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    Clinical Trial Results:
    A Randomized, Open-label, Standard-of-care comparative, Repositioning Clinical Trial to Evaluate the Efficacy and Safety of FDA-135 in combination with standard of care in the Treatment of Infection Caused by SARS-CoV-2, in Patients With early Stage COVID-19 Disease, in Primary Heatlh Care setting.

    Summary
    EudraCT number
    		 2021-001227-41
    Trial protocol
    		 ES  
    Global end of trial date
    28 Jul 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Dec 2022
    First version publication date
    25 Dec 2022
    Other versions
    Summary report(s)
    		 Synopsis Annex _1 _ICH_ E3

    Trial information

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    Trial identification
    Sponsor protocol code
    CSIC-FDA135-2021-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Agencia Estatal Consejo Superior de Investigaciones Científicas, M.P.
    Sponsor organisation address
    Calle Serrano, 117, Madrid, Spain, 28006
    Public contact
    Sponsor, Agencia Estatal Consejo Superior de Investigaciones Científicas, M.P., 34 918373112, ana.martinez@csic.es
    Scientific contact
    Sponsor, Agencia Estatal Consejo Superior de Investigaciones Científicas, M.P., 34 918373112, ana.martinez@csic.es
    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
    10 Aug 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Jul 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Jul 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to evaluate the efficacy of FDA-135 combined with standard of care on reducing the SARS-CoV-2 viral load.
    Protection of trial subjects
    All patients could be treated for symptoms due to SARS-CoV-2 infection as per standard of care recommendation: • In mild clinical conditions: o Acetaminophen 500 mg 1-4 times daily for control of fever and as an analgesic. o Non-steroidal anti-inflammatory drugs in the doses indicated as per their fact sheet. o Symptomatic treatment. o Adequate hydration. • In moderate clinical conditions: o Only in the case of suspected bacterial co-infection/superinfection antibiotic treatment will be introduced with: o Azithromycin 500 mg/24h oral for 3 days plus amoxicillin 1 g/12 hours for 7 days o OR Amoxicillin/Clavulanic Acid 875 mg/125 mg every 8 hours for 7 days. o Alternatively, levofloxacin 500 mg every 12 hours on the first day and 500 mg every 24 hours for 4 days [thereafter]. o Symptomatic treatment. o Adequate hydration. o BRONCHODILATORS: If required, they were preferably administered in pressurized cartridge with individual holding chamber (spacer), to avoid aerosol generation: salbutamol, 100 mcg/inhalation plus Ipratropium Bromide 20 mcg/inhalation: 2 inhalations every 4-6 hours; inhaled corticosteroids: only used in patients with bronchial asthma or COPD. o SYSTEMIC CORTICOSTEROIDS: Use in outpatients without the need for oxygen therapy is not recommended. Its use could be counterproductive in patients who do not require oxygen therapy. They were exclusively recommended at low doses in patients requiring oxygen therapy. o ANTITHROMBOTIC PROPHYLAXIS: Low molecular weight heparin at prophylactic doses for patients immobilized or with risk factors: Enoxaparin 4,000 IU (40 mg) subcutaneously once daily. If creatinine clearance is observed at 15-30 mL/min, enoxaparin 2000 IU (20 mg) could be administered subcutaneously once daily. Enoxaparin was not recommended if creatinine clearance was less than 15 mL/min. Bemiparin could be used as an alternative. In all cases, home isolation was required, according to the rules applicable at the time of study
    Background therapy
    		 Standard of care
    Evidence for comparator
    		 Standard of care
    Actual start date of recruitment
    24 Feb 2022
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 191
    Worldwide total number of subjects
    191
    EEA total number of subjects
    191
    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)
    1
    Adults (18-64 years)
    162
    From 65 to 84 years
    26
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 The first patient was included in the study on February 24, 2022. The last patient was included on June 30, 2022. The last patient last visit was completed on July 28, 2022.

