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    Clinical Trial Results:
    A Phase III Double-blind, Randomised, Parallel Group Comparison of the Efficacy and Safety of FP-1201-lyo (Recombinant Human Interferon Beta-1a) and Placebo in the Treatment of Patients with Moderate or Severe Acute Respiratory Distress Syndrome

    Summary
    EudraCT number
    		 2014-005260-15
    Trial protocol
    		 DE   FI   BE   ES   CZ  
    Global end of trial date
    23 May 2018

    Results information
    Results version number
    		 v2(current)
    This version publication date
    21 Sep 2019
    First version publication date
    29 Jun 2019
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Corrections to text.
    Summary report(s)
    		 SAE listing
    Adverse Events (Non-SAE)

    Trial information

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    Trial identification
    Sponsor protocol code
    FPCLI002 INTEREST
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02622724
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Faron Pharmaceuticals Ltd
    Sponsor organisation address
    Joukahaisenkatu 6 , Turku, Finland, 20520
    Public contact
    CMO, Faron Pharmaceuticals Ltd, matti.karvonen@faron.com
    Scientific contact
    CMO, Faron Pharmaceuticals Ltd, matti.karvonen@faron.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
    23 May 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 May 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    23 May 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to demonstrate the efficacy of FP-1201-lyo in improving the clinical course and outcomes based on survival and need for mechanical ventilation in patients with moderate or severe acute respiratory distress syndrome (ARDS).
    Protection of trial subjects
    The trial was performed in accordance with ethical principles that have their origin in the Declaration of Helsinki and are consistent with ICH/GCP and applicable regulatory requirements. The informed consent process of unconscious patients was documented and approved by Ethics committee and/or competent authorities before the trial started and patients consented themselves as soon as they were medically able. An Independent Data Monitoring Committee reviewed ongoing safety data in an unblinded manner.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Dec 2015
    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
    Spain: 22
    Country: Number of subjects enrolled
    United Kingdom: 54
    Country: Number of subjects enrolled
    Belgium: 24
    Country: Number of subjects enrolled
    Czech Republic: 2
    Country: Number of subjects enrolled
    Finland: 30
    Country: Number of subjects enrolled
    France: 112
    Country: Number of subjects enrolled
    Germany: 15
    Country: Number of subjects enrolled
    Italy: 37
    Worldwide total number of subjects
    296
    EEA total number of subjects
    296
    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)
    190
    From 65 to 84 years
    98
    85 years and over
    8

    Subject disposition

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    Recruitment
    Recruitment details
    		 The screening period started in the first country in November 2015 and enrolment was completed in all countries in December 2017. Of the 74 study sites across 8 countries in Europe that pre-screened subjects, 47 sites randomly assigned subjects to treatment. The study was early terminated at the long-term/extended follow-up period in May 2018.

    Pre-assignment
    Screening details
    		 Subjects were randomised in a 1:1 ratio to FP-1201-lyo and placebo, using ARDS severity and country as stratification parameters. A total of 363 subjects passed screening, 301 subjects fulfilled all criteria at randomization and were randomly assigned and finally, 296 subjects received treatment in the study. Five study subjects were not dosed.

    Period 1
    Period 1 title
    Overall study (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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 FP-1201-lyo
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    FP-1201-lyo
    Investigational medicinal product code
    FP-1201-lyo
    Other name
    Recombinant Human Interferon Beta-1a
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    10 microgram FP-1201-lyo / placebo was diluted in sterile water for injection and administered as an intravenous bolus injection once daily for six consecutive days.

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    10 microgram FP-1201-lyo / placebo was diluted in sterile water for injection and administered as an intravenous bolus injection once daily for six consecutive days.

