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    Clinical Trial Results:
    Pre-emptive tocilizumab in hypoxic COVID-19 patients, a prospective randomized trial

    Summary
    EudraCT number
    		 2020-001375-32
    Trial protocol
    		 NL  
    Global end of trial date
    19 Feb 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Oct 2022
    First version publication date
    25 Oct 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PreToVid
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    UMCG
    Sponsor organisation address
    Hanzeplein 1, Groningen, Netherlands, 9713 GZ
    Public contact
    Principal Investigator, UMCG, a.rutgers@umcg.nl
    Scientific contact
    Principal Investigator, UMCG, a.rutgers@umcg.nl
    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
    19 Feb 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Feb 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Feb 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess in a randomized comparison the effect of pre-emptive Tocilizumab in patients with hypoxia due to COVID-19 on 30-day mortality (from randomization)
    Protection of trial subjects
    There are no specific antidotes. Apheresis may be performed to dialyze tocilizumab. After treatment with tocilizumab toxicity has to be carefully examined and evaluated. During the clinical phase a daily assessment of toxicities will be performed. After discharge patients will be followed until 3 months after randomization. In the outpatient setting an assessment of toxicities will be performed. The toxicity assessment includes the following: • Complete history of symptoms and complaints • Complete physical examination • Laboratory examination of hemogram, ALT/AST, bilirubin, Creatinin, LDH; other parameters as clinically indicated • Chest X-ray when clinically indicated • Electrocardiography when indicated
    Background therapy
    		 There is no other treatment for COVID except for oxygen administration
    Evidence for comparator
    		 As high IL-6 levels are strongly associated with shorter survival in Covid-19 and IL-6 signalling can be efficiently blocked by the IL-6 inhibitor tocilizumab, we hypothesized that early (pre-emptive) intervention with tocilizumab might beneficially alter the course of Covid-19 CRS. We postulated that tocilizumab might reduce progression to hypoxemic respiratory failure and death, reduce the risk of admission to the intensive care unit (ICU) and decrease the duration of ICU and hospital stay. To this end we designed and carried out an investigator-initiated trial, the ‘Pre-emptive Tocilizumab for hospitalized Covid-19 patients’ (PreToVid) trial. This prospective randomized trial compared standard of care with or without tocilizumab in Covid-19 patients admitted to hospital and in need of oxygen supplementation.
    Actual start date of recruitment
    06 Apr 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 354
    Worldwide total number of subjects
    354
    EEA total number of subjects
    354
    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)
    153
    From 65 to 84 years
    184
    85 years and over
    17

    Subject disposition

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    Recruitment
    Recruitment details
    		 The first patient with Covid-19 in The Netherlands was diagnosed on February 27, 2020. The first patient in this trial was included on April 6, 2020, and the final patient was included on January 12, 2021. A total of 354 patients were randomized and all were included in the intention-to-treat population.

    Pre-assignment
    Screening details
    		 18 years or older, capable of providing informed consent and had confirmed SARS-CoV-2 infection. Additionally, patients were admitted to a ward and have signs compatible with hyperinflammation: need for supplemental oxygen or ferritin >2000ug/l or a doubling of serum ferritin in 20-48 hrs

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 SOC + tocilizumab
    Arm description
    		 standard of care plus tocilizumab
    Arm type
    		 Experimental

    Investigational medicinal product name
    tocilizumab
    Investigational medicinal product code
    L04AC07
    Other name
    Roactemra
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Patients in this study are treated with intravenous tociluzumab: 8 mg/kg (maximum dose 800 mg), which can be repeated at the same dose after 8 hours if the hypoxia has not improved. This is the approved dose for cytokine release syndrome.

