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    Clinical Trial Results:
    A randomized, double-blind, placebo-controlled, adaptive-design study to assess the safety and efficacy of daily 200 mg fluvoxamine as add-on therapy to standard of care in moderate severity COVID-19 patients

    Summary
    EudraCT number
    		 2020-002299-11
    Trial protocol
    		 HU  
    Global end of trial date
    31 May 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Feb 2023
    First version publication date
    01 Feb 2023
    Other versions
    Summary report(s)
    		 SD-COVID19-01 - Final Report 2022-10-26 synopsis

    Trial information

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    Trial identification
    Sponsor protocol code
    SD-COVID19-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04718480
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    SigmaDrugs Research Ltd.
    Sponsor organisation address
    Attila út 117. V. em. 4., Budapest, Hungary, 1012
    Public contact
    CEO, Andrea Fekete MD PhD, SigmaDrugs Research Ltd., 0036 309472333, andrea.fekete@sigmadrugs.com
    Scientific contact
    CEO, Andrea Fekete MD PhD, SigmaDrugs Research Ltd., 0036 309472333, andrea.fekete@sigmadrugs.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
    31 May 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 May 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    31 May 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess efficacy of fluvoxamine administration in moderate SARS-CoV-2 infected patients on short term healing.
    Protection of trial subjects
    Patient Information Sheets and Informed Consent Forms were used to confirm the subjects’ informed consent to participate in the trial. After the subject has read the Information Sheet and received verbal information about the trial, participation in the study was confirmed by signing and dating the Informed Consent Form. The Investigator (according to applicable regulatory requirements), or a medically qualified person designated by the Investigator, and under the Investigator's responsibility, informed fully the subject on all pertinent aspects of the clinical study, including the written information giving approval/favorable opinion by the Regulatory Authority / Ethics Committee, as appropriate. All participants were informed to the fullest extent possible about the study, in language and terms they were able to understand. Prior to a subject’s participation in the clinical study, the written Informed Consent Form and any other local applicable documents in accordance with local laws and regulations, have been signed, the name completed and personally dated by the subject, and by the person who conducted the informed consent discussion. A copy of the signed and dated written Informed Consent Form and Information Sheet were provided to the subject. The Informed Consent Form used by the Investigator for obtaining the subject's informed consent were reviewed and approved by the Sponsor prior to submission to the Regulatory Authority / Ethics Committee, as appropriate, for approval / favorable opinion.
    Background therapy
    		 All patients received a base therapy, as per standard of care – the actual proposed therapy of moderate and severe SARS-CoV-2 infected patients according to the „Magyar Koronavírus Kézikönyv” (Hungarian Coronavirus Handbook).
    Evidence for comparator
    		 NA Placebo controlled study.
    Actual start date of recruitment
    27 Nov 2020
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 6 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Hungary: 66
    Worldwide total number of subjects
    66
    EEA total number of subjects
    66
    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)
    50
    From 65 to 84 years
    16
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Hospitalized patients with confirmed SARS-CoV-2 infection by polymerase chain reaction (PCR) or known contact of confirmed case with syndrome consistent with coronavirus disease (COVID-19) with PCR pending were enrolled to the study. (Moderate or severe cases). The recruitment took place in Hungary between November 2020 and January 2022

    Pre-assignment
    Screening details
    		 Screening period was up to 48 hours. Preferably, after diagnosing the COVID-19, treatment was to be started on the following day (D1). A total of 90 patients were screened at 6 Hungarian study centers.