    Pre-assignment
    Screening details
    		 The patients must be diagnosed of active SARS-CoV-2 infection confirmed by compatible symptoms and a positive result in the detection tests for active infection (DTAI), rapid antigen detection test or in the PCR for viral RNA detection test.

    Period 1
    Period 1 title
    Treatment and Follow-up period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Bromhexine
    Arm description
    		 Bromhexine 16 mg (10 mL) three times a day (48 mg/day) for 7 days, given before meals (breakfast, lunch, and dinner); Plus Standard of Care for SARS-CoV-2 disease.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bromhexine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Syrup
    Routes of administration
    Oral use
    Dosage and administration details
    Bromhexine 16 mg (10 mL) three times a day (48 mg/day) for 7 days

    Arm title
    		 Standard of care
    Arm description
    		 Standard of care treatment (SOC) for SARS-CoV-2 disease: acetaminophen 500 mg 1-4 times daily, non-steroidal anti-inflammatory drugs, symptomatic treatment, and hydration for mild clinical conditions. Only if suspected bacterial co-infection/superinfection should be prescribed azithromycin 500 mg/24 h oral for 3 days plus amoxicillin 1g/12 hours for 7 days, or amoxicillin/clavulanic acid 875 mg/125 mg every 8 hour for 7 days; alternatively, levofloxacin 500 mg every 12 hours on the first day and 500 mg every 24 hour for 4 days.
    Arm type
    		 Standard of care

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Bromhexine Standard of care
    Started
    98
    93
    Completed
    96
    91
    Not completed
    2
    2
         Consent withdrawn by subject
    2
    1
         Adverse event, non-fatal
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment and Follow-up period
    Reporting group description
    		 This analysis population consist of all patients included in the “all randomized patient population” who have not violated the protocol so that it may affect the assessment of the effect of the study drug on the primary endpoint, ie, without major protocol deviations. The criteria for identifying major protocol deviations were reviewed prior to the start of the analysis and unblinding of treatment and was described in the analysis plan. Two patients were excluded from the data set due to protocol deviation. The set population was 191 patients.

    Reporting group values
    		 Treatment and Follow-up period Total
    Number of subjects
    		 191 191
    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)
    		 1 1
        Adults (18-64 years)
    		 162 162
        From 65-84 years
    		 26 26
        85 years and over
    		 2 2
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 47.8 ( 1.1 ) -
    Gender categorical
    Units: Subjects
        Female
    		 127 127
        Male
    		 64 64
    SARS-CoV-2 infection severity
    Severity of SARS-CoV-2 infection at baseline
    Units: Subjects
        Asymptomatic
    		 5 5
        Mild disease
    		 179 179
        Moderate disease
    		 7 7
    SARS-CoV-2 infection before the study
    Presence or absence of previous SARS-CoV-2 infection before the one for the selection for the study
    Units: Subjects
        No
    		 154 154
        Yes
    		 37 37
    SARS-CoV-2 complete vaccination
    Units: Subjects
        No
    		 9 9
        Yes
    		 182 182
    Systolic Blood Pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    		 123 ( 1 ) -
    Diastolic Blood Pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    		 76 ( 1 ) -
    Respiratory rate
    Units: Inspirations/minute
        arithmetic mean (standard deviation)
    		 16 ( 0.1 ) -
    Oxygen saturation
    Units: Saturation %
        arithmetic mean (standard deviation)
    		 97 ( 0.1 ) -
    Heart rate
    Units: Pulses/minute
        arithmetic mean (standard deviation)
    		 79 ( 1 ) -
    Temperature
    Axillary temperature
    Units: ºC
        arithmetic mean (standard deviation)
    		 36.5 ( 0.1 ) -
    Time from previous SARS-CoV-2 infection
    Units: Months
        arithmetic mean (standard deviation)
    		 16.3 ( 1.4 ) -
    Time from last SRS-CoV-2 vaccination dose
    Units: Month
        arithmetic mean (standard deviation)
    		 5.3 ( 0.2 ) -

    End points

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    End points reporting groups
    Reporting group title
    Bromhexine
    Reporting group description
    		 Bromhexine 16 mg (10 mL) three times a day (48 mg/day) for 7 days, given before meals (breakfast, lunch, and dinner); Plus Standard of Care for SARS-CoV-2 disease.

