dose and at 15 minutes and 90 minutes after end of study drug infusion on Day 1, and at Days 3 and 8
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only participants who received study treatment were analyzed for this endpoint.
    End point values
    		 Ensovibep 600 mg Ensovibep 225 mg Ensovibep 75 mg
    Number of subjects analysed
    95
    89
    95
    Units: h*mcg/mL
    geometric mean (geometric coefficient of variation)
        Total Ensovibep (n=93, 89, 94)
    23000 ( 23.7 )
    8570 ( 33.1 )
    3020 ( 31.4 )
        Free Ensovibep (n= 95, 89, 95)
    25200 ( 23.2 )
    8940 ( 73.2 )
    3390 ( 35.3 )
    No statistical analyses for this end point

    Secondary: Part A: Area Under the Concentration-Time Curve From Time Zero to 336 Hours (AUC 0-336h) of Total and Free Ensovibep

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    End point title
    		 Part A: Area Under the Concentration-Time Curve From Time Zero to 336 Hours (AUC 0-336h) of Total and Free Ensovibep [8]
    End point description
    Blood samples were collected to determine the AUC 0-336h of free ensovibep (ensovibep not bound to target) and total ensovibep (sum of ensovibep not bound to and bound to target) concentrations in serum. The PK analysis set included all participants with at least 1 available valid (that is, not flagged for exclusion) PK concentration measurement, who received any study treatment and with no protocol deviations that impacted PK data. Here, 'n' is number of participants analyzed for each parameter.
    End point type
    Secondary
    End point timeframe
    Data was summarized from pre-dose and at 15 minutes and 90 minutes after end of study drug infusion on Day 1, and at Days 3, 8 and 15
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only participants who received study treatment were analyzed for this endpoint.
    End point values
    		 Ensovibep 600 mg Ensovibep 225 mg Ensovibep 75 mg
    Number of subjects analysed
    95
    88
    94
    Units: h*mcg/mL
    geometric mean (geometric coefficient of variation)
        Total Ensovibep (n=93, 87, 93)
    38200 ( 23.2 )
    13800 ( 37.6 )
    5040 ( 31.9 )
        Free Ensovibep (n=95, 88, 94)
    41800 ( 23.5 )
    15300 ( 41.6 )
    5620 ( 39.1 )
    No statistical analyses for this end point

    Secondary: Part A: Area Under the Concentration-Time Curve From Time Zero to Infinity (AUCinfinity) of Total and Free Ensovibep

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    End point title
    		 Part A: Area Under the Concentration-Time Curve From Time Zero to Infinity (AUCinfinity) of Total and Free Ensovibep [9]
    End point description
    Blood samples were collected to determine the AUCinfinity of free ensovibep (ensovibep not bound to target) and total ensovibep (sum of ensovibep not bound to and bound to target) concentrations in serum. The PK analysis set included all participants with at least 1 available valid (that is, not flagged for exclusion) PK concentration measurement, who received any study treatment and with no protocol deviations that impacted PK data. Here, 'n' is number of participants analyzed for each parameter.
    End point type
    Secondary
    End point timeframe
    Data was summarized from pre-dose and at 15 minutes and 90 minutes after end of study drug infusion on Day 1, and at Days 3, 8, 15, 29, 61 and 91
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only participants who received study treatment were analyzed for this endpoint.
    End point values
    		 Ensovibep 600 mg Ensovibep 225 mg Ensovibep 75 mg
    Number of subjects analysed
    87
    82
    82
    Units: h*mcg/mL
    geometric mean (geometric coefficient of variation)
        Total Ensovibep (n=87, 77, 82)
    75400 ( 33.5 )
    27600 ( 36.3 )
    9930 ( 41.0 )
        Free Ensovibep (n=87, 82, 80)
    80100 ( 40.6 )
    29400 ( 34.8 )
    9540 ( 45.8 )
    No statistical analyses for this end point

    Secondary: Part A: Time to Reach the Maximum Concentration (Tmax) of Total and Free Ensovibep

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    End point title
    		 Part A: Time to Reach the Maximum Concentration (Tmax) of Total and Free Ensovibep [10]
    End point description
    Blood samples were collected to determine the Tmax of free ensovibep (ensovibep not bound to target) and total ensovibep (sum of ensovibep not bound to and bound to target) concentrations in serum. The PK analysis set included all participants with at least 1 available valid (that is, not flagged for exclusion) PK concentration measurement, who received any study treatment and with no protocol deviations that impacted PK data. Here, 'n' is number of participants analyzed for each parameter.
    End point type
    Secondary
    End point timeframe
    Data was summarized from pre-dose and at 15 minutes and 90 minutes after end of study drug infusion on Day 1, and at Days 3, 8, 15, 29, 61 and 91
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only participants who received study treatment were analyzed for this endpoint.
    End point values
    		 Ensovibep 600 mg Ensovibep 225 mg Ensovibep 75 mg
    Number of subjects analysed
    95
    92
    95
    Units: hour
    geometric mean (geometric coefficient of variation)
        Total Ensovibep (n=95, 90, 92)
    0.935 ( 457.5 )
    1.30 ( 693.5 )
    1.05 ( 573.6 )
        Free Ensovibep (n=95, 92, 95)
    1.01 ( 473.8 )
    1.09 ( 516.6 )
    1.24 ( 810.1 )
    No statistical analyses for this end point