    Period 1
    Period 1 title
    Treatment (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Double-blind, placebo controlled study. Placebo tablets matched active ingredients in looks and packaging.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Active
    Arm description
    		 Patients received fluvoxamin treatment in addition to standard-of-care.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fluvoxamine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The following dosing schedule will be used during the study to ensure careful dose escalation, 54 days treatment at the proposed 200 mg dose-level and tapering-off. • Day 1-2: 50 mg bedtime (2 days on this dose level) • Day 3-4: 100 mg bedtime (2 days on this dose level) • Day 5-6: 150 mg bedtime (2 days on this dose level) • Day 7-60: 2 x 100 mg (BID: morning and bedtime) (54 days on this dose level) • Day 61-65: 150 mg bedtime (5 days on this dose level) • Day 66-70: 100 mg bedtime (5 days on this dose level) • Day 71-74: 50 mg bedtime (4 days on this dose level) Whenever stop of treatment is required earlier the above tapering-off schedule should be followed if possible to reduce withdrawal symptoms. If this is not possible the patient should be closely monitored during the withdrawal period.

    Arm title
    		 Placebo
    Arm description
    		 The patients received placebo treatment matching the active arm.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    • Day 1-2: 50 mg bedtime (2 days on this dose level) • Day 3-4: 100 mg bedtime (2 days on this dose level) • Day 5-6: 150 mg bedtime (2 days on this dose level) • Day 7-60: 2 x 100 mg (BID: morning and bedtime) (54 days on this dose level) • Day 61-65: 150 mg bedtime (5 days on this dose level) • Day 66-70: 100 mg bedtime (5 days on this dose level) • Day 71-74: 50 mg bedtime (4 days on this dose level)

    Number of subjects in period 1
    		Active Placebo
    Started
    34
    32
    Completed
    23
    20
    Not completed
    11
    12
         Adverse event, serious fatal
    -
    1
         Consent withdrawn by subject
    9
    5
         Adverse event, non-fatal
    1
    3
         Lost to follow-up
    1
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Active
    Reporting group description
    		 Patients received fluvoxamin treatment in addition to standard-of-care.

    Reporting group title
    Placebo
    Reporting group description
    		 The patients received placebo treatment matching the active arm.

    Reporting group values
    		 Active Placebo Total
    Number of subjects
    		 34 32 66
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 28 22 50
        From 65-84 years
    		 6 10 16
    Age continuous
    Baseline age data
    Units: years
        arithmetic mean (standard deviation)
    		 51.3 ( 14.3 ) 55 ( 13.1 ) -
    Gender categorical
    Units: Subjects
        Female
    		 10 14 24
        Male
    		 24 18 42
    COVID19 High rik
    Patients will be stratified based on one criteria: belonging to the group at high risk for COVID-19 (comorbidities of hypertension, diabetes mellitus, chronic cardiovascular or chronic respiratory diseases) or not.
    Units: Subjects
        High-risk
    		 19 16 35
        Not high-risk
    		 15 16 31
    Somker
    Strong smokers were excluded from the study at screening
    Units: Subjects
        Smoker
    		 3 2 5
        Non-smoker
    		 31 30 61

    End points

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    End points reporting groups
    Reporting group title
    Active
    Reporting group description
    		 Patients received fluvoxamin treatment in addition to standard-of-care.

    Reporting group title
    Placebo
    Reporting group description
    		 The patients received placebo treatment matching the active arm.

    Primary: Time to achieve a score of 0-2 WHO

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    End point title
    		 Time to achieve a score of 0-2 WHO
    End point description
    Time to achieve a score of 0-2 (ambulatory state) on the WHO Ordinal Scale for Clinical Improvement This is a secondary enpoint, there were no primary endpoints specified for the trial, endpoint type was added to allow reporting.
    End point type
    Primary
    End point timeframe
    D1-D75
    End point values
    		 Active Placebo
    Number of subjects analysed
    30
    27
    Units: days
        arithmetic mean (inter-quartile range (Q1-Q3))
    10.5 (6 to 13)
    13.6 (8 to 20)
    Statistical analysis title
    		 Logrank
    Statistical analysis description
    Time to recovery (days) was assessed using Kaplan-Meyer methods. Median time to recovery in treatment groups were compared by log-rank and Wilcoxon tests. Cox regression model was applied to investigate possible significant factors influencing the time to recovery. Belonging to the high-risk group was included in the Cox regression model as independent factors. The model indicated no significant factors for the endpoint.
    Comparison groups
    Active v Placebo
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 [1]
    P-value
    		 = 0.032
    Method
    		 Logrank
    Confidence interval
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation
    Dispersion value
    0.032
    Notes
    [1] - Results of the statistical tests applied during the efficacy analysis are interpreted in a descriptive manner without formal hypothesis testing.
    Statistical analysis title
    		 Wilcoxon
    Statistical analysis description
    Time to recovery (days) was assessed using Kaplan-Meyer methods. Median time to recovery in treatment groups were compared by log-rank and Wilcoxon tests. Cox regression model was applied to investigate possible significant factors influencing the time to recovery. Belonging to the high-risk group was included in the Cox regression model as independent factors. The model indicated no significant factors for the endpoint.
    Comparison groups
    Active v Placebo
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 [2]
    P-value
    		 = 0.0352
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation
    Dispersion value
    0.0352
    Notes
    [2] - Results of the statistical tests applied during the efficacy analysis are interpreted in a descriptive manner without formal hypothesis testing.

