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    Clinical Trial Results:
    A Phase 2 Randomized Study of the Efficacy and Safety of Acalabrutinib with Best Supportive Care Versus Best Supportive Care in Subjects Hospitalized with COVID-19

    Summary
    EudraCT number
    		 2020-001644-25
    Trial protocol
    		 FR   DE   ES   SE   IT  
    Global end of trial date
    15 Nov 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Oct 2021
    First version publication date
    29 Oct 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D822FC00001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Acerta Pharma B.V.
    Sponsor organisation address
    121 Oyster Point Blvd, South San Francisco, United States, CA 94080
    Public contact
    Clinical Trial Call Center, Acerta Pharma B.V., acertamc@dlss.com
    Scientific contact
    Clinical Trial Call Center, Acerta Pharma B.V., acertamc@dlss.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
    21 Dec 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Nov 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The overall objective of the study is to evaluate the efficacy of adding acalabrutinib to BSC for the treatment of COVID-19
    Protection of trial subjects
    N/A
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Jun 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    South Africa: 9
    Country: Number of subjects enrolled
    India: 33
    Country: Number of subjects enrolled
    Turkey: 9
    Country: Number of subjects enrolled
    Japan: 3
    Country: Number of subjects enrolled
    Russian Federation: 13
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    Brazil: 52
    Country: Number of subjects enrolled
    Argentina: 18
    Country: Number of subjects enrolled
    Peru: 18
    Country: Number of subjects enrolled
    Mexico: 15
    Country: Number of subjects enrolled
    Chile: 4
    Worldwide total number of subjects
    177
    EEA total number of subjects
    3
    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)
    121
    From 65 to 84 years
    54
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 All participants had COVID-19 pneumonia (documented radiographically) requiring hospitalization and were recruited from: South Africa; India; Turkey; Japan; Russian Federation; France; Italy; Brazil; Argentina; Peru; Mexico; Chile. The first participant was randomized on 15 June 2020 and the last participant was randomized on 17 August 2020.

    Pre-assignment
    Screening details
    		 Screening assessments were performed within the 3 days prior to randomization. Of 236 screened participants, 177 were enrolled. Of the 59 participants that were screened but not enrolled, 54 were screen failures (did not meet eligibility criteria), 1 died, 1 was withdrawn by physician decision and 3 withdrew consent.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Acalabrutinib + BSC
    Arm description
    		 Participants received acalabrutinib 100mg tablet orally twice daily for 10 days, plus best supportive care per the discretion of the Investigator and institutional guidelines.
    Arm type
    		 Experimental

    Investigational medicinal product name
    acalabrutinib
    Investigational medicinal product code
    ACP-196
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg twice daily for 10 days.

    Arm title
    		 BSC alone
    Arm description
    		 Participants received best supportive care per the discretion of the Investigator and institutional guidelines.
    Arm type
    		 Standard of care

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Acalabrutinib + BSC BSC alone
    Started
    89
    88
    Completed
    74
    77
    Not completed
    15
    11
         Adverse event, serious fatal
    8
    9
         Consent withdrawn by subject
    5
    1
         Study terminated by sponsor incorrectly entered
    2
    -
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Acalabrutinib + BSC
    Reporting group description
    		 Participants received acalabrutinib 100mg tablet orally twice daily for 10 days, plus best supportive care per the discretion of the Investigator and institutional guidelines.

    Reporting group title
    BSC alone
    Reporting group description
    		 Participants received best supportive care per the discretion of the Investigator and institutional guidelines.

    Reporting group values
    		 Acalabrutinib + BSC BSC alone Total
    Number of subjects
    		 89 88 177
    Age Categorical
    Units: Participants
        < 65 years
    		 61 60 121
        >= 65 years
    		 28 28 56
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 56.7 ( 13.3 ) 56.7 ( 14.8 ) -
    Sex: Female, Male
    Units: Participants
        MALE
    		 60 64 124
        FEMALE
    		 29 24 53
    Ethnicity (NIH/OMB)
    Units: Subjects
        HISPANIC OR LATINO
    		 48 47 95
        NOT HISPANIC OR LATINO
    		 41 41 82
        NOT REPORTED
    		 0 0 0
    Race (NIH/OMB)
    Units: Subjects
        WHITE
    		 40 48 88
        BLACK OR AFRICAN AMERICAN
    		 3 5 8
        AMERICAN INDIAN OR ALASKA NATIVE
    		 7 3 10
        ASIAN
    		 23 13 36
        NATIVE HAWAIIAN OR OTHER PACIFIC ISLANDER
    		 0 0 0
        OTHER
    		 14 19 33
        NOT REPORTED
    		 2 0 2

    End points

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    End points reporting groups
    Reporting group title
    Acalabrutinib + BSC
    Reporting group description
    		 Participants received acalabrutinib 100mg tablet orally twice daily for 10 days, plus best supportive care per the discretion of the Investigator and institutional guidelines.

