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    Clinical Trial Results:
    A Phase 2a Randomised, Double-Blind, Placebo-Controlled Repeat Dose Trial of the Activity of MDT-637 in Healthy Subjects Challenged with RSV-A (Memphis 37b)

    Summary
    EudraCT number
    		 2012-001107-20
    Trial protocol
    		 GB  
    Global end of trial date
    09 Apr 2014

    Results information
    Results version number
    		 v2(current)
    This version publication date
    23 Jul 2016
    First version publication date
    06 Aug 2015
    Other versions
    		 v1 (removed from public view)
    Version creation reason
    • Correction of full data set
    QC'd

    Trial information

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    Trial identification
    Sponsor protocol code
    MDT-637-CP-201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Teva: MCD-CS-001
    Sponsors
    Sponsor organisation name
    Teva Branded Pharmaceutical Products, R&D Inc
    Sponsor organisation address
    41 Moores Road, Frazer, PA, United States, 19355
    Public contact
    Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc, +1 215-591-3000, ustevatrials@tevapharm.com
    Scientific contact
    Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc, +1 215-591-3000, ustevatrials@tevapharm.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 Mar 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Apr 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary efficacy objective and endpoint of the study is to evaluate the antiviral effect (as defined by reduction in AUC of viral load) of aerosolized MDT-637, in a manner which mimics the timing of the infection and potential treatment application in infants and children.
    Protection of trial subjects
    This study was conducted in full accordance with the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Consolidated Guideline (E6), and any applicable national and local laws and regulations (eg, Code of Federal Regulations Title 21, Parts 50, 54, 56, 312, and 314; European Union (EU) Directive 2001/20/EC on the approximation of the laws, regulations, and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical studies on medicinal products for human use). Information regarding any investigational study centers participating in this study that could not comply with these standards was documented. Each investigator was responsible for performing the study in accordance with the protocol, ICH guidelines, and GCP, and for collecting, recording, and reporting the data accurately and properly. Agreement of each investigator to conduct and administer this study in accordance with the protocol was documented in separate study agreements with the sponsor and other forms as required by national authorities in the country where the study center is located. Written and/or oral information about the study was provided to all subjects in a language understandable by the subjects. The information included an adequate explanation of the aims, methods, anticipated benefits, potential hazards, and insurance arrangements in force. Written informed consent was obtained from each subject before any study procedures or assessments were done. It was explained to the subjects that they were free to refuse entry into the study and were free to withdraw from the study at any time without prejudice to future treatment. Each subject’s willingness to participate was documented in writing in a consent form that was signed by the subject with the date of that signature indicated. Each investigator kept the original consent forms, and copies were given to the subjects.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Oct 2013
    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
    United Kingdom: 143
    Worldwide total number of subjects
    143
    EEA total number of subjects
    143
    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)
    143
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 144 healthy volunteers were screened, enrolled, entered quarantine and were inoculated. One subject withdrew after inoculation but before treatment for personal reasons. This subject was not included in listings, summary tables, or analyses because subjects had to be both inoculated and treated for inclusion in any of the analysis populations.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Subject
    Blinding implementation details
    Subjects and investigators remained blinded to the treatment assigned during the study, as did the sponsor’s clinical personnel who were blinded until the database was locked for analysis and the treatment assignment revealed. The randomization code list was computer generated according to a randomization specification, using a permuted block algorithm and including stratification by quarantine. Subjects were randomly assigned to treatment through pre-packing of the study drug.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 MDT-637 BD
    Arm description
    		 MDT-637 administered twice a day (BD) via dry-powder, aerosol inhaler at a dose of approximately 132 mcg with daily administration at 0800 and 2000 hours. Placebo administered via the same dry-powder aerosol inhaler at 1400 hours. Dosing commenced on Days 2, 3, 4 or 5, post-inoculum dependent on a positive non-qPCR nasal wash result for the presence of the challenge virus. The total dose was up to 21 consecutive doses (14 active, 7 placebo) dispensed over 7 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MDT-637
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    MDT-637 was administered in aerosolized form via a proprietary, hand-held device: an MDT-637 EP1C Inhaler. Subjects breathed through a commercially available facemask that was attached to the device. Each dose of MDT-637 was 132 mcg (ex-face mask). Study drug (active or placebo) was administered by passive/tidal inhalation, delivered in approximately 2 minutes and approximately 32 tidal breaths. All doses were administered within the Quarantine Unit.