    Secondary: Part A: Apparent Total Body Clearance (CL) of Total and Free Ensovibep

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    End point title
    		 Part A: Apparent Total Body Clearance (CL) of Total and Free Ensovibep [11]
    End point description
    Blood samples were collected to determine the CL of free ensovibep (ensovibep not bound to target) and total ensovibep (sum of ensovibep not bound to and bound to target) concentrations in serum. The PK analysis set included all participants with at least 1 available valid (that is, not flagged for exclusion) PK concentration measurement, who received any study treatment and with no protocol deviations that impacted PK data. Here, 'n' is number of participants analyzed for each parameter.
    End point type
    Secondary
    End point timeframe
    Data was summarized from pre-dose and at 15 minutes and 90 minutes after end of study drug infusion on Day 1, and at Days 3, 8, 15, 29, 61 and 91
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only participants who received study treatment were analyzed for this endpoint.
    End point values
    		 Ensovibep 600 mg Ensovibep 225 mg Ensovibep 75 mg
    Number of subjects analysed
    84
    80
    74
    Units: mL/h
    geometric mean (geometric coefficient of variation)
        Total Ensovibep (n=77, 78, 74)
    8.07 ( 35.4 )
    8.11 ( 36.1 )
    7.48 ( 42.1 )
        Free Ensovibep (n=84, 80, 74)
    7.55 ( 37.3 )
    7.64 ( 35.3 )
    7.78 ( 43.0 )
    No statistical analyses for this end point

    Secondary: Part A: Terminal Elimination Rate Constant (Lambda z) of Total and Free Ensovibep

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    End point title
    		 Part A: Terminal Elimination Rate Constant (Lambda z) of Total and Free Ensovibep [12]
    End point description
    Blood samples were collected to determine the lambda z of free ensovibep (ensovibep not bound to target) and total ensovibep (sum of ensovibep not bound to and bound to target) concentrations in serum. The PK analysis set included all participants with at least 1 available valid (that is, not flagged for exclusion) PK concentration measurement, who received any study treatment and with no protocol deviations that impacted PK data. Here, 'n' is number of participants analyzed for each parameter.
    End point type
    Secondary
    End point timeframe
    Data was summarized from pre-dose and at 15 minutes and 90 minutes after end of study drug infusion on Day 1, and at Days 3, 8, 15, 29, 61 and 91
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only participants who received study treatment were analyzed for this endpoint.
    End point values
    		 Ensovibep 600 mg Ensovibep 225 mg Ensovibep 75 mg
    Number of subjects analysed
    84
    79
    74
    Units: per hour
    geometric mean (geometric coefficient of variation)
        Total Ensovibep (n=83, 70, 72)
    0.003 ( 52.1 )
    0.002 ( 50.6 )
    0.002 ( 39.5 )
        Free Ensovibep (n=84, 79, 74)
    0.003 ( 69.6 )
    0.003 ( 48.3 )
    0.003 ( 61.2 )
    No statistical analyses for this end point

    Secondary: Part A: Terminal Elimination Half-Life (T1/2) of Total and Free Ensovibep

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    End point title
    		 Part A: Terminal Elimination Half-Life (T1/2) of Total and Free Ensovibep [13]
    End point description
    Blood samples were collected to determine the T1/2 of free ensovibep (ensovibep not bound to target) and total ensovibep (sum of ensovibep not bound to and bound to target) concentrations in serum. The PK analysis set included all participants with at least 1 available valid (that is, not flagged for exclusion) PK concentration measurement, who received any study treatment and with no protocol deviations that impacted PK data. Here, 'n' is number of participants analyzed for each parameter.
    End point type
    Secondary
    End point timeframe
    Data was summarized from pre-dose and at 15 minutes and 90 minutes after end of study drug infusion on Day 1, and at Days 3, 8, 15, 29, 61 and 91
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only participants who received study treatment were analyzed for this endpoint.
    End point values
    		 Ensovibep 600 mg Ensovibep 225 mg Ensovibep 75 mg
    Number of subjects analysed
    90
    83
    83
    Units: hour
    geometric mean (geometric coefficient of variation)
        Total Ensovibep (n=89, 81, 83)
    274 ( 54.0 )
    290 ( 53.8 )
    309 ( 39.8 )
        Free Ensovibep (n=90, 83, 81)
    262 ( 67.7 )
    234 ( 48.3 )
    215 ( 60.6 )
    No statistical analyses for this end point

