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    Clinical Trial Results:
    A prospective, multicenter, randomized PHASE II clinical trial of enzalutamide treatment to decrease the morbidity in patients with Corona virus disease 2019 (COVID-19)

    Summary
    EudraCT number
    2020-002027-10
    Trial protocol
    SE  
    Global end of trial date
    26 May 2021

    Results information
    Results version number
    v1(current)
    This version publication date
    18 Apr 2022
    First version publication date
    18 Apr 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    COVIDENZA
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT04475601
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Norrlands universitetssjukhus
    Sponsor organisation address
    Department of surgery and perioperative science, M31 By 6M, third floor Umeå university, Umeå, Sweden, 90185
    Public contact
    Andreas Josefsson, Norrlands universitetssjukhus, +46 0703805395, andreas.josefsson@umu.se
    Scientific contact
    Andreas Josefsson, Norrlands universitetssjukhus, +46 0703805395, andreas.josefsson@umu.se
    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
    01 Nov 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 May 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    26 May 2021
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Clinical status as assessed by the 7-point ordinal scale up to 30 days after inclusion
    Protection of trial subjects
    AE were assessed, for all patients, from the time of signed informed consent until 45 days. All reported SAEs that had not been resolved by the end of the study was followed up until the event had subsided (or disappeared), the condition was stabilized, the event was otherwise explained or the study subject was lost to follow-up. Data Safety Monitoring Board (DSMB) met regularly until patients had been followed for at least 3 weeks. The DSMB was able to stop randomization for safety reasons.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    29 Jul 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
    Sweden: 42
    Worldwide total number of subjects
    42
    EEA total number of subjects
    42
    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)
    25
    From 65 to 84 years
    17
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Subject eligibility (that subjects fulfill all inclusion criteria and do not meet any exclusion criteria) was established before inclusion, treatment, or randomization. An eligibility form was used prior to randomization in the eCRF.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Intervention
    Arm description
    Enzalutamide 160 mg once daily
    Arm type
    Experimental

    Investigational medicinal product name
    Enzalutamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    160mg once daily (4x40mg tablets) for 5 days

    Arm title
    Control
    Arm description
    Standard of care
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    Intervention Control
    Started
    30
    12
    Completed
    29
    9
    Not completed
    1
    3
         Adverse event, serious fatal
    -
    1
         Consent withdrawn by subject
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    -

    Reporting group values
    Overall trial Total
    Number of subjects
    42 42
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    30 30
        From 65-84 years
    12 12
        85 years and over
    0 0
    Gender categorical
    Units: Subjects
        Female
    11 11
        Male
    31 31

    End points

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    End points reporting groups
    Reporting group title
    Intervention
    Reporting group description
    Enzalutamide 160 mg once daily

    Reporting group title
    Control
    Reporting group description
    Standard of care

    Primary: Clinical status as assessed by the 7-point ordinal scale

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    End point title
    Clinical status as assessed by the 7-point ordinal scale
    End point description
    Clinical status as assessed by the 7-point ordinal scale up to 30 days after inclusion: 1) Not hospitalized, no limitations on activities. 2) Not hospitalized, limitation on activities; 3) Hospitalized, not requiring supplemental oxygen; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 6) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 7) Death;
    End point type
    Primary
    End point timeframe
    Clinical status as assessed by the 7-point ordinal scale up to 30 days after inclusion.
    End point values
    Intervention Control
    Number of subjects analysed
    30
    12
    Units: 7 point ordinal scale
        number (not applicable)
    30
    12
    Statistical analysis title
    Intention to treat statistical analysis
    Statistical analysis description
    All randomized subjects were included in the ITT analysis set.
    Comparison groups
    Intervention v Control
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    < 0.05
    Method
    Regression, Cox
    Confidence interval
    Notes
    [1] - Clinical parameters and laboratory assessments were summarized in total and stratified for gender, center and study arm. Continuous variables were summarized using standard statistical measures, i.e. the number of observations, number of missing observations, mean, standard deviation, minimum, 1st quartile, median, 3rd quartile and maximum. Categorical variables were summarized in frequency tables.