    Reporting group title
    Standard of care
    Reporting group description
    		 Standard of care treatment (SOC) for SARS-CoV-2 disease: acetaminophen 500 mg 1-4 times daily, non-steroidal anti-inflammatory drugs, symptomatic treatment, and hydration for mild clinical conditions. Only if suspected bacterial co-infection/superinfection should be prescribed azithromycin 500 mg/24 h oral for 3 days plus amoxicillin 1g/12 hours for 7 days, or amoxicillin/clavulanic acid 875 mg/125 mg every 8 hour for 7 days; alternatively, levofloxacin 500 mg every 12 hours on the first day and 500 mg every 24 hour for 4 days.

    Primary: Change in ORF1ab viral load (Ct) Day4-Baseline

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    End point title
    		 Change in ORF1ab viral load (Ct) Day4-Baseline
    End point description
    Baseline – 4 days difference ORF1ab RT-PCR number of cycles. The viral load was estimated by the number of cycles (Cts) until detection of three specific genes of the SARS-Cov-2 pathogenic viral strain, using the TaqPath COVID-19 CE-IVD RT-PCR Kit (Thermofisher, USA), which detects three highly conserved regions of the RNA SARS-CoV-2 virus along with an internal positive control (MS2-IPC) in a single PCR reaction: genes encoding ORF1ab, N Protein, S Protein, with a sensitivity of >99% and Specificity of 99.5%. For the correct interpretation of data: an increase in the number of amplified cycles means a better result as a reduction in the viral load. So, the difference D4-D0 positive means an improvement, better as the figure is higher. If the difference D4-D0 is negative, it means a worsening.
    End point type
    Primary
    End point timeframe
    Baseline - Day 4 of treatment
    End point values
    		 Bromhexine Standard of care
    Number of subjects analysed
    98
    93
    Units: Number of RT-PCR cycles
        arithmetic mean (standard error)
    13.5 ( 2.6 )
    14.4 ( 2.8 )
    Attachments
    		 ORF1ab RT-PCR Ct Baseline-Day4
    Statistical analysis title
    		 Student t test for independent groups
    Statistical analysis description
    Student t test for independent groups
    Comparison groups
    Bromhexine v Standard of care
    Number of subjects included in analysis
    191
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.817
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.7
         upper limit
    		 8.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.8

    Primary: Change in N Protein viral load (Ct) Day4-Baseline

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    End point title
    		 Change in N Protein viral load (Ct) Day4-Baseline
    End point description
    Baseline – 4 days difference ORF1ab RT-PCR number of cycles. The viral load was estimated by the number of cycles (Cts) until detection of three specific genes of the SARS-Cov-2 pathogenic viral strain, using the TaqPath COVID-19 CE-IVD RT-PCR Kit (Thermofisher, USA), which detects three highly conserved regions of the RNA SARS-CoV-2 virus along with an internal positive control (MS2-IPC) in a single PCR reaction: genes encoding ORF1ab, N Protein, S Protein, with a sensitivity of >99% and Specificity of 99.5%. For the correct interpretation of data: an increase in the number of amplified cycles means a better result as a reduction in the viral load. So, the difference D4-D0 positive means an improvement, better as the figure is higher. If the difference D4-D0 is negative, it means a worsening.
    End point type
    Primary
    End point timeframe
    Baseline - Day 4 of treatment
    End point values
    		 Bromhexine Standard of care
    Number of subjects analysed
    98
    93
    Units: Number of RT-PCR cycles
        arithmetic mean (standard error)
    7.7 ( 1.9 )
    6.4 ( 1.8 )
    Attachments
    		 N Protein RT-PCR Ct Baseline-Day4
    Statistical analysis title
    		 Student t test for independent groups
    Comparison groups
    Bromhexine v Standard of care
    Number of subjects included in analysis
    191
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.603
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.4
         upper limit
    		 3.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.6