    Secondary: Part A: Apparent Volume of Distribution (Vz) of Total and Free Ensovibep

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    End point title
    		 Part A: Apparent Volume of Distribution (Vz) of Total and Free Ensovibep [14]
    End point description
    Blood samples were collected to determine the Vz of free ensovibep (ensovibep not bound to target) and total ensovibep (sum of ensovibep not bound to and bound to target) concentrations in serum. The PK analysis set included all participants with at least 1 available valid (that is, not flagged for exclusion) PK concentration measurement, who received any study treatment and with no protocol deviations that impacted PK data. Here, 'n' is number of participants analyzed for each parameter.
    End point type
    Secondary
    End point timeframe
    Data was summarized from pre-dose and at 15 minutes and 90 minutes after end of study drug infusion on Day 1, and at Days 3, 8, 15, 29, 61 and 91
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only participants who received study treatment were analyzed for this endpoint.
    End point values
    		 Ensovibep 600 mg Ensovibep 225 mg Ensovibep 75 mg
    Number of subjects analysed
    84
    80
    74
    Units: mL
    geometric mean (geometric coefficient of variation)
        Total Ensovibep (n=77, 78, 74)
    3230 ( 35.0 )
    3310 ( 37.5 )
    3330 ( 38.7 )
        Free Ensovibep (n=84, 80, 74)
    2760 ( 46.1 )
    2590 ( 36.4 )
    2470 ( 45.6 )
    No statistical analyses for this end point

    Secondary: Part B: Change From Baseline in Log10 SARS-CoV-2 Viral Load Through Day 8

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    End point title
    		 Part B: Change From Baseline in Log10 SARS-CoV-2 Viral Load Through Day 8
    End point description
    The SARS-CoV-2 viral load was measured by means of a nasopharyngeal swab, followed by quantitative reverse transcription-polymerase chain reaction assay at a central laboratory. The multiple comparison procedure-modeling methodology was used. The Part B of the study was not initiated based on regulatory feedback indicating that with evolving treatment options, a placebo controlled design was no longer considered to be appropriate.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and Days 3, 5 and 8
    End point values
    		 Phase 3/Part B: Ensovibep 75 mg Phase 3/Part B: Placebo
    Number of subjects analysed
    0 [15]
    0 [16]
    Units: log10 values
        least squares mean (standard error)
    ( )
    ( )
    Notes
    [15] - Part B was not initiated.
    [16] - Part B was not initiated.
    No statistical analyses for this end point

    Secondary: Part B: Time to Sustained Clinical Recovery

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    End point title
    		 Part B: Time to Sustained Clinical Recovery
    End point description
    Sustained clinical recovery was defined as follows; 1. All symptoms from the modified FDA COVID-19 questionnaire scored as moderate or severe at baseline were subsequently scored as mild or absent, and 2. All symptoms from the modified FDA COVID-19 questionnaire scored as mild or absent at baseline were subsequently scored as absent, with no subsequent worsening, up to Day 29. The Part B of the study was not initiated based on regulatory feedback indicating that with evolving treatment options, a placebo controlled design was no longer considered to be appropriate.
    End point type
    Secondary
    End point timeframe
    Up to Day 29
    End point values
    		 Phase 3/Part B: Ensovibep 75 mg Phase 3/Part B: Placebo
    Number of subjects analysed
    0 [17]
    0 [18]
    Units: days
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [17] - Part B was not initiated.
    [18] - Part B was not initiated.
    No statistical analyses for this end point

    Secondary: Part B: Percentage of Participants With Treatment-Emergent Anti-Drug Antibody (ADA) Response to Ensovibep

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    End point title
    		 Part B: Percentage of Participants With Treatment-Emergent Anti-Drug Antibody (ADA) Response to Ensovibep
    End point description
    Treatment-emergent ADA was defined as any participant with a 1. 2-fold (1 dilution) increase in titer than the minimum required dilution if no ADAs were detected at baseline (treatment-induced ADA); or, 2. 4-fold (2 dilutions) increase in titer compared with baseline if ADAs were detected at baseline (treatment-boosted ADA). The Part B of the study was not initiated based on regulatory feedback indicating that with evolving treatment options, a placebo controlled design was no longer considered to be appropriate.
    End point type
    Secondary
    End point timeframe
    Pre-dose on Day 1 and Days 15, 29, 61 and 91 postdose of Ensovibep
    End point values
    		 Phase 3/Part B: Ensovibep 75 mg Phase 3/Part B: Placebo
    Number of subjects analysed
    0 [19]
    0 [20]
    Units: percentage of participants
        number (not applicable)
    Notes
    [19] - Part B was not initiated.
    [20] - Part B was not initiated.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent adverse events were reported from first dose of study treatment (Day 1) until end of study treatment, up to a maximum duration of 98 days.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    Ensovibep 600 mg
    Reporting group description
    		 Participants received single IV infusion of ensovibep 600 mg on Day 1.