    Secondary: Safety evaluation

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    End point title
    Safety evaluation
    End point description
    End point type
    Secondary
    End point timeframe
    45 days
    End point values
    Intervention Control
    Number of subjects analysed
    30
    12
    Units: Events
    30
    12
    No statistical analyses for this end point

    Secondary: Duration of supplemental oxygen

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    End point title
    Duration of supplemental oxygen
    End point description
    Total days of extra oxygen described as any additional oxygen given to the patient at any time during the day between 00-24.
    End point type
    Secondary
    End point timeframe
    Up to 45 days
    End point values
    Intervention Control
    Number of subjects analysed
    29
    10
    Units: Days
        median (standard deviation)
    6 ± 4.4
    1 ± 0.7
    No statistical analyses for this end point

    Secondary: Need of mechanical ventilation

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    End point title
    Need of mechanical ventilation
    End point description
    No formal analysis was performed due to too few events.
    End point type
    Secondary
    End point timeframe
    Evaluated for 30 days and after 6 months.
    End point values
    Intervention Control
    Number of subjects analysed
    30
    12
    Units: Number
    2
    1
    No statistical analyses for this end point

    Secondary: Laboratory assessment

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    End point title
    Laboratory assessment
    End point description
    The local clinical lab were used for all laboratory evaluation. Hb, LPK, B-lymphocytes, CRP, IL-6, ASAT, ALAT, ALP, Krea, D-dimer Different units and concentration were used for different parameters.
    End point type
    Secondary
    End point timeframe
    Day 0, 2, 4 and 6
    End point values
    Intervention Control
    Number of subjects analysed
    0 [2]
    0 [3]
    Units: Units per ml
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [2] - This analysis compose of many different parameters. No individual mean deviation can be reported.
    [3] - This analysis compose of many different parameters. No individual mean deviation can be reported.
    No statistical analyses for this end point

    Secondary: Virus load assessment

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    End point title
    Virus load assessment
    End point description
    PCR based SARS-CoV-2 measurement from upper respiratory tract
    End point type
    Secondary
    End point timeframe
    Day 0, 2, 4 and 6
    End point values
    Intervention Control
    Number of subjects analysed
    16 [4]
    5 [5]
    Units: Delta CT
        median (full range (min-max))
    -6 (-20 to 6)
    -1 (-8 to 4.5)
    Notes
    [4] - Day 6
    [5] - Day 6
    No statistical analyses for this end point

    Secondary: Hospital stay (days)

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    End point title
    Hospital stay (days)
    End point description
    End point type
    Secondary
    End point timeframe
    Evaluated for 45 days and after 6 months
    End point values
    Intervention Control
    Number of subjects analysed
    29
    10
    Units: Days
        median (standard deviation)
    9 ± 3
    6 ± 4.4
    No statistical analyses for this end point

    Secondary: Re-admission to hospital due to rebound COVID-19

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    End point title
    Re-admission to hospital due to rebound COVID-19
    End point description
    Any hospitalization any time during any day between 00-24 will be considered as admitted to the hospital that day. Only if the patient has been home from one day to the next it will be described as re-admission (and at least 12 hours). Any worsening symptoms considered to be a consequence from COVID-19 requiring re-hospitalization is regarded as a rebound event. Rehabilitation at hospital with stable symptoms is not regarded as a rebound event.
    End point type
    Secondary
    End point timeframe
    Evaluated for 45 days and after 6 months
    End point values
    Intervention Control
    Number of subjects analysed
    30
    12
    Units: Number
    1
    0
    No statistical analyses for this end point