    Arm title
    		 MDT-637 TDS
    Arm description
    		 MDT-637 administered three times a day (TDS) via dry-powder, aerosol inhaler at a dose of approximately 132 mcg with daily administration at 0800, 1400 and 2000 hours. Dosing commenced on Days 2, 3, 4 or 5, post-inoculum dependent on a positive non-qPCR nasal wash result for the presence of the challenge virus. The total dose was up to 21 consecutive doses dispensed over 7 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MDT-637
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    MDT-637 was administered in aerosolized form via a proprietary, hand-held device: an MDT-637 EP1C Inhaler. Subjects breathed through a commercially available facemask that was attached to the device. Each dose of MDT-637 was 132 mcg (ex-face mask). Study drug (active or placebo) was administered by passive/tidal inhalation, delivered in approximately 2 minutes and approximately 32 tidal breaths. All doses were administered within the Quarantine Unit.

    Arm title
    		 Placebo
    Arm description
    		 Inhalation grade lactose administered three times a day via dry-powder, aerosol inhaler at 0800, 1400 and 2000 hours. Placebo Dosing commenced on Days 2, 3, 4 or 5, post-inoculum dependent on a positive non-qPCR nasal wash result for the presence of the challenge virus. The total dose was up to 21 consecutive doses dispensed over 7 days.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Inhalation grade lactose
    Investigational medicinal product code
    Other name
    placebo
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Placebo was administered in aerosolized form via a proprietary, hand-held device: an MDT-637 EP1C Inhaler. Subjects breathed through a commercially available facemask that was attached to the device. Study drug (active or placebo) was administered by passive/tidal inhalation, delivered in approximately 2 minutes and approximately 32 tidal breaths. All doses were administered within the Quarantine Unit.

    Number of subjects in period 1
    		MDT-637 BD MDT-637 TDS Placebo
    Started
    48
    48
    47
    Completed
    48
    48
    47

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    MDT-637 BD
    Reporting group description
    		 MDT-637 administered twice a day (BD) via dry-powder, aerosol inhaler at a dose of approximately 132 mcg with daily administration at 0800 and 2000 hours. Placebo administered via the same dry-powder aerosol inhaler at 1400 hours. Dosing commenced on Days 2, 3, 4 or 5, post-inoculum dependent on a positive non-qPCR nasal wash result for the presence of the challenge virus. The total dose was up to 21 consecutive doses (14 active, 7 placebo) dispensed over 7 days.

    Reporting group title
    MDT-637 TDS
    Reporting group description
    		 MDT-637 administered three times a day (TDS) via dry-powder, aerosol inhaler at a dose of approximately 132 mcg with daily administration at 0800, 1400 and 2000 hours. Dosing commenced on Days 2, 3, 4 or 5, post-inoculum dependent on a positive non-qPCR nasal wash result for the presence of the challenge virus. The total dose was up to 21 consecutive doses dispensed over 7 days.

    Reporting group title
    Placebo
    Reporting group description
    		 Inhalation grade lactose administered three times a day via dry-powder, aerosol inhaler at 0800, 1400 and 2000 hours. Placebo Dosing commenced on Days 2, 3, 4 or 5, post-inoculum dependent on a positive non-qPCR nasal wash result for the presence of the challenge virus. The total dose was up to 21 consecutive doses dispensed over 7 days.