    Number of subjects in period 1
    		FP-1201-lyo Placebo
    Started
    144
    152
    Completed Day 28
    105
    115
    Completed Day 90
    96
    101
    Completed Day 180
    73
    74
    Completed study (Day 360)
    51
    49
    Completed
    51
    49
    Not completed
    93
    103
         Adverse event, serious fatal
    51
    53
         Consent withdrawn by subject
    2
    3
         Lost to follow-up
    2
    4
         Early termination of the study
    38
    43

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    FP-1201-lyo
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group values
    		 FP-1201-lyo Placebo Total
    Number of subjects
    		 144 152 296
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 58.3 ± 17.20 58.4 ± 13.95 -
    Gender categorical
    Units: Subjects
        Female
    		 42 61 103
        Male
    		 102 91 193
    APACHE II, baseline
    APACHE II (Acute Physiology and Chronic Health Evaluation II) was used as an assessment of the severity of the disease and estimation of mortality of the patients admitted to the ICU.
    Units: APACHE II score
        arithmetic mean (standard deviation)
    		 21.82 ± 8.75 22.97 ± 7.67 -

    End points

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    End points reporting groups
    Reporting group title
    FP-1201-lyo
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Subject analysis set title
    All subjects
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full Analysis Set (FAS); all subjects who recieved at least 1 dose of study treatment

    Primary: Composite endpoint (VDFsurv) at Day 28

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    End point title
    		 Composite endpoint (VDFsurv) at Day 28
    End point description
    Composite endpoint include any-cause death by Day 28 and the number of days free of mechanical ventilation (VFDsurv) within 28 days among survivors. Ventilator-free days (VDFs) correspond to those days when unassisted breathing (UAB) was possible for a complete calendar day. For the initiation of the VFD count at least two consecutive calendar days of UAB were required. UAB was defined as: sponstaneously breathing with face mask, nasal prong oxygen or room air, T-piece breathing, tracheostomy mask breathing, CPAP less than or equal to 5 cmH2O without pressure support or intermittent mandatory ventilation assistance, use of CPAP or BIPAP solely for sleep apnoea management.
    End point type
    Primary
    End point timeframe
    VDFsurv is a composite measure of all-cause mortality and the number of days free of mechanical ventilation (VFD) within 28 days among survivors.
    End point values
    		 FP-1201-lyo Placebo
    Number of subjects analysed
    144
    152
    Units: days
        median (full range (min-max))
    10 (-1 to 26)
    8.5 (-1 to 26)
    Statistical analysis title
    		 Primary Efficacy Analysis VDFsurv
    Statistical analysis description
    A non-parametric analysis has been performed as the data distribution is non-normal and negatively skewed. This involved a generalised Wilcoxon rank sum-based stratification test which assigns ranks within strata and compares two treatments within strata (Van Elteren hypothesis test)
    Comparison groups
    Placebo v FP-1201-lyo
    Number of subjects included in analysis
    296
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.8219 [2]
    Method
    		 Van Elteren hypothesis test
    Parameter type
    		 Median difference (net)
    Confidence interval
    Notes
    [1] - Analysis were performed on Full Analysis Set (FAS, n=296), defined as all randomised subjects that received atleast one dose of study drug. Primary endpoint was analysed also for the Per Protocol population (PP, n=285), which consisted of subjects from FAS population but excluded subjects with major protocol deviations and subjects who received less than three doses of study drug.
    [2] - For the Per Protocol population (PP, n=285) p=0.5032 (the overall median VDFsurv was 11.0 days with FP-1201-lyo and 8.0 days with placebo)

    Secondary: Mortality (all causes)

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    End point title
    		 Mortality (all causes)
    End point description
    Full Analysis Set (FAS), defined as all randomised subjects that received atleast one dose of study drug. Mortality all-causes and mortality in ICU from randomisation up to day 28.
    End point type
    Secondary
    End point timeframe
    Mortality all-causes from randomisation up to day 28.
    End point values
    		 FP-1201-lyo Placebo
    Number of subjects analysed
    144
    152
    Units: Percentage of subjects
    number (confidence interval 95%)
        Mortality, day 28
    26.4 (19 to 34)
    23.0 (17 to 31)
        Mortality in ICU, day 28
    25.7 (19 to 34)
    23.0 (17 to 31)
    No statistical analyses for this end point

