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    Clinical Trial Results:
    To determine whether administration of almitrine bismesylate can ameliorate hypoxaemia in Covid-19 and augment effectiveness of supplementary oxygen therapy and respiratory support

    Summary
    EudraCT number
    		 2020-002567-57
    Trial protocol
    		 GB  
    Global end of trial date
    03 Mar 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Aug 2023
    First version publication date
    27 Aug 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    6.0
    Additional study identifiers
    ISRCTN number
    		 ISRCTN11713182
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Oxford / Clinical Trials and Research Governance
    Sponsor organisation address
    Joint Research Office, Boundary Brook House, Churchill Drive, Headington, Oxford, United Kingdom, OX3 7LE
    Public contact
    CTRG, University of Oxford / Clinical Trials and Research Governance, 00 000000, ctrg@admin.ox.ac.uk
    Scientific contact
    CTRG, University of Oxford / Clinical Trials and Research Governance, 00 000000, ctrg@admin.ox.ac.uk
    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
    16 Dec 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Mar 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Mar 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To determine whether administration of almitrine bismesylate can ameliorate hypoxaemia in Covid-19 and augment the effectiveness of supplemental oxygen therapy and respiratory support.
    Protection of trial subjects
    The trial was conduction in accordance with Good Clinical Practice (GCP) and with the Declaration of Helsinki, to ensure the protection of trial subjects.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Feb 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
    United Kingdom: 27
    Worldwide total number of subjects
    27
    EEA total number of subjects
    0
    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)
    17
    From 65 to 84 years
    10
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients with severe COVID-19 pneumonia were recruited from three acute hospitals in the United Kingdom.

    Pre-assignment
    Screening details
    		 Patients admitted to hospital with confirmed or suspected COVID-19 infection were first identified by their clinical teams and then approached for their interest. Screening was then performed and eligible patients/representatives were offered participation in the trial. Given the pandemic setting, no formal screening log was kept.

    Period 1
    Period 1 title
    IMP administration (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Almitrine capsules were manufactured for the trial, alongside identical placebo capsules. Packs of treatment (almitrine or placebo) were supplied with kit numbers, which were allocated by an online randomisation system (Sealed Envelope), such that both local investigators and participants remained blinded.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Almitrine
    Arm description
    		 Participants receiving almitrine (2 x 50 mg capsules initially, then 1 x 50 mg capsule 4-hourly for 7 days)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Almitrine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Nasogastric use , Oral use
    Dosage and administration details
    2 x 50 mg capsules initially, then 1 x 50 mg capsule 4-hourly for 7 days

    Arm title
    		 Placebo
    Arm description
    		 Patients receiving placebo (2 capsules initially, then 1 capsule 4-hourly for 7 days)
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo capsules
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Nasogastric use , Oral use
    Dosage and administration details
    2 capsules initially, then 1 capsule 4-hourly for 7 days

    Number of subjects in period 1
    		Almitrine Placebo
    Started
    13
    14
    Completed
    11
    13
    Not completed
    2
    1
         Consent withdrawn by subject
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Almitrine
    Reporting group description
    		 Participants receiving almitrine (2 x 50 mg capsules initially, then 1 x 50 mg capsule 4-hourly for 7 days)

    Reporting group title
    Placebo
    Reporting group description
    		 Patients receiving placebo (2 capsules initially, then 1 capsule 4-hourly for 7 days)

    Reporting group values
    		 Almitrine Placebo Total
    Number of subjects
    		 13 14 27
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.0 ± 14.4 56.4 ± 13.9 -
    Gender categorical
    Units: Subjects
        Female
    		 5 5 10
        Male
    		 8 9 17
    Diabetic
    Patients with established diagnosis of diabetes
    Units: Subjects
        Diabetes
    		 4 1 5
        No diabetes
    		 9 13 22
    Hypertension
    Patients with established diagnosis of hypertension
    Units: Subjects
        Hypertension
    		 5 5 10
        No hypertension
    		 8 9 17
    Body mass index
    Body mass index (BMI) at point of recruitment. Note that this data was not available for 3 patients (1 in the placebo group, 2 in the almitrine group).
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 34.4 ± 7.4 32.7 ± 7.6 -

    End points

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    End points reporting groups
    Reporting group title
    Almitrine
    Reporting group description
    		 Participants receiving almitrine (2 x 50 mg capsules initially, then 1 x 50 mg capsule 4-hourly for 7 days)

    Reporting group title
    Placebo
    Reporting group description
    		 Patients receiving placebo (2 capsules initially, then 1 capsule 4-hourly for 7 days)

    Subject analysis set title
    Almitrine vs. placebo
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Intention to treat analysis, based on allocation to almitrine or placebo group. Note that some participants in both group did not complete the full course of treatment, and others (two in the almitrine group and one in the placebo group) did not complete the protocol due to withdrawal of consent.