    Reporting group values
    		 MDT-637 BD MDT-637 TDS Placebo Total
    Number of subjects
    		 48 48 47 143
    Age categorical
    Units: Subjects
        Ages 18 - 44
    		 48 48 47 143
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 24 ± 4.62 25.5 ± 5.8 24.5 ± 5.47 -
    Gender categorical
    Units: Subjects
        Female
    		 17 13 11 41
        Male
    		 31 35 36 102
    Ethnicity
    Units: Subjects
        White
    		 39 46 42 127
        Black or African American
    		 3 1 2 6
        Asian
    		 4 1 1 6
        Other or mixed
    		 2 0 2 4
    Nasal wash procedure tolerated at pre-challenge baseline
    Units: Subjects
        Yes
    		 48 48 46 142
        No
    		 0 0 1 1
    History of smoking
    Units: Subjects
        Never smoked
    		 29 28 21 78
        Previous smoker
    		 14 8 9 31
        Current smoker
    		 5 12 17 34
    Alcohol use history
    Units: Subjects
        Never
    		 3 3 4 10
        Previous user
    		 1 1 1 3
        Current user
    		 44 44 42 130
    Any known allergies?
    Units: Subjects
        Yes
    		 12 8 10 30
        Not recorded
    		 1 1 0 2
        No
    		 35 39 37 111
    Height
    Units: cm
        arithmetic mean (standard deviation)
    		 174.75 ± 8.046 175.64 ± 8.922 178.43 ± 8.658 -
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 71.77 ± 10.05 72.01 ± 9.471 75.41 ± 11.87 -
    Body mass index (BMI)
    Units: kg/m^2
        arithmetic mean (standard deviation)
    		 23.5 ± 2.55 23.3 ± 2.14 23.6 ± 2.76 -

    End points

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    End points reporting groups
    Reporting group title
    MDT-637 BD
    Reporting group description
    		 MDT-637 administered twice a day (BD) via dry-powder, aerosol inhaler at a dose of approximately 132 mcg with daily administration at 0800 and 2000 hours. Placebo administered via the same dry-powder aerosol inhaler at 1400 hours. Dosing commenced on Days 2, 3, 4 or 5, post-inoculum dependent on a positive non-qPCR nasal wash result for the presence of the challenge virus. The total dose was up to 21 consecutive doses (14 active, 7 placebo) dispensed over 7 days.

    Reporting group title
    MDT-637 TDS
    Reporting group description
    		 MDT-637 administered three times a day (TDS) via dry-powder, aerosol inhaler at a dose of approximately 132 mcg with daily administration at 0800, 1400 and 2000 hours. Dosing commenced on Days 2, 3, 4 or 5, post-inoculum dependent on a positive non-qPCR nasal wash result for the presence of the challenge virus. The total dose was up to 21 consecutive doses dispensed over 7 days.

    Reporting group title
    Placebo
    Reporting group description
    		 Inhalation grade lactose administered three times a day via dry-powder, aerosol inhaler at 0800, 1400 and 2000 hours. Placebo Dosing commenced on Days 2, 3, 4 or 5, post-inoculum dependent on a positive non-qPCR nasal wash result for the presence of the challenge virus. The total dose was up to 21 consecutive doses dispensed over 7 days.

    Subject analysis set title
    ITT-I MDT-637 BD
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects who were randomized to the MDT-637 BD treatment arm and met the criteria for the Intent-to-Treat Infected (ITT-I) population. The Intent-to-Treat Infected population by non-quantitative polymerase chain reaction (non-qPCR) method (ITT-I) was defined as all randomized subjects who received study drug, received challenge virus RSV-A, and provided at least one post-baseline positive non-qPCR result through day 5 post challenge virus administration. It was the primary population for efficacy analysis.

    Subject analysis set title
    ITT-I MDT-637 TDS
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects who were randomized to the MDT-637 TDS treatment arm and met the criteria for the Intent-to-Treat Infected (ITT-I) population. The Intent-to-Treat Infected population by non-quantitative polymerase chain reaction (non-qPCR) method (ITT-I) was defined as all randomized subjects who received study drug, received challenge virus RSV-A, and provided at least one post-baseline positive non-qPCR result through day 5 post challenge virus administration. It was the primary population for efficacy analysis.

    Subject analysis set title
    ITT-I Placebo
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects who were randomized to the Placebo treatment arm and met the criteria for the Intent-to-Treat Infected (ITT-I) population. The Intent-to-Treat Infected population by non-quantitative polymerase chain reaction (non-qPCR) method (ITT-I) was defined as all randomized subjects who received study drug, received challenge virus RSV-A, and provided at least one post-baseline positive non-qPCR result through day 5 post challenge virus administration. It was the primary population for efficacy analysis.

    Subject analysis set title
    PK MDT-637 BD
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The pharmacokinetic population consisted of all ITT-I or ITT-I-qPCR subjects who had sufficient data to calculate the pharmacokinetic parameters.

    Subject analysis set title
    PK MDT-637 TDS
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The pharmacokinetic population consisted of all ITT-I or ITT-I-qPCR subjects who had sufficient data to calculate the pharmacokinetic parameters.