    Primary: Change in S Protein viral load (Ct) Day4-Baseline

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    End point title
    		 Change in S Protein viral load (Ct) Day4-Baseline
    End point description
    Baseline – 4 days difference ORF1ab RT-PCR number of cycles. The viral load was estimated by the number of cycles (Cts) until detection of three specific genes of the SARS-Cov-2 pathogenic viral strain, using the TaqPath COVID-19 CE-IVD RT-PCR Kit (Thermofisher, USA), which detects three highly conserved regions of the RNA SARS-CoV-2 virus along with an internal positive control (MS2-IPC) in a single PCR reaction: genes encoding ORF1ab, N Protein, S Protein, with a sensitivity of >99% and Specificity of 99.5%. For the correct interpretation of data: an increase in the number of amplified cycles means a better result as a reduction in the viral load. So, the difference D4-D0 positive means an improvement, better as the figure is higher. If the difference D4-D0 is negative, it means a worsening.
    End point type
    Primary
    End point timeframe
    Baseline - Day 4 of treatment
    End point values
    		 Bromhexine Standard of care
    Number of subjects analysed
    98
    93
    Units: Number of RT-PCR cycles
        arithmetic mean (standard error)
    9.7 ( 3 )
    13.8 ( 3 )
    Attachments
    		 S Protein RT-PCR Ct Baseline-Day4
    Statistical analysis title
    		 Student t test for independent groups
    Comparison groups
    Bromhexine v Standard of care
    Number of subjects included in analysis
    191
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.34
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    4.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.3
         upper limit
    		 12.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.2

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Timeframe from Day 1 to Day 28
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Bromhexine plus standard of care
    Reporting group description
    		 Bromhexine 16 mg (10 mL) three times a day (48 mg/day) for 7 days, given before meals (breakfast, lunch, and dinner); Plus Standard of Care for SARS-CoV-2 disease.

    Reporting group title
    Standard of care
    Reporting group description
    		 Standard of care treatment (SOC) for SARS-CoV-2 disease: acetaminophen 500 mg 1-4 times daily, non-steroidal anti-inflammatory drugs, symptomatic treatment, and hydration for mild clinical conditions. Only if suspected bacterial co-infection/superinfection should be prescribed azithromycin 500 mg/24 h oral for 3 days plus amoxicillin 1g/12 hours for 7 days, or amoxicillin/clavulanic acid 875 mg/125 mg every 8 hour for 7 days; alternatively, levofloxacin 500 mg every 12 hours on the first day and 500 mg every 24 hour for 4 days.

    Serious adverse events
    		 Bromhexine plus standard of care Standard of care
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 93 (1.08%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary thrombosis
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Bromhexine plus standard of care Standard of care
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 98 (8.16%)
    4 / 93 (4.30%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 98 (2.04%)
    0 / 93 (0.00%)
         occurrences all number
    2
    0
    Blood and lymphatic system disorders
    Leucocytosis
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 93 (0.00%)
         occurrences all number
    1
    0
    Transaminases increased
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 93 (0.00%)
         occurrences all number
    1
    0
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 93 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 93 (0.00%)
         occurrences all number
    1
    0
    Diarrhoea
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 93 (0.00%)
         occurrences all number
    1
    0
    Dry mouth
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 93 (0.00%)
         occurrences all number
    1
    0
    Mouth ulceration
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 93 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 93 (0.00%)
         occurrences all number
    1
    0
    Tooth abscess
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 93 (1.08%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 93 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Mononucleosis syndrome
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 93 (0.00%)
         occurrences all number
    1
    0
    Oral candidiasis
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 93 (1.08%)
         occurrences all number
    0
    1
    Sinusitis
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 93 (1.08%)
         occurrences all number
    0
    1
    Tonsillitis
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 93 (1.08%)
         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.
    None reported
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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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