    Reporting group title
    Ensovibep 225 mg
    Reporting group description
    		 Participants received single IV infusion of ensovibep 225 mg on Day 1.

    Reporting group title
    Ensovibep 75 mg
    Reporting group description
    		 Participants received single IV infusion of ensovibep 75 mg on Day 1.

    Reporting group title
    Ensovibep Total
    Reporting group description
    		 Participants received single IV infusion of ensovibep on Day 1.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received single IV infusion of placebo matching with ensovibep on Day 1.

    Serious adverse events
    		 Ensovibep 600 mg Ensovibep 225 mg Ensovibep 75 mg Ensovibep Total Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 100 (0.00%)
    2 / 98 (2.04%)
    1 / 102 (0.98%)
    3 / 300 (1.00%)
    9 / 100 (9.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    2
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 300 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cor pulmonale
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 300 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Hiatus hernia
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 300 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 300 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 300 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paranasal sinus inflammation
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    1 / 102 (0.98%)
    1 / 300 (0.33%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 300 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 300 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 98 (1.02%)
    0 / 102 (0.00%)
    1 / 300 (0.33%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 98 (1.02%)
    0 / 102 (0.00%)
    1 / 300 (0.33%)
    4 / 100 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    Sepsis
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 300 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 300 (0.00%)
    2 / 100 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Ensovibep 600 mg Ensovibep 225 mg Ensovibep 75 mg Ensovibep Total Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    51 / 100 (51.00%)
    40 / 98 (40.82%)
    40 / 102 (39.22%)
    131 / 300 (43.67%)
    53 / 100 (53.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 100 (1.00%)
    2 / 98 (2.04%)
    2 / 102 (1.96%)
    5 / 300 (1.67%)
    0 / 100 (0.00%)
         occurrences all number
    1
    2
    2
    5
    0
    Phlebitis superficial
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    1 / 300 (0.33%)
    0 / 100 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    General disorders and administration site conditions
    Adverse drug reaction
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    1 / 300 (0.33%)
    0 / 100 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Asthenia
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 300 (0.00%)
    1 / 100 (1.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Fatigue
         subjects affected / exposed
    2 / 100 (2.00%)
    0 / 98 (0.00%)
    1 / 102 (0.98%)
    3 / 300 (1.00%)
    1 / 100 (1.00%)
         occurrences all number
    2
    0
    1
    3
    1
    Infusion site haematoma
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 300 (0.00%)
    2 / 100 (2.00%)
         occurrences all number
    0
    0
    0
    0
    2
    Infusion site swelling
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    1 / 102 (0.98%)
    1 / 300 (0.33%)
    0 / 100 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 100 (0.00%)
    2 / 98 (2.04%)
    1 / 102 (0.98%)
    3 / 300 (1.00%)
    0 / 100 (0.00%)
         occurrences all number
    0
    2
    1
    3
    0
    Swelling face
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    1 / 102 (0.98%)
    1 / 300 (0.33%)
    0 / 100 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Pyrexia
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 300 (0.00%)
    1 / 100 (1.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Pain
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 98 (1.02%)
    0 / 102 (0.00%)
    2 / 300 (0.67%)
    0 / 100 (0.00%)
         occurrences all number
    1
    1
    0
    2
    0
    Vessel puncture site haematoma
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 98 (1.02%)
    1 / 102 (0.98%)
    2 / 300 (0.67%)
    0 / 100 (0.00%)
         occurrences all number
    0
    1
    1
    2
    0
    Immune system disorders
    Allergy to chemicals
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    1 / 102 (0.98%)
    1 / 300 (0.33%)
    0 / 100 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Reproductive system and breast disorders
    Menstruation irregular
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    1 / 102 (0.98%)
    1 / 300 (0.33%)
    0 / 100 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Heavy menstrual bleeding
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 300 (0.00%)
    1 / 100 (1.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Dysmenorrhoea
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    1 / 102 (0.98%)
    1 / 300 (0.33%)
    0 / 100 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 98 (1.02%)
    0 / 102 (0.00%)
    1 / 300 (0.33%)
    0 / 100 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 300 (0.00%)
    1 / 100 (1.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Haemoptysis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 98 (1.02%)
    0 / 102 (0.00%)
    1 / 300 (0.33%)
    0 / 100 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Cough
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    1 / 300 (0.33%)