    Subject analysis set title
    PK Placebo
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The pharmacokinetic population consisted of all ITT-I or ITT-I-qPCR subjects who had sufficient data to calculate the pharmacokinetic parameters.

    Primary: Area Under the Curve of Viral Load from Day 2 to Day 12 Post Challenge

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    End point title
    		 Area Under the Curve of Viral Load from Day 2 to Day 12 Post Challenge
    End point description
    Subjects were challenged with RSV-A inoculum on day 0. Viral load was measured by non-quantitative polymerase chain reaction (non-qPCR) on nasal wash which was performed twice daily. AUC of viral load was calculated by a linear trapezoidal summation method using actual sampling times in the calculations. PFU = plaque-forming units.
    End point type
    Primary
    End point timeframe
    Day 2 to the last day of discharge from quarantine (usually Day 12)
    End point values
    		 ITT-I MDT-637 BD ITT-I MDT-637 TDS ITT-I Placebo
    Number of subjects analysed
    32
    31
    35
    Units: Log10 PFU/mL-days
        arithmetic mean (confidence interval 95%)
    33.95 (29.718 to 38.182)
    30.62 (25.161 to 36.079)
    29.175 (24.299 to 34.051)
    Statistical analysis title
    		 AUC of Viral Load: MDT-637 TDS to Placebo
    Statistical analysis description
    Since there were 3 pairwise comparisons for the primary endpoint, a fixed-sequence testing procedure was used in the following order: 1. MDT-637 TDS vs. placebo 2. MDT-637 BD vs. placebo 3. MDT-637 TDS vs. MDT-637 BD
    Comparison groups
    ITT-I Placebo v ITT-I MDT-637 TDS
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6692 [1]
    Method
    		 ANOVA
    Parameter type
    		 Difference of LSM
    Point estimate
    1.445
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.25
         upper limit
    		 8.141
    Notes
    [1] - Single fixed effect of treatment. Comparison was performed at the 0.05 significance level.
    Statistical analysis title
    		 AUC of Viral Load: MDT-637 BD to Placebo
    Statistical analysis description
    Since there were 3 pairwise comparisons for the primary endpoint, a fixed-sequence testing procedure was used in the following order: 1. MDT-637 TDS vs. placebo 2. MDT-637 BD vs. placebo 3. MDT-637 TDS vs. MDT-637 BD
    Comparison groups
    ITT-I Placebo v ITT-I MDT-637 BD
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1566 [2]
    Method
    		 ANOVA
    Parameter type
    		 Difference of LSM
    Point estimate
    4.775
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.865
         upper limit
    		 11.416
    Notes
    [2] - Single fixed effect of treatment. Comparison was performed at the 0.05 significance level.
    Statistical analysis title
    		 AUC of Viral Load: MDT-637 TDA to MDT-637-BD
    Statistical analysis description
    Since there were 3 pairwise comparisons for the primary endpoint, a fixed-sequence testing procedure was used in the following order: 1. MDT-637 TDS vs. placebo 2. MDT-637 BD vs. placebo 3. MDT-637 TDS vs. MDT-637 BD
    Comparison groups
    ITT-I MDT-637 BD v ITT-I MDT-637 TDS
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3364 [3]
    Method
    		 ANOVA
    Parameter type
    		 Difference of LSM
    Point estimate
    -3.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.172
         upper limit
    		 3.512
    Notes
    [3] - Single fixed effect of treatment. Comparison was performed at the 0.05 significance level.