    Reporting group title
    BSC alone
    Reporting group description
    		 Participants received best supportive care per the discretion of the Investigator and institutional guidelines.

    Primary: Percentage of participants alive and free of respiratory failure at Day 14

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    End point title
    		 Percentage of participants alive and free of respiratory failure at Day 14
    End point description
    Respiratory failure, is defined based on resource utilization of any of the following modalities: a) Endotracheal intubation and mechanical ventilation b) Oxygen delivered by high-flow nasal cannula (heated, humidified, oxygen delivered via reinforced nasal cannula at flow rates >20 L/min with fraction of delivered oxygen ≥0.5) c) Non-invasive positive pressure ventilation or continuous positive airway pressure d) Extracorporeal membrane oxygenation
    End point type
    Primary
    End point timeframe
    At Day 14
    End point values
    		 Acalabrutinib + BSC BSC alone
    Number of subjects analysed
    89
    88
    Units: Percentage of participants
        number (confidence interval 95%)
    83.1 (74.8 to 91.5)
    90.9 (84.3 to 97.5)
    Statistical analysis title
    		 Statistical analysis
    Statistical analysis description
    Stratified analysis of the proportion of subjects alive and free of respiratory failure at Day 28. Stratified analysis, adjusting for age (<65 vs >=65 years) and comorbidities (present vs absent).
    Comparison groups
    Acalabrutinib + BSC v BSC alone
    Number of subjects included in analysis
    177
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.121
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.48
    Confidence interval
         level
    		 95.01%
         sides
    2-sided
         lower limit
    		 0.19
         upper limit
    		 1.22

    Secondary: Number of participants with Adverse Events and Serious Adverse Events

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    End point title
    		 Number of participants with Adverse Events and Serious Adverse Events
    End point description
    Using the safety analysis set: If the participant receives at least 1 dose of acalabrutinib, they are summarized in the Acalabrutinib + BSC group. Otherwise, they are summarized in the BSC alone group. The number of participants in the BSC alone group (91) is greater than the number of participants randomized to this group (88) because three participants randomized to Acalabrutinib + BSC did not receive any acalabrutinib and therefore are included in the BSC alone group for the safety analysis set.
    End point type
    Secondary
    End point timeframe
    Screening to 28 (+3) days after last dose of acalabrutinib (for acalabrutinib + BSC participants) or to 38 (+3) days after randomization (for BSC alone participants)
    End point values
    		 Acalabrutinib + BSC BSC alone
    Number of subjects analysed
    89 [1]
    88 [2]
    Units: Participants
        Any Adverse Event
    43
    37
        Any Serious Adverse Event
    7
    2
    Notes
    [1] - Counts are out of the safety analysis set (86 subjects)
    [2] - Counts are out of the safety analysis set (91 subjects)
    No statistical analyses for this end point

    Secondary: Percentage of participants alive and free of respiratory failure at Day 28

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    End point title
    		 Percentage of participants alive and free of respiratory failure at Day 28
    End point description
    Respiratory failure, is defined based on resource utilization of any of the following modalities: a) Endotracheal intubation and mechanical ventilation b) Oxygen delivered by highflow nasal cannula (heated, humidified, oxygen delivered via reinforced nasal cannula at flow rates >20 L/min with fraction of delivered oxygen ≥0.5) c) Non-invasive positive pressure ventilation or continuous positive airway pressure d) Extracorporeal membrane oxygenation
    End point type
    Secondary
    End point timeframe
    At Day 28
    End point values
    		 Acalabrutinib + BSC BSC alone
    Number of subjects analysed
    89
    88
    Units: Percentage of participants
        number (confidence interval 95%)
    84.3 (76.1 to 92.4)
    88.6 (81.4 to 95.8)
    No statistical analyses for this end point

    Secondary: Percent change from baseline in C-reactive protein.