    Secondary: Time to clinical improvement

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    End point title
    		 Time to clinical improvement
    End point description
    Time to clinical recovery after treatment, defined as days from randomization (Day 1) to ANY THREE items of the following four: 1.) resolution from fever: oral or tympanic (core body) temperature ≤ 37.5 °C, axillary, forehead or wrist (surface body) temperature ≤ 37.0 °C for at least 48 hours without antipyretics 2.) return of respiratory rate to normal (≤ 20 / min) 3.) normalization of SpO2 ( ≥95% without oxygen support ) 4.) cough remission (any reduction in cough-burden Visual Analogue Scale, compared to Day 1 baseline)
    End point type
    Secondary
    End point timeframe
    D1-D75
    End point values
    		 Active Placebo
    Number of subjects analysed
    32
    30
    Units: days
        arithmetic mean (standard deviation)
    2.1 ( 1.24 )
    2.3 ( 3.6 )
    Statistical analysis title
    		 Kaplan-Meyer method ITT
    Statistical analysis description
    Time to recovery (days) was assessed using Kaplan-Meyer methods. Median time to recovery in treatment groups were compared by log-rank and Wilcoxon tests. Time to recovery was also characterized using descriptive statistical methods including the calculation of the 95% confidence intervals.
    Comparison groups
    Active v Placebo
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.8845
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Copy of Kaplan-Meyer method
    Statistical analysis description
    Time to recovery (days) was assessed using Kaplan-Meyer methods. Median time to recovery in treatment groups were compared by log-rank and Wilcoxon tests. Time to recovery was also characterized using descriptive statistical methods including the calculation of the 95% confidence intervals.
    Comparison groups
    Active v Placebo
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.3577
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Time course of cough burden

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    End point title
    		 Time course of cough burden
    End point description
    Assessed by a cough burden visual analogue scale (VAS) completed by the patient during study visits.
    End point type
    Secondary
    End point timeframe
    D1-D75
    End point values
    		 Active Placebo
    Number of subjects analysed
    17
    17
    Units: VAS value
        arithmetic mean (inter-quartile range (Q1-Q3))
    0.2 (0 to 0.2)
    0.9 (0 to 1.3)
    Statistical analysis title
    		 Mixed linear models
    Statistical analysis description
    Variable was assessed using mixed linear models including the treatment, time, time*treatment interaction, belonging to the high-risk group as independent factors and baseline values as a covariate. The model was also re-fitted without factors that turned to be non-significant.
    Comparison groups
    Active v Placebo
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.713
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [3] - VAS values decreased during the study in both treatment groups. It must be noted that baseline VAS values were higher in the Placebo group. The mixed model indicated significant difference between treatment groups even with the baseline VAS value included in the model.