    Secondary: Duration of Viral Shedding by Tissue Culture

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    End point title
    		 Duration of Viral Shedding by Tissue Culture
    End point description
    Duration of virus shedding was calculated as the number of days elapsed from the date of first detection of RSV-A to the date when virus first became undetectable.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 12
    End point values
    		 ITT-I MDT-637 BD ITT-I MDT-637 TDS ITT-I Placebo
    Number of subjects analysed
    29
    28
    32
    Units: days
        arithmetic mean (standard deviation)
    5.4 ± 2.16
    4.8 ± 1.91
    5.5 ± 1.92
    Statistical analysis title
    		 Duration Viral Shedding: MDT-637 TDS to Placebo
    Statistical analysis description
    Duration of Viral Shedding by Tissue Culture
    Comparison groups
    ITT-I MDT-637 TDS v ITT-I Placebo
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2139 [4]
    Method
    		 ANOVA
    Parameter type
    		 Difference of LSM
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.7
         upper limit
    		 0.4
    Notes
    [4] - Comparison was performed at the 0.05 significance level.
    Statistical analysis title
    		 Duration Viral Shedding: MDT-637 BD to Placebo
    Statistical analysis description
    Duration of Viral Shedding by Tissue Culture
    Comparison groups
    ITT-I Placebo v ITT-I MDT-637 BD
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9682 [5]
    Method
    		 ANOVA
    Parameter type
    		 Difference of LSM
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1
         upper limit
    		 1
    Notes
    [5] - Comparison was performed at the 0.05 significance level.
    Statistical analysis title
    		 Duration Viral Shedding: MDT-637 TDS - MDT-637-BD
    Statistical analysis description
    Duration of Viral Shedding by Tissue Culture
    Comparison groups
    ITT-I MDT-637 BD v ITT-I MDT-637 TDS
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2396 [6]
    Method
    		 ANOVA
    Parameter type
    		 Difference of LSM
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.7
         upper limit
    		 0.4
    Notes
    [6] - Comparison was performed at the 0.05 significance level.

    Secondary: Peak Virus Shedding By Tissue Culture

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    End point title
    		 Peak Virus Shedding By Tissue Culture
    End point description
    Peak virus shedding was calculated as maximum viral load assessment.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 12
    End point values
    		 ITT-I MDT-637 BD ITT-I MDT-637 TDS ITT-I Placebo
    Number of subjects analysed
    29
    28
    32
    Units: log10PFU/mL
        arithmetic mean (standard deviation)
    4.43 ± 1.4084
    4.58 ± 1.5063
    4.512 ± 1.1619
    Statistical analysis title
    		 Peak Virus Shedding: MDT-637 TDS to Placebo
    Statistical analysis description
    Peak Virus Shedding By Tissue Culture
    Comparison groups
    ITT-I MDT-637 TDS v ITT-I Placebo
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8468 [7]
    Method
    		 ANOVA
    Parameter type
    		 Difference in LSM
    Point estimate
    0.068
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.631
         upper limit
    		 0.767
    Notes
    [7] - Comparison was performed at the 0.05 significance level.
    Statistical analysis title
    		 Peak Virus Shedding: MDT-637 BD to Placebo
    Statistical analysis description
    Peak Virus Shedding By Tissue Culture
    Comparison groups
    ITT-I Placebo v ITT-I MDT-637 BD
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8154 [8]
    Method
    		 ANOVA
    Parameter type
    		 Difference in LSM
    Point estimate
    -0.082
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.774
         upper limit
    		 0.611
    Notes
    [8] - Comparison was performed at the 0.05 significance level.
    Statistical analysis title
    		 Peak Virus Shedding: MDT-637-TDS to MDT-637-BD
    Statistical analysis description
    Peak Virus Shedding By Tissue Culture
    Comparison groups
    ITT-I MDT-637 BD v ITT-I MDT-637 TDS
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6785 [9]
    Method
    		 ANOVA
    Parameter type
    		 Difference in LSM
    Point estimate
    0.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.566
         upper limit
    		 0.865
    Notes
    [9] - Comparison was performed at the 0.05 significance level.