    Primary: Level of respiratory support

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    End point title
    		 Level of respiratory support
    End point description
    Change in level of respiratory support over 7 days of IMP (almitrine or placebo) administration, based on COMET initiative ordinal scale (Level 0=no respiratory support; Level 1=simple inspired oxygen therapy; Level 2=non-invasive respiratory support (including CPAP, NIV, high flow nasal oxygen); Level 3=invasive respiratory support involving intubation and mechanical ventilation; Level 4=extra corporeal membrane oxygenation (ECMO); Level 5=dead). Intention to treat analysis, based on allocation to almitrine or placebo group. Note that some participants in both group did not complete the full course of treatment, and others (two in the almitrine group and one in the placebo group) did not complete the protocol due to withdrawal of consent.
    End point type
    Primary
    End point timeframe
    Measured over 7 days of IMP (almitrine or placebo) administration
    End point values
    		 Almitrine Placebo Almitrine vs. placebo
    Number of subjects analysed
    13
    14
    27
    Units: Level of respiratory support
        number (not applicable)
    0
    0
    0.86
    Statistical analysis title
    		 Ordinal logistic regression model
    Statistical analysis description
    An ordinal logistic regression model incorporating all available data was used to provide the odds of being at a higher (worse) respiratory support level in the almitrine group, compared with the placebo group. The outcome was an odds ratio of 0.86 (0.23, 3.12), i.e. the odds of being in a higher support level are slightly lower for the intervention group compared with the placebo group, but this difference was not statistically significant (p=0.8204).
    Comparison groups
    Almitrine v Placebo
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.8204
    Method
    		 Regression, Logistic
    Confidence interval
    Notes
    [1] - As above.

    Secondary: 30 day survival

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    End point title
    		 30 day survival
    End point description
    Number of patients alive or dead at 30 days. This data was not available for 3 patients, who withdrew consent for follow up (2 in the almitrine group, 1 in the placebo group. For the remaining patient, the number who died by 30 days was 7/11 in the almitrine group and 6/13 in the placebo group. There was no statical difference between groups (P=0.551).
    End point type
    Secondary
    End point timeframe
    Survival at 30 days
    End point values
    		 Almitrine Placebo
    Number of subjects analysed
    11
    13
    Units: Number of patients
        Alive
    4
    7
        Dead
    7
    6
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The window for adverse event reporting was from the first dose of IMP (almitrine/placebo) until 48 h after the final dose of IMP.
    Adverse event reporting additional description
    Due to the pandemic setting and the high rate of adverse events in severe COVID-19 infection, only Serious Adverse Reactions were recorded/reported, as specified in the protocol. No SARs occurred. Other adverse events were not routinely recorded, but blood alanine transaminase (ALT) and lactate levels were measured daily during IMP administration.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26
    Reporting groups
    Reporting group title
    Almitrine
    Reporting group description
    		 Participants receiving almitrine (2 x 50 mg capsules initially, then 1 x 50 mg capsule 4-hourly for 7 days). Due to the pandemic setting and the high rate of adverse events in severe COVID-19 infection, only Serious Adverse Reactions were recorded/reported, as specified in the protocol. No SARs occurred. Other adverse events were not routinely recorded, but blood alanine transaminase (ALT) and lactate levels were measured daily during IMP administration, so where these values became abnormal, this is listed below as an adverse event. The total number of deaths listed below relates to deaths within the adverse event reporting window (excluding those who withdrew consent for further data collection).

    Reporting group title
    Placebo
    Reporting group description
    		 Patients receiving placebo (2 capsules initially, then 1 capsule 4-hourly for 7 days). Due to the pandemic setting and the high rate of adverse events in severe COVID-19 infection, only Serious Adverse Reactions were recorded/reported, as specified in the protocol. No SARs occurred. Other adverse events were not routinely recorded, but blood alanine transaminase (ALT) and lactate levels were measured daily during IMP administration, so where these values became abnormal, this is listed below as an adverse event. The total number of deaths listed below relates to deaths within the adverse event reporting window (excluding those who withdrew consent for further data collection).

    Serious adverse events
    		 Almitrine Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 14 (0.00%)
         number of deaths (all causes)
    3
    2
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Almitrine Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 13 (15.38%)
    5 / 14 (35.71%)
    Gastrointestinal disorders
    Deranged alanine transaminase
    Additional description: Deranged alanine transaminase (ALT), defined as ALT more than three times the upper limit of normal. The ALT become deranged in 6 participants during the period of IMP administration, including 2 in the almitrine group and 4 in the placebo group
         subjects affected / exposed
    2 / 13 (15.38%)
    4 / 14 (28.57%)
         occurrences all number
    2
    4
    Metabolism and nutrition disorders
    Elevated blood lactate
    Additional description: Elevated blood lactate, defined as a value above 4 mmol/L. The lactate became abnormal in 1 participant during the period of IMP administration, who was in the placebo group.
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 14 (7.14%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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 study was terminated early, before meeting the planned recruitment target. The primary reason was the lack of eligible participants, due to the reduction in case numbers and reduced severity of disease. The study therefore lacks power.
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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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