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    End point title
    		 Percent change from baseline in C-reactive protein.
    End point description
    Baseline is defined as the result obtained on the date of randomization. If no result was obtained on the date of randomization, the last result prior to the date of randomization is used. Percent change from baseline at Day X is calculated by multiplying the following result by 100%: (Day X value - Baseline value)/Baseline value. The mean of this result for all analyzed patients is taken to get the mean percent change from baseline.
    End point type
    Secondary
    End point timeframe
    Days 3, 5, 7, 10, 14, 28
    End point values
    		 Acalabrutinib + BSC BSC alone
    Number of subjects analysed
    89
    88
    Units: Percent change
    arithmetic mean (standard deviation)
        Day 3
    -15.06 ( 95.82 )
    -15.25 ( 91.61 )
        Day 5
    -12.48 ( 113.38 )
    -41.07 ( 92.59 )
        Day 7
    -45.71 ( 106.84 )
    -23.41 ( 223.06 )
        Day 10/ Discharge
    -16.84 ( 194.71 )
    -29.32 ( 166.35 )
        Day 10
    -35.53 ( 126.84 )
    -23.41 ( 203.02 )
        Day 14
    -12.49 ( 187.37 )
    -17.26 ( 256.87 )
        Day 28
    -30.28 ( 192.90 )
    -63.74 ( 75.28 )
    No statistical analyses for this end point

    Secondary: Percent change from baseline in ferritin

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    End point title
    		 Percent change from baseline in ferritin
    End point description
    Baseline is defined as the result obtained on the date of randomization. If no result was obtained on the date of randomization, the last result prior to the date of randomization is used. Percent change from baseline at Day X is calculated by multiplying the following result by 100%: (Day X value - Baseline value)/Baseline value. The mean of this result for all analyzed patients is taken to get the mean percent change from baseline.
    End point type
    Secondary
    End point timeframe
    Days 3, 5, 7, 10, 14, 28
    End point values
    		 Acalabrutinib + BSC BSC alone
    Number of subjects analysed
    89
    88
    Units: Percent change
    arithmetic mean (standard deviation)
        Day 3
    9.84 ( 92.66 )
    6.49 ( 40.23 )
        Day 5
    12.92 ( 105.09 )
    -12.76 ( 43.18 )
        Day 7
    -8.93 ( 53.52 )
    -8.79 ( 36.40 )
        Day 10/ Discharge
    -9.09 ( 58.85 )
    1.35 ( 125.95 )
        Day 10
    -5.99 ( 73.71 )
    6.84 ( 178.23 )
        Day 14
    -18.81 ( 67.85 )
    -26.80 ( 46.10 )
        Day 28
    -66.82 ( 18.24 )
    -66.05 ( 21.67 )
    No statistical analyses for this end point

    Secondary: Percent change from baseline in absolute lymphocyte count

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    End point title
    		 Percent change from baseline in absolute lymphocyte count
    End point description
    Baseline is defined as the result obtained on the date of randomization. If no result was obtained on the date of randomization, the last result prior to the date of randomization is used. Percent change from baseline at Day X is calculated by multiplying the following result by 100%: (Day X value - Baseline value)/Baseline value. The mean of this result for all analyzed patients is taken to get the mean percent change from baseline.
    End point type
    Secondary
    End point timeframe
    Days 3, 5, 7, 10, 14, 28
    End point values
    		 Acalabrutinib + BSC BSC alone
    Number of subjects analysed
    89
    88
    Units: Percent change
    arithmetic mean (standard deviation)
        Day 3
    31.74 ( 59.32 )
    36.82 ( 79.91 )
        Day 5
    55.79 ( 101.57 )
    87.25 ( 140.37 )
        Day 7
    51.72 ( 91.82 )
    79.33 ( 119.73 )
        Day 10/ Discharge
    78.34 ( 95.88 )
    99.65 ( 149.02 )
        Day 10
    98.55 ( 113.66 )
    83.08 ( 105.56 )
        Day 14
    74.65 ( 124.47 )
    91.58 ( 123.63 )
        Day 28
    89.35 ( 100.24 )
    96.62 ( 97.30 )
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Median overall survival, calculated using the Kaplan-Meier technique. Confidence interval for median overall survival (days) is derived based on Brookmeyer-Crowley method with log-log transformation.
    End point type
    Secondary
    End point timeframe
    From randomization until 90 days after randomization.
    End point values
    		 Acalabrutinib + BSC BSC alone
    Number of subjects analysed
    89
    88
    Units: Days
    median (confidence interval 95%)
        Median overall survival
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    No statistical analyses for this end point