    Secondary: Total Area Under the Curve (AUC) of Virus Shedding by Tissue Culture

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    End point title
    		 Total Area Under the Curve (AUC) of Virus Shedding by Tissue Culture
    End point description
    AUC of virus shedding post challenge, per day (cumulative endpoint) for day X (where X was from day 2 after the viral challenge through to day 12) was calculated based on tissue culture data by linear trapezoidal summation method.
    End point type
    Secondary
    End point timeframe
    Day 2 to day 12
    End point values
    		 ITT-I MDT-637 BD ITT-I MDT-637 TDS ITT-I Placebo
    Number of subjects analysed
    32
    31
    35
    Units: Log10PFU/mL-days
        arithmetic mean (standard deviation)
    14.683 ± 8.4465
    14.767 ± 8.8548
    13.831 ± 7.4745
    Statistical analysis title
    		 AUC Viral Shedding: MDT-637 TDS to Placebo
    Statistical analysis description
    Total Area Under the Curve (AUC) of Virus Shedding by Tissue Culture
    Comparison groups
    ITT-I MDT-637 TDS v ITT-I Placebo
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6466 [10]
    Method
    		 ANOVA
    Parameter type
    		 Difference of LSM
    Point estimate
    0.936
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.103
         upper limit
    		 4.974
    Notes
    [10] - Comparison was performed at the 0.05 significance level.
    Statistical analysis title
    		 AUC Viral Shedding: MDT-637 BD to Placebo
    Statistical analysis description
    Total Area Under the Curve (AUC) of Virus Shedding by Tissue Culture
    Comparison groups
    ITT-I Placebo v ITT-I MDT-637 BD
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6736 [11]
    Method
    		 ANOVA
    Parameter type
    		 Difference of LSM
    Point estimate
    0.852
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.152
         upper limit
    		 4.857
    Notes
    [11] - Comparison was performed at the 0.05 significance level.
    Statistical analysis title
    		 AUC Viral Shedding: MDT-637 TDS to MDT-637 BD
    Statistical analysis description
    Total Area Under the Curve (AUC) of Virus Shedding by Tissue Culture
    Comparison groups
    ITT-I MDT-637 BD v ITT-I MDT-637 TDS
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9681 [12]
    Method
    		 ANOVA
    Parameter type
    		 Difference of LSM
    Point estimate
    0.083
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.043
         upper limit
    		 4.21
    Notes
    [12] - Comparison was performed at the 0.05 significance level.

    Secondary: Kaplan-Meier Estimates for Time to Peak Shedding by Tissue Culture

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    End point title
    		 Kaplan-Meier Estimates for Time to Peak Shedding by Tissue Culture
    End point description
    Time to peak shedding was calculated as the number of days between time of first detection of RSV-A and time of maximum viral load.
    End point type
    Secondary
    End point timeframe
    Day 1 to day 12
    End point values
    		 ITT-I MDT-637 BD ITT-I MDT-637 TDS ITT-I Placebo
    Number of subjects analysed
    29
    28
    32
    Units: days
        median (confidence interval 95%)
    3 (1 to 3)
    2 (1 to 2)
    2 (2 to 3)
    Statistical analysis title
    		 Time to Peak Shedding: MDT-637 TDS to Placebo
    Statistical analysis description
    Kaplan-Meier Estimates for Time to Peak Shedding by Tissue Culture
    Comparison groups
    ITT-I MDT-637 TDS v ITT-I Placebo
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3619 [13]
    Method
    		 Logrank
    Confidence interval
    Notes
    [13] - Comparison was performed at the 0.05 significance level.
    Statistical analysis title
    		 Time to Peak Shedding: MDT-637 BD to Placebo
    Statistical analysis description
    Kaplan-Meier Estimates for Time to Peak Shedding by Tissue Culture
    Comparison groups
    ITT-I Placebo v ITT-I MDT-637 BD
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7184 [14]
    Method
    		 Logrank
    Confidence interval
    Notes
    [14] - Comparison was performed at the 0.05 significance level.
    Statistical analysis title
    		 Time to Peak Shedding: MDT-637 TDS to MDT-637-BD
    Statistical analysis description
    Kaplan-Meier Estimates for Time to Peak Shedding by Tissue Culture
    Comparison groups
    ITT-I MDT-637 BD v ITT-I MDT-637 TDS
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1851 [15]
    Method
    		 Logrank
    Confidence interval
    Notes
    [15] - Comparison was performed at the 0.05 significance level.

    Secondary: Kaplan-Meier Estimates for Time to Resolution from Peak Viral Shedding by Tissue Culture