    0 / 100 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 300 (0.00%)
    1 / 100 (1.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Rhinitis allergic
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    1 / 102 (0.98%)
    1 / 300 (0.33%)
    0 / 100 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Throat irritation
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 300 (0.00%)
    1 / 100 (1.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 100 (2.00%)
    0 / 98 (0.00%)
    1 / 102 (0.98%)
    3 / 300 (1.00%)
    0 / 100 (0.00%)
         occurrences all number
    2
    0
    1
    3
    0
    Depression
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    1 / 300 (0.33%)
    0 / 100 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Insomnia
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    1 / 300 (0.33%)
    0 / 100 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    3 / 100 (3.00%)
    1 / 98 (1.02%)
    1 / 102 (0.98%)
    5 / 300 (1.67%)
    1 / 100 (1.00%)
         occurrences all number
    3
    1
    1
    5
    1
    Alanine aminotransferase increased
         subjects affected / exposed
    7 / 100 (7.00%)
    3 / 98 (3.06%)
    1 / 102 (0.98%)
    11 / 300 (3.67%)
    2 / 100 (2.00%)
         occurrences all number
    7
    3
    1
    11
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    6 / 100 (6.00%)
    3 / 98 (3.06%)
    1 / 102 (0.98%)
    10 / 300 (3.33%)
    2 / 100 (2.00%)
         occurrences all number
    6
    3
    1
    10
    2
    Amylase increased
         subjects affected / exposed
    4 / 100 (4.00%)
    1 / 98 (1.02%)
    1 / 102 (0.98%)
    6 / 300 (2.00%)
    2 / 100 (2.00%)
         occurrences all number
    4
    1
    1
    6
    2
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 98 (1.02%)
    0 / 102 (0.00%)
    2 / 300 (0.67%)
    0 / 100 (0.00%)
         occurrences all number
    1
    1
    0
    2
    0
    Blood bilirubin increased
         subjects affected / exposed
    3 / 100 (3.00%)
    0 / 98 (0.00%)
    1 / 102 (0.98%)
    4 / 300 (1.33%)
    0 / 100 (0.00%)
         occurrences all number
    3
    0
    1
    4
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    3 / 100 (3.00%)
    1 / 98 (1.02%)
    1 / 102 (0.98%)
    5 / 300 (1.67%)
    1 / 100 (1.00%)
         occurrences all number
    3
    1
    1
    5
    1
    Blood creatinine increased
         subjects affected / exposed
    6 / 100 (6.00%)
    4 / 98 (4.08%)
    3 / 102 (2.94%)
    13 / 300 (4.33%)
    6 / 100 (6.00%)
         occurrences all number
    7
    4
    3
    14
    6
    Blood glucose increased
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 98 (0.00%)
    1 / 102 (0.98%)
    2 / 300 (0.67%)
    1 / 100 (1.00%)
         occurrences all number
    1
    0
    1
    2
    1
    Blood pressure increased
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 98 (1.02%)
    1 / 102 (0.98%)
    2 / 300 (0.67%)
    1 / 100 (1.00%)
         occurrences all number
    0
    1
    1
    2
    1
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    1 / 300 (0.33%)
    0 / 100 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Blood phosphorus decreased
         subjects affected / exposed
    2 / 100 (2.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    2 / 300 (0.67%)
    1 / 100 (1.00%)
         occurrences all number
    2
    0
    0
    2
    1
    Blood sodium increased
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    1 / 102 (0.98%)
    1 / 300 (0.33%)
    0 / 100 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Blood uric acid increased
         subjects affected / exposed
    0 / 100 (0.00%)
    3 / 98 (3.06%)
    1 / 102 (0.98%)
    4 / 300 (1.33%)
    1 / 100 (1.00%)
         occurrences all number
    0
    3
    1
    4
    1
    Blood sodium decreased
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 98 (1.02%)
    0 / 102 (0.00%)
    1 / 300 (0.33%)
    1 / 100 (1.00%)
         occurrences all number
    0
    1
    0
    1
    1
    Fibrin D dimer increased
         subjects affected / exposed
    5 / 100 (5.00%)
    2 / 98 (2.04%)
    4 / 102 (3.92%)
    11 / 300 (3.67%)
    3 / 100 (3.00%)
         occurrences all number
    5
    3
    4
    12
    3
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    3 / 100 (3.00%)
    1 / 98 (1.02%)
    3 / 102 (2.94%)
    7 / 300 (2.33%)
    1 / 100 (1.00%)
         occurrences all number
    3
    1
    3
    7
    1
    C-reactive protein increased
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 98 (0.00%)
    1 / 102 (0.98%)
    2 / 300 (0.67%)
    0 / 100 (0.00%)
         occurrences all number
    1
    0
    1
    2
    0
    Haematocrit decreased
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 98 (1.02%)
    0 / 102 (0.00%)
    1 / 300 (0.33%)
    1 / 100 (1.00%)
         occurrences all number
    0
    1
    0
    1
    1
    Hepatic enzyme increased
         subjects affected / exposed
    2 / 100 (2.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    2 / 300 (0.67%)
    2 / 100 (2.00%)
         occurrences all number
    2
    0
    0
    2
    2
    Haemoglobin decreased
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 98 (1.02%)
    0 / 102 (0.00%)
    1 / 300 (0.33%)
    1 / 100 (1.00%)
         occurrences all number
    0
    1
    0
    1
    1
    Lipase increased
         subjects affected / exposed
    6 / 100 (6.00%)
    0 / 98 (0.00%)
    3 / 102 (2.94%)
    9 / 300 (3.00%)
    1 / 100 (1.00%)
         occurrences all number
    6
    0
    3
    9
    1
    International normalised ratio increased