    Secondary: Days free of Mechanical Ventilation

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    End point title
    		 Days free of Mechanical Ventilation
    End point description
    The Total number of days free of Mechanical ventilation has been derived from the Patient Status report recorded on each day during the 28-day period. Patients who died during this period have been assigned a value of zero. This variable differs from the calculated Ventilation Free Days (VFD) endpoint which contributes to the VFDsurv primary efficacy endpoint as it require additional conditions of unassisted breating (UAB) to be met.
    End point type
    Secondary
    End point timeframe
    The Total number of days free of Mechanical ventilation has been derived from the Patient Status report recorded on each day during the 28-day period.
    End point values
    		 FP-1201-lyo Placebo
    Number of subjects analysed
    144
    152
    Units: Days
        median (full range (min-max))
    10 (0 to 26)
    9.0 (0 to 26)
    Statistical analysis title
    		 Days free of Mechanical Ventilation
    Statistical analysis description
    Van Elteren hypothesis test as the distribution was non-normal and negatively skewed by patients who are assigned scores of zero (0) in the event of death.
    Comparison groups
    FP-1201-lyo v Placebo
    Number of subjects included in analysis
    296
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4678
    Method
    		 Van Elteren p-values
    Confidence interval

    Secondary: Days free of Organ Failure

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    End point title
    		 Days free of Organ Failure
    End point description
    End point type
    Secondary
    End point timeframe
    The total number of days free of Organ Failure (Sequential Organ Failure Assessment, SOFA) has been derived from the Patient Status report recorded on each day during the 28-day period.
    End point values
    		 FP-1201-lyo Placebo
    Number of subjects analysed
    144
    152
    Units: Days
        median (full range (min-max))
    0 (0 to 28)
    0 (0 to 28)
    Statistical analysis title
    		 Days free of Organ Failure
    Comparison groups
    FP-1201-lyo v Placebo
    Number of subjects included in analysis
    296
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1547
    Method
    		 Van Elteren p-values
    Confidence interval

    Secondary: Days free of Renal Support

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    End point title
    		 Days free of Renal Support
    End point description
    End point type
    Secondary
    End point timeframe
    The total number of days free of Renal Support has been derived from the Patient Status report recorded on each day during the 28-day period.
    End point values
    		 FP-1201-lyo Placebo
    Number of subjects analysed
    144
    152
    Units: Days
        median (full range (min-max))
    28 (0 to 28)
    27 (0 to 28)
    Statistical analysis title
    		 Days free of Renal Support
    Comparison groups
    FP-1201-lyo v Placebo
    Number of subjects included in analysis
    296
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7243
    Method
    		 Van Elteren p-values
    Confidence interval

    Secondary: Days free of Vasoactive Support

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    End point title
    		 Days free of Vasoactive Support
    End point description
    End point type
    Secondary
    End point timeframe
    The total number of days free of vasoactive support has been derived from the Patient Status report recorded on each day during the 28-day period.
    End point values
    		 FP-1201-lyo Placebo
    Number of subjects analysed
    144
    152
    Units: Days
        median (full range (min-max))
    20 (0 to 28)
    21 (0 to 28)
    Statistical analysis title
    		 Days free of Vasoactive Support
    Comparison groups
    FP-1201-lyo v Placebo
    Number of subjects included in analysis
    296
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.939
    Method
    		 Van Elteren p-values
    Confidence interval

    Secondary: Number of ICU Care free Days

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    End point title
    		 Number of ICU Care free Days
    End point description
    End point type
    Secondary
    End point timeframe
    The total number of days free of ICU care has been derived from the Patient Status report recorded on each day during the 28-day period.
    End point values
    		 FP-1201-lyo Placebo
    Number of subjects analysed
    144
    152
    Units: Days
        median (full range (min-max))
    6 (0 to 24)
    3.50 (0 to 24)
    Statistical analysis title
    		 ICU Care-Free Days
    Comparison groups
    FP-1201-lyo v Placebo
    Number of subjects included in analysis
    296
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3392
    Method
    		 Van Elteren p-values
    Confidence interval