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    End point title
    		 Kaplan-Meier Estimates for Time to Resolution from Peak Viral Shedding by Tissue Culture
    End point description
    Time to resolution from peak viral shedding was calculated as number of days between time of maximum viral load and first time when virus became undetectable.
    End point type
    Secondary
    End point timeframe
    Day 1 to day 12
    End point values
    		 ITT-I MDT-637 BD ITT-I MDT-637 TDS ITT-I Placebo
    Number of subjects analysed
    29
    28
    32
    Units: days
        median (confidence interval 95%)
    3 (2 to 4)
    3 (2 to 3)
    3 (2 to 4)
    Statistical analysis title
    		 Time to Resolve: MDT-637 TDS to Placebo
    Statistical analysis description
    Kaplan-Meier Estimates for Time to Resolution from Peak Viral Shedding by Tissue Culture
    Comparison groups
    ITT-I MDT-637 TDS v ITT-I Placebo
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3896 [16]
    Method
    		 Logrank
    Confidence interval
    Notes
    [16] - Comparison was performed at the 0.05 significance level.
    Statistical analysis title
    		 Time to Resolve: MDT-637 BD to Placebo
    Statistical analysis description
    Kaplan-Meier Estimates for Time to Resolution from Peak Viral Shedding by Tissue Culture
    Comparison groups
    ITT-I Placebo v ITT-I MDT-637 BD
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7798 [17]
    Method
    		 Logrank
    Confidence interval
    Notes
    [17] - Comparison was performed at the 0.05 significance level.
    Statistical analysis title
    		 Time to Resolve: MDT-637 TDS to MDT-637 BD
    Statistical analysis description
    Kaplan-Meier Estimates for Time to Resolution from Peak Viral Shedding by Tissue Culture
    Comparison groups
    ITT-I MDT-637 BD v ITT-I MDT-637 TDS
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5583 [18]
    Method
    		 Logrank
    Confidence interval
    Notes
    [18] - Comparison was performed at the 0.05 significance level.

    Secondary: Duration of Virus Shedding By Quantitative Polymerase Chain Reaction Assay

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    End point title
    		 Duration of Virus Shedding By Quantitative Polymerase Chain Reaction Assay
    End point description
    Duration of virus shedding was calculated as the number of days elapsed from the date of first detection of RSV-A to the date when virus first became undetectable.
    End point type
    Secondary
    End point timeframe
    Day 1 to day 12
    End point values
    		 ITT-I MDT-637 BD ITT-I MDT-637 TDS ITT-I Placebo
    Number of subjects analysed
    32
    31
    34
    Units: days
        arithmetic mean (standard deviation)
    17.69 ± 9.204
    15.4 ± 9.363
    16.63 ± 9.133
    Statistical analysis title
    		 Duration Viral Shedding: MDT-637 TDS to Placebo
    Statistical analysis description
    Duration of Virus Shedding By Quantitative Polymerase Chain Reaction Assay
    Comparison groups
    ITT-I MDT-637 TDS v ITT-I Placebo
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5931 [19]
    Method
    		 ANOVA
    Parameter type
    		 Difference of LSM
    Point estimate
    -1.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.78
         upper limit
    		 3.32
    Notes
    [19] - Comparison was performed at the 0.05 significance level.
    Statistical analysis title
    		 Duration Viral Shedding: MDT-637 BD to Placebo
    Statistical analysis description
    Duration of Virus Shedding By Quantitative Polymerase Chain Reaction Assay
    Comparison groups
    ITT-I Placebo v ITT-I MDT-637 BD
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6436 [20]
    Method
    		 ANOVA
    Parameter type
    		 Difference of LSM
    Point estimate
    1.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.46
         upper limit
    		 5.57
    Notes
    [20] - Comparison was performed at the 0.05 significance level.
    Statistical analysis title
    		 Duration Viral Shedding: MDT-637 TDS to MDT-637 BD
    Statistical analysis description
    Duration of Virus Shedding By Quantitative Polymerase Chain Reaction Assay
    Comparison groups
    ITT-I MDT-637 BD v ITT-I MDT-637 TDS
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3286 [21]
    Method
    		 ANOVA
    Parameter type
    		 Difference of LSM
    Point estimate
    -2.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.9
         upper limit
    		 2.33
    Notes
    [21] - Comparison was performed at the 0.05 significance level.