    Secondary: Percentage of participants alive and discharged from ICU

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    End point title
    		 Percentage of participants alive and discharged from ICU
    End point description
    End point type
    Secondary
    End point timeframe
    At Day 14 and at Day 28
    End point values
    		 Acalabrutinib + BSC BSC alone
    Number of subjects analysed
    89
    88
    Units: Percentage of participants
    number (not applicable)
        At Day 14
    78.7
    89.8
        At Day 28
    83.1
    87.5
    No statistical analyses for this end point

    Secondary: Time from randomization to first occurrence of respiratory failure or death on study due to any cause

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    End point title
    		 Time from randomization to first occurrence of respiratory failure or death on study due to any cause
    End point description
    Median time to first occurrence of respiratory failure or death, calculated using the Kaplan-Meier technique. Confidence interval for median overall survival (days) is derived based on Brookmeyer-Crowley method with log-log transformation.
    End point type
    Secondary
    End point timeframe
    From randomization to 28 days after randomization.
    End point values
    		 Acalabrutinib + BSC BSC alone
    Number of subjects analysed
    89
    88
    Units: Days
        median (confidence interval 95%)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    Statistical analysis title
    		 Statistical analysis
    Statistical analysis description
    Stratified analysis of time to first occurrence of respiratory failure or death through Day 28
    Comparison groups
    Acalabrutinib + BSC v BSC alone
    Number of subjects included in analysis
    177
    Analysis specification
    Pre-specified
    Analysis type
    		 [3]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.758
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.323
         upper limit
    		 1.722
    Notes
    [3] - No formal hypothesis testing for this endpoint.

    Secondary: Number of days alive and free of respiratory failure

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    End point title
    		 Number of days alive and free of respiratory failure
    End point description
    Respiratory failure, is defined based on resource utilization of any of the following modalities: a) Endotracheal intubation and mechanical ventilation b) Oxygen delivered by highflow nasal cannula (heated, humidified, oxygen delivered via reinforced nasal cannula at flow rates >20 L/min with fraction of delivered oxygen ≥0.5) c) Non-invasive positive pressure ventilation or continuous positive airway pressure d) Extracorporeal membrane oxygenation
    End point type
    Secondary
    End point timeframe
    From randomization to 28 days after randomization.
    End point values
    		 Acalabrutinib + BSC BSC alone
    Number of subjects analysed
    89
    88
    Units: Days
        arithmetic mean (standard deviation)
    24.8 ( 8.0 )
    25.3 ( 7.1 )
    No statistical analyses for this end point

    Secondary: Number of days with respiratory failure

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    End point title
    		 Number of days with respiratory failure
    End point description
    Respiratory failure, is defined based on resource utilization of any of the following modalities: a) Endotracheal intubation and mechanical ventilation b) Oxygen delivered by high-flow nasal cannula (heated, humidified, oxygen delivered via reinforced nasal cannula at flow rates >20 L/min with fraction of delivered oxygen ≥0.5) c) Non-invasive positive pressure ventilation or continuous positive airway pressure d) Extracorporeal membrane oxygenation For participants who die (due to any cause) prior to Day 28, days from death to Day 28 are counted as days with respiratory failure. For participants in hospital and experiencing respiratory failure at the time they withdraw from the study, days from last known status to Day 28 are counted as days with respiratory failure.
    End point type
    Secondary
    End point timeframe
    From randomization to 28 days after randomization.
    End point values
    		 Acalabrutinib + BSC BSC alone
    Number of subjects analysed
    89
    88
    Units: Days
        arithmetic mean (standard deviation)
    3.2 ( 8.0 )
    2.7 ( 7.1 )
    No statistical analyses for this end point

    Secondary: Number of days hospitalized

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    End point title
    		 Number of days hospitalized
    End point description
    For this summary, the hospitalization must be considered clinically indicated to count as a day hospitalized. For participants who die (due to any cause) prior to Day 28, days from death to Day 28 are counted as days hospitalized. For participants in hospital at the time they withdraw from the study, days from last known status to Day 28 are counted as days hospitalized.
    End point type
    Secondary
    End point timeframe
    From randomization to 28 days after randomization.
    End point values
    		 Acalabrutinib + BSC BSC alone
    Number of subjects analysed
    89
    88
    Units: Days
        arithmetic mean (standard deviation)
    12.2 ( 8.6 )
    10.4 ( 7.4 )
    No statistical analyses for this end point