    Secondary: Time to negative COVID-19 nucleic acid results

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    End point title
    		 Time to negative COVID-19 nucleic acid results
    End point description
    PCR testing was performed at visit days and according to standard-of-care and not due to study considerations, therefore time to PCR negativity can be biased. In a few cases PCR negativity was never confirmed as it was no longer clinically indicated after the clinical signs have resolved.
    End point type
    Secondary
    End point timeframe
    D1-D75
    End point values
    		 Active Placebo
    Number of subjects analysed
    17
    20
    Units: days
        arithmetic mean (standard deviation)
    24.6 ( 23.27 )
    15.2 ( 15.89 )
    Statistical analysis title
    		 Logrank
    Statistical analysis description
    The endpoint was assessed using Kaplan-Meyer methods. Median time to negative COVID-19 nucleid acid were compared by log-rank and Wilcoxon tests. Endpoint was also characterized using descriptive statistical methods including the calculation of the 95% confidence intervals. Cox regression model was applied to investigate possible significant factors influencing the time to recovery. Belonging to the high-risk group was included in the Cox regression model as independent factor.
    Comparison groups
    Active v Placebo
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1641
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Wilcoxon
    Statistical analysis description
    The endpoint was assessed using Kaplan-Meyer methods. Median time to negative COVID-19 nucleid acid were compared by log-rank and Wilcoxon tests. Endpoint was also characterized using descriptive statistical methods including the calculation of the 95% confidence intervals. Cox regression model was applied to investigate possible significant factors influencing the time to recovery. Belonging to the high-risk group was included in the Cox regression model as independent factor.
    Comparison groups
    Active v Placebo
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 [4]
    P-value
    		 = 0.0946
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [4] - It must be noted that patients could be discharged from hospital without negative PCR result. PCR testing was performed at visit days and according to standard-of-care and not due to study considerations, therefore time to PCR negativity can be biased. In a few cases PCR negativity was never confirmed as it was no longer clinically indicated after the clinical signs have resolved.

    Secondary: Rate of patients with native chest CT recovery

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    End point title
    		 Rate of patients with native chest CT recovery
    End point description
    Rate of patients with native chest CT recovery from the acute stage of COVID-19 by Day 45 visit
    End point type
    Secondary
    End point timeframe
    D45
    End point values
    		 Active Placebo
    Number of subjects analysed
    24
    21
    Units: patients
        native chest CT recovery
    14
    12
        No native chest CT recovery
    10
    9
    Statistical analysis title
    		 Fisher’s exact test
    Statistical analysis description
    Rates were compared by two-sample chi-square tests. Number of cases and ratios by treatment groups were also calculated together with the 95% Clopper-Pearson confidence intervals.
    Comparison groups
    Active v Placebo
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Rate of patients requiring oxygen supplementation

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    End point title
    		 Rate of patients requiring oxygen supplementation
    End point description
    Rate of patients requiring oxygen supplementation. Those patients who required oxygen supplementation during the study; required oxygen supplementation at baseline already.
    End point type
    Secondary
    End point timeframe
    D1-D75
    End point values
    		 Active Placebo
    Number of subjects analysed
    34
    32
    Units: patients
        Patient requiring O2 supplementation
    30
    30
        Patient not requiring O2 supplementation
    4
    2
    Statistical analysis title
    		 Fisher’s exact test
    Statistical analysis description
    Rates were compared by two-sample chi-square tests. Number of cases and ratios by treatment groups were also calculated together with the 95% Clopper-Pearson confidence intervals.
    Comparison groups
    Active v Placebo
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.6733
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Long-term efficacy of fluvoxamine in preventing pulmonary pathology (fibrosis)

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    End point title
    		 Long-term efficacy of fluvoxamine in preventing pulmonary pathology (fibrosis)
    End point description
    Long-term efficacy of fluvoxamine in preventing pulmonary pathology (fibrosis), as monitored by native chest CT - Presence / quantification (e.g. percentage) / absence of: 1.) Reticular abnormality, 2.) Traction bronchiectasis and bronchiolectasias, 3.) Honeycombing.
    End point type
    Secondary
    End point timeframe
    6 Months
    End point values
    		 Active Placebo
    Number of subjects analysed
    25
    20
    Units: Patients
        Pulmonary fibrosis present
    6
    6
        No pulmonary fibrosis detected
    19
    14
    Statistical analysis title
    		 LTP generalized linear model
    Statistical analysis description
    Rate was analysed using generalized linear models including treatment, belonging to the high risk group as fix factors. Only presence of pulmonary fibrosis was analysed this way as for the other parameters the model did not converge.
    Comparison groups
    Active v Placebo
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.3617
    Method
    		 Generelised linear model
    Confidence interval