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 300 (0.00%)
    2 / 100 (2.00%)
         occurrences all number
    0
    0
    0
    0
    2
    Liver function test increased
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 300 (0.00%)
    1 / 100 (1.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Monocyte count increased
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    1 / 102 (0.98%)
    1 / 300 (0.33%)
    0 / 100 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Pancreatic enzymes increased
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 300 (0.00%)
    1 / 100 (1.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Monocyte count decreased
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    1 / 102 (0.98%)
    1 / 300 (0.33%)
    1 / 100 (1.00%)
         occurrences all number
    0
    0
    1
    1
    1
    Serum ferritin decreased
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    1 / 102 (0.98%)
    1 / 300 (0.33%)
    0 / 100 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Prothrombin time prolonged
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 300 (0.00%)
    3 / 100 (3.00%)
         occurrences all number
    0
    0
    0
    0
    3
    Platelet count increased
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 98 (1.02%)
    0 / 102 (0.00%)
    1 / 300 (0.33%)
    0 / 100 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    White blood cell count increased
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    1 / 300 (0.33%)
    0 / 100 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Bone contusion
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 300 (0.00%)
    1 / 100 (1.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Fall
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 300 (0.00%)
    1 / 100 (1.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Post procedural complication
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 98 (1.02%)
    0 / 102 (0.00%)
    1 / 300 (0.33%)
    0 / 100 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Infusion related reaction
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    1 / 102 (0.98%)
    1 / 300 (0.33%)
    0 / 100 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Ligament sprain
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 300 (0.00%)
    1 / 100 (1.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Procedural pain
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 300 (0.00%)
    1 / 100 (1.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Skin abrasion
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 98 (1.02%)
    0 / 102 (0.00%)
    1 / 300 (0.33%)
    0 / 100 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 98 (1.02%)
    0 / 102 (0.00%)
    1 / 300 (0.33%)
    1 / 100 (1.00%)
         occurrences all number
    0
    1
    0
    1
    1
    Headache
         subjects affected / exposed
    2 / 100 (2.00%)
    2 / 98 (2.04%)
    4 / 102 (3.92%)
    8 / 300 (2.67%)
    1 / 100 (1.00%)
         occurrences all number
    4
    2
    4
    10
    1
    Neuropathy peripheral
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    1 / 300 (0.33%)
    0 / 100 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    3 / 102 (2.94%)
    3 / 300 (1.00%)
    0 / 100 (0.00%)
         occurrences all number
    0
    0
    3
    3
    0
    Eosinophilia
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    1 / 300 (0.33%)
    1 / 100 (1.00%)
         occurrences all number
    1
    0
    0
    1
    1
    Haemorrhagic diathesis
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 300 (0.00%)
    1 / 100 (1.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 98 (1.02%)
    0 / 102 (0.00%)
    1 / 300 (0.33%)
    1 / 100 (1.00%)
         occurrences all number
    0
    1
    0
    1
    1
    Leukopenia
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 98 (1.02%)
    0 / 102 (0.00%)
    1 / 300 (0.33%)
    0 / 100 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Lymphadenopathy
         subjects affected / exposed
    2 / 100 (2.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    2 / 300 (0.67%)
    0 / 100 (0.00%)
         occurrences all number
    2
    0
    0
    2
    0
    Lymphocytosis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 98 (1.02%)
    0 / 102 (0.00%)
    1 / 300 (0.33%)
    0 / 100 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Neutropenia
         subjects affected / exposed
    3 / 100 (3.00%)
    1 / 98 (1.02%)
    4 / 102 (3.92%)
    8 / 300 (2.67%)
    1 / 100 (1.00%)
         occurrences all number
    3
    1
    4
    8
    1
    Eye disorders
    Abnormal sensation in eye
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 300 (0.00%)
    1 / 100 (1.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Uveitis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 98 (1.02%)
    0 / 102 (0.00%)
    1 / 300 (0.33%)
    0 / 100 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Disorder of globe
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 300 (0.00%)
    1 / 100 (1.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Vision blurred
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 300 (0.00%)
    1 / 100 (1.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 98 (0.00%)
    1 / 102 (0.98%)
    2 / 300 (0.67%)
    0 / 100 (0.00%)
         occurrences all number
    1
    0
    1
    2
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 300 (0.00%)
    2 / 100 (2.00%)
         occurrences all number
    0
    0
    0
    0
    2
    Constipation
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 98 (1.02%)
    0 / 102 (0.00%)