    Secondary: Mortality at 6 months

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    End point title
    Mortality at 6 months
    End point description
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    Intervention Control
    Number of subjects analysed
    30
    12
    Units: Number
    0
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    45 days
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    CTCAE
    Dictionary version
    5.0
    Reporting groups
    Reporting group title
    Intervention
    Reporting group description
    Treated with Enzalutamid

    Reporting group title
    Control
    Reporting group description
    -

    Serious adverse events
    Intervention Control
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 30 (13.33%)
    2 / 12 (16.67%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    1
    Nervous system disorders
    Transient ischaemic attack
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 12 (8.33%)
         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
    Pneumomediastinum
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory disorder
    Additional description: Worsening of respiratory symptoms
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 12 (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
    Pyelonephritis
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Intervention Control
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 30 (40.00%)
    1 / 12 (8.33%)
    Investigations
    Alanine aminotransferase increased
    Additional description: Reported as increased ASAT and ALAT
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Aspartate aminotransferase increased
    Additional description: Reported as ASAT and ALAT increased
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Seizure
    Additional description: Partial epilepsia
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnea
    Additional description: Breathing difficulties
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Cough
    Additional description: Increased coughing in the evenings
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Pneumonia
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Epistaxis
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
    Additional description: Red, itching dots on leg
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Urinary incontinence
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Urinary retention
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Gout
    Additional description: Gout period
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal pain
    Additional description: Pain in wrist
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Mucosal infection
    Additional description: Mucosal infection groins
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Aug 2020
    2 more sites included
    08 Sep 2020
    Another member in the DSMB was included. -Two more sites -Clarifying the primary end-point is assessed by time to changes in clinical status including both worsening (need of mechanical ventilation) and improving (discharge from hospital) -Definition of the secondary end-point was clarified from Admission to ICU to need of mechanical ventilation. -Including the possibility to analyze virus load in naso-pharynx swabs also in the following phases of the study. -Added a inclusion criteria that the patients should not have had more than 3 days in hospital at inclusion -Exclusion criterias were modified: -Instead of previous enzalutamide and tamoxifen treatment only we broadened it to include all hormonal treatment for prostate or breast cancer. -NOAK (Non-vitamin-K antagonist anticoagulants) was allowed and Clopidogrel was included as exclusion criteria -“Unstable cardiovascular disease” was changed to “current symptoms of unstable cardiovascular disease” -Immunosuppressive medication was specified to allow any corticosteroids used for COVID-19 and up to 10mg/day equivalent dose of prednisolone prior to inclusion. -Transitory Ischemic Attack was allowed -“Previous seizure” was specified to “Epileptic seizure “ -Excluded registration of concomitant medication in the form of topical administrated treatments -Defined re-hospitalization event to include “Any worsening symptoms considered to be a consequence from COVID-19 requiring re-hospitalization is regarded as a rebound event. Rehabilitation at hospital with stable symptoms is not regarded as a rebound event” -In the section of AE there is a list of symptoms that was not mandatory to report as adverse events because they were symptoms of COVID-19 disease (e.g fever). Hospitalization due to COVID-19 - phrase deleted. The incorrect phrasing "symptoms and deaths due to COVID-19 should not be reported as SAE or SUSAR" was deleted. 2 ICF forms signed by doctor and patient separately allowed
    02 Feb 2021
    Adding one in the steering group -Adding “Pharmacokinetic interaction of enzalutamide with other drugs” as a secondary objective -Adverse events relatedness was updated to also include the definition “unlikely related” to study drug. -All blood samples at 6 months were excluded from the protocol. The scientific value of assessing laboratory parameters at 6 months in the study is no longer judged to be higher compared to the risk of reinfection with SARS-CoV-2 at the 6 months follow- up, both due the outcome of the study and the ongoing vaccination programme. All these analysis were excluded from the statistical analysis section.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    29 Nov 2020
    Recruitment stop after recommendation from Data Safety Monitoring Board.
    -

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The study was stopped early due to inferiority after safety analysis.

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/34980495
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