    Secondary: Rate of patients treated with antiviral and immunmodulant therapy or reconvalescent plasma against COVID-19 disease

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    End point title
    		 Rate of patients treated with antiviral and immunmodulant therapy or reconvalescent plasma against COVID-19 disease
    End point description
    Rate of patients treated with antiviral and immunmodulant therapy or reconvalescent plasma against COVID-19 disease
    End point type
    Secondary
    End point timeframe
    D1-D75
    End point values
    		 Active Placebo
    Number of subjects analysed
    34
    32
    Units: patients
        Antiviral therapy Yes
    30
    28
        Antiviral therapy No
    4
    4
        Immunmodulant therapy Yes
    3
    2
        Immunmodulant therapy No
    31
    30
        Reconvalescent plasma Yes
    0
    1
        Reconvalescent plasma No
    34
    31
    Statistical analysis title
    		 ITT Antiviral Fisher's test
    Statistical analysis description
    Rates was compared by two-sample chi-square tests. Number of cases and ratios by treatment groups were also calculated together with the 95% Clopper-Pearson confidence intervals. General linear models were not fitted (with logit link) as only 1 patient received reconvalescent plasma therapy, 5 patients received immunmodulant therapy and almost all (58 of 67 patients) received antiviral therapy.
    Comparison groups
    Active v Placebo
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 1
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 ITT Immunomdulant Fisher's test
    Statistical analysis description
    Rates was compared by two-sample chi-square tests. Number of cases and ratios by treatment groups were also calculated together with the 95% Clopper-Pearson confidence intervals. General linear models were not fitted (with logit link) as only 1 patient received reconvalescent plasma therapy, 5 patients received immunmodulant therapy and almost all (58 of 67 patients) received antiviral therapy.
    Comparison groups
    Active v Placebo
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 1
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 ITT Reconvlescent plasma Fisher's test
    Statistical analysis description
    Rates was compared by two-sample chi-square tests. Number of cases and ratios by treatment groups were also calculated together with the 95% Clopper-Pearson confidence intervals. General linear models were not fitted (with logit link) as only 1 patient received reconvalescent plasma therapy, 5 patients received immunmodulant therapy and almost all (58 of 67 patients) received antiviral therapy.
    Comparison groups
    Active v Placebo
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.4848
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Time to achieve a WHO score of 0-1

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    End point title
    		 Time to achieve a WHO score of 0-1
    End point description
    Time to achieve a score of 0-1 (No limitation of activities) on the WHO Ordinal Scale for Clinical Improvement
    End point type
    Secondary
    End point timeframe
    D1-D75
    End point values
    		 Active Placebo
    Number of subjects analysed
    28
    22
    Units: days
        arithmetic mean (inter-quartile range (Q1-Q3))
    18.4 (13 to 22)
    23.1 (14 to 29)
    Statistical analysis title
    		 ITT WHO<=1 Logrank
    Statistical analysis description
    Time to WHO score of 0-1 was assessed using Kaplan-Meyer methods. Median time to recovery in treatment groups were compared by log-rank and Wilcoxon tests. Time to recovery was also characterized using descriptive statistical methods including the calculation of the 95% confidence intervals. Cox regression model was applied to investigate possible significant factors influencing the time to recovery. Belonging to the high-risk group was included in the Cox regression model as independent fac
    Comparison groups
    Active v Placebo
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.066
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 ITT WHO<=1 Wilcoxon
    Statistical analysis description
    Time to WHO score of 0-1 was assessed using Kaplan-Meyer methods. Median time to recovery in treatment groups were compared by log-rank and Wilcoxon tests. Time to recovery was also characterized using descriptive statistical methods including the calculation of the 95% confidence intervals. Cox regression model was applied to investigate possible significant factors influencing the time to recovery. Belonging to the high-risk group was included in the Cox regression model as independent fac
    Comparison groups
    Active v Placebo
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0393
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Time to achieve a score of 0 WHO