    Secondary: Number of days in ICU

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    End point title
    		 Number of days in ICU
    End point description
    For this summary, the ICU stay must be considered clinically indicated to count as a day in ICU. For participants who die (due to any cause) prior to Day 90, days from death to Day 90 are counted as days in ICU.
    End point type
    Secondary
    End point timeframe
    From randomization to 90 days after randomization.
    End point values
    		 Acalabrutinib + BSC BSC alone
    Number of subjects analysed
    89
    88
    Units: Days
        arithmetic mean (standard deviation)
    10.4 ( 25.5 )
    9.7 ( 25.8 )
    No statistical analyses for this end point

    Secondary: Number of days alive outside of hospital at Day 28

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    End point title
    		 Number of days alive outside of hospital at Day 28
    End point description
    End point type
    Secondary
    End point timeframe
    From randomization to 28 days after randomization.
    End point values
    		 Acalabrutinib + BSC BSC alone
    Number of subjects analysed
    89
    88
    Units: Days
        arithmetic mean (standard deviation)
    15.1 ( 8.4 )
    17.0 ( 7.3 )
    No statistical analyses for this end point

    Secondary: Number of days alive outside of hospital at Day 90

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    End point title
    		 Number of days alive outside of hospital at Day 90
    End point description
    End point type
    Secondary
    End point timeframe
    From randomization to 90 days after randomization.
    End point values
    		 Acalabrutinib + BSC BSC alone
    Number of subjects analysed
    89
    88
    Units: Days
        arithmetic mean (standard deviation)
    66.8 ( 28.2 )
    71.3 ( 24.5 )
    No statistical analyses for this end point

    Secondary: Percent change from baseline in oxygenation index

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    End point title
    		 Percent change from baseline in oxygenation index
    End point description
    Baseline is defined as the result obtained on the date of randomization. Percent change from baseline at Day X is calculated by multiplying the following result by 100%: (Day X value - Baseline value)/Baseline value. The mean of this result for all analyzed patients is taken to get the mean percent change from baseline.
    End point type
    Secondary
    End point timeframe
    Days 3, 5, 7, 10, 14, 28
    End point values
    		 Acalabrutinib + BSC BSC alone
    Number of subjects analysed
    89
    88
    Units: Percent change
    arithmetic mean (standard deviation)
        Day 3
    11.65 ( 29.40 )
    12.20 ( 33.88 )
        Day 5
    23.94 ( 41.72 )
    33.09 ( 51.50 )
        Day 7
    30.58 ( 57.79 )
    54.51 ( 84.75 )
        Day 10/ Discharge
    54.25 ( 71.71 )
    62.10 ( 80.79 )
        Day 10
    64.44 ( 84.02 )
    80.52 ( 101.48 )
        Day 14
    70.39 ( 77.27 )
    83.71 ( 84.96 )
        Day 28
    80.93 ( 89.61 )
    90.68 ( 95.43 )
    No statistical analyses for this end point

    Secondary: Time from randomization to clinical improvement of at least 2 points on a 9-point category ordinal scale

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    End point title
    		 Time from randomization to clinical improvement of at least 2 points on a 9-point category ordinal scale
    End point description
    9-point category ordinal scale: 0. * Uninfected, no clinical or virological evidence of infection 1. Ambulatory, no limitation of activities 2. Ambulatory, limitation of activities 3. Hospitalized – mild disease, no oxygen therapy 4. Hospitalized – mild disease, oxygen by mask or nasal prongs 5. Hospitalized – severe disease, non-invasive ventilation or high flow oxygen 6. Hospitalised – severe disease, intubation and mechanical ventilation 7. Hospitalized – severe disease, ventilation and additional organ support, such as pressors, renal replacement therapy, extracorporeal membrane oxygenation 8. Death Median time to first occurrence of respiratory failure or death, calculated using the Kaplan-Meier technique. Confidence interval for median overall survival (days) is derived based on Brookmeyer-Crowley method with log-log transformation.
    End point type
    Secondary
    End point timeframe
    From randomization to 28 days after randomization.
    End point values
    		 Acalabrutinib + BSC BSC alone
    Number of subjects analysed
    77
    83
    Units: Days
        median (confidence interval 95%)
    10.00 (8.00 to 12.00)
    10.00 (8.00 to 11.00)
    Statistical analysis title
    		 Statistical analysis
    Statistical analysis description
    Stratified analysis of time from randomization to clinical improvement of at least 2 points on a 9-point category ordinal scale. Stratified analysis, adjusting for age (<65 vs >=65 years) and comorbidities (present vs absent).
    Comparison groups
    Acalabrutinib + BSC v BSC alone
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    		 [4]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.967
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 1.353
    Notes
    [4] - No formal hypothesis testing for this endpoint.