    2 / 300 (0.67%)
    0 / 100 (0.00%)
         occurrences all number
    1
    1
    0
    2
    0
    Aphthous ulcer
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 98 (1.02%)
    0 / 102 (0.00%)
    1 / 300 (0.33%)
    0 / 100 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Diarrhoea
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 98 (1.02%)
    1 / 102 (0.98%)
    3 / 300 (1.00%)
    1 / 100 (1.00%)
         occurrences all number
    1
    1
    1
    3
    1
    Haemorrhoids
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    1 / 300 (0.33%)
    0 / 100 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Dyspepsia
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 300 (0.00%)
    1 / 100 (1.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Nausea
         subjects affected / exposed
    3 / 100 (3.00%)
    1 / 98 (1.02%)
    0 / 102 (0.00%)
    4 / 300 (1.33%)
    2 / 100 (2.00%)
         occurrences all number
    3
    1
    0
    4
    2
    Pancreatitis
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    1 / 102 (0.98%)
    1 / 300 (0.33%)
    0 / 100 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Vomiting
         subjects affected / exposed
    3 / 100 (3.00%)
    2 / 98 (2.04%)
    1 / 102 (0.98%)
    6 / 300 (2.00%)
    1 / 100 (1.00%)
         occurrences all number
    3
    2
    1
    6
    1
    Hepatobiliary disorders
    Nonalcoholic fatty liver disease
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    1 / 300 (0.33%)
    0 / 100 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Dermatitis contact
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 98 (1.02%)
    0 / 102 (0.00%)
    1 / 300 (0.33%)
    2 / 100 (2.00%)
         occurrences all number
    0
    1
    0
    1
    2
    Eczema
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 300 (0.00%)
    1 / 100 (1.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Petechiae
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    1 / 102 (0.98%)
    1 / 300 (0.33%)
    0 / 100 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Rash papular
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    1 / 102 (0.98%)
    1 / 300 (0.33%)
    0 / 100 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Rash
         subjects affected / exposed
    3 / 100 (3.00%)
    1 / 98 (1.02%)
    0 / 102 (0.00%)
    4 / 300 (1.33%)
    0 / 100 (0.00%)
         occurrences all number
    3
    1
    0
    4
    0
    Rash maculo-papular
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    1 / 300 (0.33%)
    1 / 100 (1.00%)
         occurrences all number
    1
    0
    0
    1
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    1 / 102 (0.98%)
    1 / 300 (0.33%)
    0 / 100 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Hydronephrosis
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 300 (0.00%)
    1 / 100 (1.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Ureterolithiasis
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 300 (0.00%)
    1 / 100 (1.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Renal pain
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    1 / 102 (0.98%)
    1 / 300 (0.33%)
    0 / 100 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    1 / 300 (0.33%)
    0 / 100 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Myalgia
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    1 / 102 (0.98%)
    1 / 300 (0.33%)
    0 / 100 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Back pain
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 98 (1.02%)
    0 / 102 (0.00%)
    1 / 300 (0.33%)
    1 / 100 (1.00%)
         occurrences all number
    0
    1
    0
    1
    1
    Arthritis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    1 / 300 (0.33%)
    0 / 100 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Pain in extremity
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    1 / 102 (0.98%)
    1 / 300 (0.33%)
    0 / 100 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Myositis
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    1 / 102 (0.98%)
    1 / 300 (0.33%)
    0 / 100 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    6 / 100 (6.00%)
    2 / 98 (2.04%)
    1 / 102 (0.98%)
    9 / 300 (3.00%)
    4 / 100 (4.00%)
         occurrences all number
    6
    2
    1
    9
    4
    COVID-19 pneumonia
         subjects affected / exposed
    2 / 100 (2.00%)
    2 / 98 (2.04%)
    0 / 102 (0.00%)
    4 / 300 (1.33%)
    1 / 100 (1.00%)
         occurrences all number
    2
    2
    0
    4
    1
    Bronchitis
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    1 / 102 (0.98%)
    1 / 300 (0.33%)
    1 / 100 (1.00%)
         occurrences all number
    0
    0
    1
    1
    1
    Cystitis
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 300 (0.00%)
    1 / 100 (1.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Eye infection bacterial
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 98 (1.02%)
    0 / 102 (0.00%)
    1 / 300 (0.33%)
    0 / 100 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Gastroenteritis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    1 / 300 (0.33%)
    0 / 100 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    5 / 100 (5.00%)
    1 / 98 (1.02%)
    3 / 102 (2.94%)
    9 / 300 (3.00%)
    5 / 100 (5.00%)
         occurrences all number
    5
    1
    4
    10
    5
    Genital infection fungal
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 98 (1.02%)
    0 / 102 (0.00%)
    1 / 300 (0.33%)
    0 / 100 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Otitis media
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    1 / 300 (0.33%)