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    End point title
    		 Time to achieve a score of 0 WHO
    End point description
    Time to achieve a score of 0 (Uninfected) on the WHO Ordinal Scale for Clinical Improvement
    End point type
    Secondary
    End point timeframe
    D1-D75
    End point values
    		 Active Placebo
    Number of subjects analysed
    21
    19
    Units: days
        arithmetic mean (standard deviation)
    37.4 ( 17.63 )
    44.5 ( 21.55 )
    Statistical analysis title
    		 ITT WHO=0 Logrank
    Statistical analysis description
    Time to WHO=0 was assessed using Kaplan-Meyer methods. Median time to recovery in treatment groups were compared by log-rank and Wilcoxon tests. Time to recovery was also characterized using descriptive statistical methods including the calculation of the 95% confidence intervals. Cox regression model was applied to investigate possible significant factors influencing the time to recovery. Belonging to the high-risk group was included in the Cox regression model as independent factor.
    Comparison groups
    Active v Placebo
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.577
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 ITT WHO=0 Wilcoxon
    Statistical analysis description
    Time to WHO=0 was assessed using Kaplan-Meyer methods. Median time to recovery in treatment groups were compared by log-rank and Wilcoxon tests. Time to recovery was also characterized using descriptive statistical methods including the calculation of the 95% confidence intervals. Cox regression model was applied to investigate possible significant factors influencing the time to recovery. Belonging to the high-risk group was included in the Cox regression model as independent factor.
    Comparison groups
    Active v Placebo
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.5327
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Change in the total score of PHQ-9 questionnaire from baseline

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    End point title
    		 Change in the total score of PHQ-9 questionnaire from baseline
    End point description
    Endpoint was measured by Patient Health Questionnaire (PHQ-9)
    End point type
    Secondary
    End point timeframe
    D1-D75
    End point values
    		 Active Placebo
    Number of subjects analysed
    23
    20
    Units: points
        arithmetic mean (standard deviation)
    1.1 ( 1.65 )
    0.8 ( 1.51 )
    Statistical analysis title
    		 ITT applied mixed model
    Statistical analysis description
    Change in the total score of PHQ-9 questionnaire from baseline. Visit*treatment interaction was assessed.
    Comparison groups
    Active v Placebo
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.7467
    Method
    		 Mixed models analysis
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported from screening to end-of-study visit.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25
    Reporting groups
    Reporting group title
    Active
    Reporting group description
    		 Patients received fluvoxamin treatment in addition to standard-of-care.

    Reporting group title
    Placebo
    Reporting group description
    		 The patients received placebo treatment matching the active arm.