    Arm title
    		 Standard of Care (SOC)
    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
    		SOC + tocilizumab Standard of Care (SOC)
    Started
    174
    180
    30-day mortality
    170
    177
    Completed
    170
    177
    Not completed
    4
    3
         Consent withdrawn by subject
    4
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    SOC + tocilizumab
    Reporting group description
    		 standard of care plus tocilizumab

    Reporting group title
    Standard of Care (SOC)
    Reporting group description
    		 standard of care

    Reporting group values
    		 SOC + tocilizumab Standard of Care (SOC) Total
    Number of subjects
    		 174 180 354
    Age categorical
    Units: Subjects
        18-65
    		 81 89 170
        >65
    		 93 91 184
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 67 (60 to 74) 66 (56 to 75) -
    Gender categorical
    Units: Subjects
        Female
    		 57 59 116
        Male
    		 117 121 238

    End points

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    End points reporting groups
    Reporting group title
    SOC + tocilizumab
    Reporting group description
    		 standard of care plus tocilizumab

    Reporting group title
    Standard of Care (SOC)
    Reporting group description
    		 standard of care

    Primary: 30-day survival

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    End point title
    		 30-day survival
    End point description
    End point type
    Primary
    End point timeframe
    30 days after inclusion
    End point values
    		 SOC + tocilizumab Standard of Care (SOC)
    Number of subjects analysed
    174
    180
    Units: 347
        alive at 30 days
    153
    146
        death at 30 days
    21
    34
    Statistical analysis title
    		 Primary analysis
    Statistical analysis description
    The primary analysis–the difference in 30-day mortality between the two arms–entailed Cox regression analysis with adjustment for only the stratification factor ICU-eligibility
    Comparison groups
    SOC + tocilizumab v Standard of Care (SOC)
    Number of subjects included in analysis
    354
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.1 [1]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Notes
    [1] - The 0.10 significance level was chosen because of the phase II design, in which a p-value below 0.10 would indicate that further investigation for efficacy would be warranted.

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    until 30 days after randomization
    Adverse event reporting additional description
    AEs of CTCAE grade ≥ 4 will be reported
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    5
    Reporting groups
    Reporting group title
    SOC + tocilizumab
    Reporting group description
    		 The patients in this group received standard of care with tocilizumab. AEs of CTCAE grade ≥ 4 are reported from the first study-related procedure until 30 days following the last dose of tocilizumab.

    Reporting group title
    standard of care
    Reporting group description
    		 The patients in this group received standard of care, no tocilizumab. AEs of CTCAE grade ≥ 4 are reported from the first study-related procedure until 30 days following the last dose of tocilizumab. Adverse events grade of the standard arm are reported until 30 days after randomization.

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: only SAEs are reported, reporting of non serious AEs was not requested
    Serious adverse events
    		 SOC + tocilizumab standard of care
    Total subjects affected by serious adverse events
         subjects affected / exposed
    45 / 174 (25.86%)
    53 / 180 (29.44%)
         number of deaths (all causes)
    21
    34
         number of deaths resulting from adverse events
    9
    9
    Blood and lymphatic system disorders
    thromboembolic event
    alternative assessment type: Systematic
         subjects affected / exposed
    8 / 174 (4.60%)
    4 / 180 (2.22%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sepsis
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 174 (1.15%)
    5 / 180 (2.78%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    Bacteraemia
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 174 (1.72%)
    4 / 180 (2.22%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Immune system disorders
    Worsening of disease
    Additional description: patients got to ICU or dead due to the COVID progression
    alternative assessment type: Systematic
         subjects affected / exposed
    32 / 174 (18.39%)
    40 / 180 (22.22%)
         occurrences causally related to treatment / all
    0 / 32
    0 / 40
         deaths causally related to treatment / all
    0 / 18
    0 / 28
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 SOC + tocilizumab standard of care
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 174 (0.00%)
    0 / 180 (0.00%)

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Apr 2020
    Adding 11 hospitals for participating in the study
    17 Apr 2020
    Adding another two hospital for participating in the study
    24 Apr 2020
    Adding three hospitals for participating in the study
    08 May 2020
    Adding another hospitals for participating in the study and changing a PI for one of the participating hospitals
    19 Jun 2020
    adding secondary endpoint: To asses in a randomized comparison quality of life and pulmonary function after 3 months (after randomization) (Synopsis; 6.2, 13.2) adding risk classification: Negligible (Synopsis) protocol changed for multicenter study, clarification of assessments and other text. Patient information updated for way of sampling, questionnaires and sharing SAEs with sponsor of tocilizumab.
    24 Sep 2020
    Change in second meeting DSMB adding stratification for dexamethason and remdesivir. Update of DSMB charter

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/34228774
    http://www.ncbi.nlm.nih.gov/pubmed/35960720
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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