    Secondary: Number of days in hospital

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    End point title
    		 Number of days in hospital
    End point description
    End point type
    Secondary
    End point timeframe
    The total number of days in hospital has been derived from the Patient Status report recorded on each day during the 28-day period.
    End point values
    		 FP-1201-lyo Placebo
    Number of subjects analysed
    144
    152
    Units: Days
        median (full range (min-max))
    28 (8 to 28)
    28 (8 to 28)
    Statistical analysis title
    		 Number of days in hospital
    Comparison groups
    FP-1201-lyo v Placebo
    Number of subjects included in analysis
    296
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7029
    Method
    		 Van Elteren p-values
    Confidence interval

    Secondary: Neutralising Antibodies to IFN Beta-1a

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    End point title
    		 Neutralising Antibodies to IFN Beta-1a
    End point description
    Neutralizing antibodies can interfere with the biological and clinical response to treatment. The ADAs were determined first and if present, the NAbs were also determined. The last observation performed, whether at Day 28, upon last day in the ICU or upon early termination, was derived. Interferon beta-1a ADA (BAb) and NAb were summarised categorically (using Positive/Negative classification). As a very high proportion of the results in both treatment groups was negative, no formal statistical testing was done. The majority of subjects were not tested for IFN beta NAb; of those tested on pre-dose, 1 (0.3 %) study subject in the FP-1201-lyo group was positive, whilst no positive results were observed on the last day in ICU.
    End point type
    Secondary
    End point timeframe
    The immunological response to FP-1201-lyo was assessed through monitoring of anti-drug antibodies (ADAs) and Neutralising Antibodies to IFN beta 1a (NAbs) on pre-dose Day 1 and at Day 28, the last day in ICU or early termination, if earlier
    End point values
    		 FP-1201-lyo Placebo
    Number of subjects analysed
    144
    150
    Units: Subjects
    number (not applicable)
        Presence of IFN beta-1a BAb, pre-dose
    2
    2
        Presence of IFN beta-1a BAb, D28/last day in ICU
    0
    1
    No statistical analyses for this end point

    Secondary: Evaluation of Pharmacodynamics with MxA

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    End point title
    		 Evaluation of Pharmacodynamics with MxA
    End point description
    To evaluate the pharmacodynamics of FP-1201-lyo with Myxovirus resistance protein A (MxA), as one of the best markers for IFN beta bioactivity. This response was measured on Day 1 Pre-dose and daily thereafter until Day 14 in the ICU. The Last observation performed whether Day 14 or earlier has been derived. The change from baseline (Day 1 Pre-dose) has been calculated. The mean (adjusted) difference in blood MxA response was significantly higher (p<0.05) in the active group versus the placebo group by 23.76 (95% CI: 12.77, 34.75). There was substantial variation in individual MxA responses.
    End point type
    Secondary
    End point timeframe
    Evaluation of pharmacodynamics using MxA biomarker from baseline to Day 14
    End point values
    		 All subjects
    Number of subjects analysed
    296 [3]
    Units: ng/mL
        least squares mean (confidence interval 95%)
    23.8 (12.8 to 34.8)
    Notes
    [3] - MxA LS(adjusted) mean change PF-1201-lyo and Placebo from baseline to Last Observation Performed.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    The Adverse Event reporting period extended from signing of informed consent to Day 28. All deaths were reported as SAEs throughout the study, up until Day 360. See attachments:
    Adverse event reporting additional description
    The Adverse Event reporting period extended from signing of informed consent to Day 28. AEs occuring after Day 28 were to be reported if the investigator considered a causal relationship with the study drug. However, all deaths were reported as SAEs throughout the study, up until day 360.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21
    Frequency threshold for reporting non-serious adverse events: 0%
    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: The adverse events are reported in the attachments; FPCLI002 SAE listing contain information on all SAEs and FPCLI002 adverse events listing contain information on all non-serious events

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Oct 2015
    Defining and describing in more detail the study monitoring procedures of IDMC
    22 Oct 2015
    The substantial changes included: - addition of APACHEII scoring to access severity of disease - prolongation of reporting time for deaths as SAE to the end of study and clarification on collection of AEs. - clarifying the rigth of the investigator to make an independent decision to break the treatment code in case of an emergency - Addition of an ECG to the Six-Minute Walk Test as a safety precaution
    29 Aug 2017
    The main analysis of the study and reporting use Day 28 and Day 90 data instead of Day 180 data.

    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/29132404
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