    Serious adverse events
    		 Active Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 34 (8.82%)
    3 / 32 (9.38%)
         number of deaths (all causes)
    1
    1
         number of deaths resulting from adverse events
    1
    1
    Gastrointestinal disorders
    Ascites
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    cholecystolithiasis
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatomegaly
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumothorax
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 32 (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
    COVID-19
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 0.05%
    Non-serious adverse events
    		 Active Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    30 / 34 (88.24%)
    29 / 32 (90.63%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    4 / 34 (11.76%)
    7 / 32 (21.88%)
         occurrences all number
    4
    7
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    3 / 34 (8.82%)
    1 / 32 (3.13%)
         occurrences all number
    3
    1
    Chest pain
         subjects affected / exposed
    3 / 34 (8.82%)
    0 / 32 (0.00%)
         occurrences all number
    3
    0
    Fatigue
         subjects affected / exposed
    5 / 34 (14.71%)
    3 / 32 (9.38%)
         occurrences all number
    5
    3
    Oedema peripheral
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 32 (0.00%)
         occurrences all number
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 34 (5.88%)
    1 / 32 (3.13%)
         occurrences all number
    2
    1
    Dyspnoea
         subjects affected / exposed
    1 / 34 (2.94%)
    3 / 32 (9.38%)
         occurrences all number
    1
    3
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    3 / 34 (8.82%)
    1 / 32 (3.13%)
         occurrences all number
    3
    1
    Insomnia
         subjects affected / exposed
    4 / 34 (11.76%)
    1 / 32 (3.13%)
         occurrences all number
    4
    1
    Investigations
    Blood glucose increased
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 32 (0.00%)
         occurrences all number
    2
    0
    Electrocardiogram repolarisation abnormality
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 32 (0.00%)
         occurrences all number
    2
    0
    Injury, poisoning and procedural complications
    Overdose
         subjects affected / exposed
    1 / 34 (2.94%)
    2 / 32 (6.25%)
         occurrences all number
    1
    2
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    3 / 34 (8.82%)
    3 / 32 (9.38%)
         occurrences all number
    3
    3
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 34 (5.88%)
    2 / 32 (6.25%)
         occurrences all number
    2
    2
    Hypoaesthesia
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 32 (0.00%)
         occurrences all number
    2
    0
    Tremor
         subjects affected / exposed
    3 / 34 (8.82%)
    1 / 32 (3.13%)
         occurrences all number
    3
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 32 (0.00%)
         occurrences all number
    2
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 32 (0.00%)
         occurrences all number
    2
    0
    Gastrointestinal disorders
    Dry mouth
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    0
    2
    Hepatobiliary disorders
    Hepatomegaly
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 32 (0.00%)
         occurrences all number
    2
    0
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    2 / 34 (5.88%)
    3 / 32 (9.38%)
         occurrences all number
    2
    3
    Night sweats
         subjects affected / exposed
    2 / 34 (5.88%)
    1 / 32 (3.13%)
         occurrences all number
    2
    1
    Renal and urinary disorders
    Renal pain
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    0
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 32 (0.00%)
         occurrences all number
    2
    0
    Back pain
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    0
    2
    Infections and infestations
    COVID-19
         subjects affected / exposed
    1 / 34 (2.94%)
    4 / 32 (12.50%)
         occurrences all number
    1
    4
    Clostridium difficile infection
         subjects affected / exposed
    1 / 34 (2.94%)
    3 / 32 (9.38%)
         occurrences all number
    1
    3
    Nasopharyngitis
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 32 (0.00%)
         occurrences all number
    2
    0
    Pneumonia
         subjects affected / exposed
    1 / 34 (2.94%)
    3 / 32 (9.38%)
         occurrences all number
    1
    3
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    3 / 34 (8.82%)
    2 / 32 (6.25%)
         occurrences all number
    3
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Jan 2021
    ◦ Amended inclusion-exclusion criteria: clarification regarding mild-moderate-severe COVID disease state as per Hungarian Coronavirus Handbook ◦ Malignancy exclusion criterion limited to the past 5 years ◦ Clarification of oxygen saturation, smoking, timing of first dose, start of AE collection period, CT imaging ◦ Age range: 18-80 years ◦ Implementation of flexible visit windows at Day 7, 14 and 21 visits ◦ Rationalization of temperature measurements ◦ Reduction of mandatory hospitalization period according to current standard of care ◦ Visit details for patients quarantined at home ◦ Determination of patient compliance ◦ Instruction of concurrent administration of fluvoxamin with benzodiazepins
    02 Nov 2021
    • Protocol v 4.0 implemented adaptive changes to the study based on the interim analysis, and also streamlined study flow to be in line with standard COVID care, based on study sites feedback ◦ Amended inclusion criteria to enrol severe but not critical state patients and to exlcude patients who undervent >10 days of COVID care previously ◦ Primary endpoint was reclassified as efficacy endpoint (SEC 00) ◦ New secondary endpoint of achievement of 1 or 0 score using WHO ordinal scale ◦ Rationalization of biomarkers: extension of biomarker follow-up to Day 30 and deleting IL-8 from the determinations ◦ Setting target patient number to 100

    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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