    0 / 100 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Pancreatitis viral
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    1 / 102 (0.98%)
    1 / 300 (0.33%)
    0 / 100 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Oral candidiasis
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 300 (0.00%)
    1 / 100 (1.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Pyelonephritis
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 300 (0.00%)
    1 / 100 (1.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Pneumonia
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    1 / 102 (0.98%)
    1 / 300 (0.33%)
    0 / 100 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Pharyngitis bacterial
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    1 / 300 (0.33%)
    0 / 100 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Sinusitis
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 300 (0.00%)
    2 / 100 (2.00%)
         occurrences all number
    0
    0
    0
    0
    2
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 98 (1.02%)
    1 / 102 (0.98%)
    2 / 300 (0.67%)
    1 / 100 (1.00%)
         occurrences all number
    0
    1
    1
    2
    1
    Sinusitis bacterial
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    1 / 102 (0.98%)
    1 / 300 (0.33%)
    0 / 100 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 98 (0.00%)
    1 / 102 (0.98%)
    2 / 300 (0.67%)
    1 / 100 (1.00%)
         occurrences all number
    1
    0
    1
    2
    1
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 300 (0.00%)
    1 / 100 (1.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Diabetes mellitus
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 300 (0.00%)
    1 / 100 (1.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Hyperamylasaemia
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 300 (0.00%)
    1 / 100 (1.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Hyperglycaemia
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 98 (1.02%)
    0 / 102 (0.00%)
    2 / 300 (0.67%)
    0 / 100 (0.00%)
         occurrences all number
    1
    1
    0
    2
    0
    Hyperkalaemia
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    1 / 102 (0.98%)
    1 / 300 (0.33%)
    0 / 100 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Hyperlipidaemia
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 98 (1.02%)
    0 / 102 (0.00%)
    1 / 300 (0.33%)
    0 / 100 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Hypernatraemia
         subjects affected / exposed
    0 / 100 (0.00%)
    3 / 98 (3.06%)
    0 / 102 (0.00%)
    3 / 300 (1.00%)
    1 / 100 (1.00%)
         occurrences all number
    0
    3
    0
    3
    1
    Hyperlipasaemia
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 98 (0.00%)
    0 / 102 (0.00%)
    0 / 300 (0.00%)
    1 / 100 (1.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 98 (1.02%)
    0 / 102 (0.00%)
    1 / 300 (0.33%)
    1 / 100 (1.00%)
         occurrences all number
    0
    1
    0
    1
    1
    Hypokalaemia
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 98 (1.02%)
    0 / 102 (0.00%)
    1 / 300 (0.33%)
    0 / 100 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Oct 2021
    - The key changes included clarification regarding the laboratory data available at the time of the database lock (DBL), unblinding after DBL, and statistical analysis. - For the primary analysis some of the biomarker assessments may not be fully completed. In this context, updates have been made to the unblinding process after the primary analysis for Part A. - The primary estimand wording was updated to follow recently published guidelines (FDA 2021). The COVID-19 related hospitalizations were added as intercurrent events for the primary endpoint; a composite strategy was to be used to handle these intercurrent events. - The definition of adverse event of special interest was updated and was no longer limited to adverse event onset within 24 h after dosing, it included infusion-site reactions and any type of hypersensitivity reactions (Grade >= 2). The reporting requirements and follow-up testing for renal events were adjusted. - The end of study assessments were clarified per a footnote in the assessment schedule. - The study stopping rules were clarified to follow common terminology criteria for adverse events grading and to explicitly include laboratory findings. - A clarification was added to distinguish between hospitalizations due to worsening of COVID-19 (secondary endpoint) and between hospitalizations meant for isolating patients following a positive SARS-CoV-2 test (not counted towards secondary endpoint). - The requirements for viral genotyping were updated to ensure that all reverse transcription-polymerase chain reaction positive samples at Baseline and from Day 8 onwards, or last positive sample in case of no viral load from Day 8 onwards, were sequenced. - In the statistical section, clarification on the multiple comparison procedure-modeling procedure was added and the symptom scores in Long COVID-19 questionnaire were explained. - Also, 2 local amendments for the USA and for India were incorporated into this global amendment.

    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.
    The Part B of the study was not initiated based on regulatory feedback indicating that with evolving treatment options, a placebo controlled design was no longer considered to be appropriate.
    For support, Contact us.
    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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