    Secondary: Pharmacokinetics of acalabrutinib

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    End point title
    		 Pharmacokinetics of acalabrutinib [5]
    End point description
    Summary of plasma concentrations (ng/mL) of acalabrutinib
    End point type
    Secondary
    End point timeframe
    Day 3 and Day 7
    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: This objective is to assess pharmacokinetics of acalabrutinib. This end point is not applicable to BSC alone arm as this arm does not contain acalabruinib
    End point values
    		 Acalabrutinib + BSC
    Number of subjects analysed
    66
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Day 3, Pre-dose
    15.359 ( 195.1 )
        Day 3, 0.5 hours post-dose
    54.580 ( 139.7 )
        Day 3, 1 hour post-dose
    56.120 ( 141.6 )
        Day 3, 2 hours post-dose
    90.173 ( 104.3 )
        Day 3, 4 hours post-dose
    36.841 ( 179.2 )
        Day 3, 6 hours post-dose
    23.551 ( 205.0 )
        Day 7, 1 hour post-dose
    117.015 ( 60.3 )
        Day 7, 4 hours post-dose
    17.454 ( 108.6 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetics of ACP-5862

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    End point title
    		 Pharmacokinetics of ACP-5862 [6]
    End point description
    Summary of plasma concentrations (ng/mL) of ACP-5862
    End point type
    Secondary
    End point timeframe
    Day 3 and Day 7
    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: This objective is to assess pharmacokinetics of acalabrutinib. This end point is not applicable to BSC alone arm as this arm does not contain acalabruinib
    End point values
    		 Acalabrutinib + BSC
    Number of subjects analysed
    66
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Day 3, Pre-dose
    71.526 ( 94.8 )
        Day 3, 0.5 hours post-dose
    125.332 ( 109.9 )
        Day 3, 1 hour post-dose
    144.784 ( 95.1 )
        Day 3, 2 hours post-dose
    213.370 ( 72.7 )
        Day 3, 4 hours post-dose
    154.437 ( 70.3 )
        Day 3, 6 hours post-dose
    113.769 ( 82.8 )
        Day 7, 1 hour post-dose
    156.133 ( 68.0 )
        Day 7, 4 hours post-dose
    95.392 ( 69.7 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug until last study visit
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Acalabrutinib + BSC
    Reporting group description
    		 -

    Reporting group title
    BSC alone
    Reporting group description
    		 -

    Serious adverse events
    		 Acalabrutinib + BSC BSC alone
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 86 (8.14%)
    2 / 91 (2.20%)
         number of deaths (all causes)
    7
    10
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Ischaemic stroke
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pleural effusion
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 91 (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
    2 / 86 (2.33%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 91 (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
    Bacterial sepsis
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Mucosal infection
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 86 (2.33%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 86 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Acalabrutinib + BSC BSC alone
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 86 (11.63%)
    2 / 91 (2.20%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    10 / 86 (11.63%)
    2 / 91 (2.20%)
         occurrences all number
    11
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Apr 2020
    Changes were implemented to address the FDA comments.
    28 Apr 2020
    The overall rationale for the amendment was to remove Part 2 of the study based on Health Authority feedback.
    23 Jun 2020
    The overall rationale for the amendment was to address feedback from global study sites that are managing local challenges around the world during the COVID-19 pandemic.
    24 Jul 2020
    The overall rationale for the amendment was to provide clarification regarding laboratory tests for hepatitis B virus (HBV) and hepatitis C virus (HCV) during screening.

    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.
    Improvements in BSC have reduced mortality and morbidity which in turn minimizes the impact that additional treatment regimens can have on prognosis and recovery. Variability in population and BSC performance poses challenges to demonstrate benefit.
    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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