    Secondary: Peak Virus Shedding By Quantitative Polymerase Chain Reaction Assay

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    End point title
    		 Peak Virus Shedding By Quantitative Polymerase Chain Reaction Assay
    End point description
    Peak virus shedding was calculated as maximum viral load assessment.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 12
    End point values
    		 ITT-I MDT-637 BD ITT-I MDT-637 TDS ITT-I Placebo
    Number of subjects analysed
    32
    31
    34
    Units: log10PFU/mL
        arithmetic mean (standard deviation)
    6.108 ± 1.1872
    5.822 ± 1.7543
    5.952 ± 1.3753
    Statistical analysis title
    		 Peak Viral Shedding: MDT-637 TDS to Placebo
    Statistical analysis description
    Peak Virus Shedding By Quantitative Polymerase Chain Reaction Assay
    Comparison groups
    ITT-I Placebo v ITT-I MDT-637 TDS
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7186 [22]
    Method
    		 ANOVA
    Parameter type
    		 Difference of LSM
    Point estimate
    -0.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.847
         upper limit
    		 0.586
    Notes
    [22] - Comparison was performed at the 0.05 significance level.
    Statistical analysis title
    		 Peak Viral Shedding: MDT-637 BD to Placebo
    Statistical analysis description
    Peak Virus Shedding By Quantitative Polymerase Chain Reaction Assay
    Comparison groups
    ITT-I Placebo v ITT-I MDT-637 BD
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6644 [23]
    Method
    		 ANOVA
    Parameter type
    		 Difference of LSM
    Point estimate
    0.156
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.555
         upper limit
    		 0.866
    Notes
    [23] - Comparison was performed at the 0.05 significance level.
    Statistical analysis title
    		 Peak Viral Shedding: MDT-637 TDS to MDT-637 BD
    Statistical analysis description
    Peak Virus Shedding By Quantitative Polymerase Chain Reaction Assay
    Comparison groups
    ITT-I MDT-637 BD v ITT-I MDT-637 TDS
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4364 [24]
    Method
    		 ANOVA
    Parameter type
    		 Difference of LSM
    Point estimate
    -0.286
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.013
         upper limit
    		 0.441
    Notes
    [24] - Comparison was performed at the 0.05 significance level.

    Secondary: Kaplan-Meier Estimates for Time to Peak Shedding By Quantitative Polymerase Chain Reaction Assay

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    End point title
    		 Kaplan-Meier Estimates for Time to Peak Shedding By Quantitative Polymerase Chain Reaction Assay
    End point description
    Time to peak virus shedding from the nasal mucosa was calculated as the number of days between time of first detection of RSV-A and time of maximum viral load.
    End point type
    Secondary
    End point timeframe
    Day 1 to day 12
    End point values
    		 ITT-I MDT-637 BD ITT-I MDT-637 TDS ITT-I Placebo
    Number of subjects analysed
    32
    31
    34
    Units: days
        median (confidence interval 95%)
    4 (3.5 to 4)
    3.5 (3 to 4)
    4 (3 to 5)
    Statistical analysis title
    		 Time to Peak Shedding: MDT-637 TDS to Placebo
    Statistical analysis description
    Kaplan-Meier Estimates for Time to Peak Shedding By Quantitative Polymerase Chain Reaction Assay
    Comparison groups
    ITT-I MDT-637 TDS v ITT-I Placebo
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2303 [25]
    Method
    		 Logrank
    Confidence interval
    Notes
    [25] - Comparison was performed at the 0.05 significance level.
    Statistical analysis title
    		 Time to Peak Shedding: MDT-637 BD to Placebo
    Statistical analysis description
    Kaplan-Meier Estimates for Time to Peak Shedding By Quantitative Polymerase Chain Reaction Assay
    Comparison groups
    ITT-I Placebo v ITT-I MDT-637 BD
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7188 [26]
    Method
    		 Logrank
    Confidence interval
    Notes
    [26] - Comparison was performed at the 0.05 significance level.
    Statistical analysis title
    		 Time to Peak Shedding: MDT-637 TDS to MDT-637-BD
    Statistical analysis description
    Kaplan-Meier Estimates for Time to Peak Shedding By Quantitative Polymerase Chain Reaction Assay
    Comparison groups
    ITT-I MDT-637 BD v ITT-I MDT-637 TDS
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4078 [27]
    Method
    		 Logrank
    Confidence interval
    Notes
    [27] - Comparison was performed at the 0.05 significance level.

    Secondary: Kaplan-Meier Estimates for Time to Resolution from Peak Viral Shedding By Quantitative Polymerase Chain Reaction Assay

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    End point title
    		 Kaplan-Meier Estimates for Time to Resolution from Peak Viral Shedding By Quantitative Polymerase Chain Reaction Assay
    End point description
    Time to resolution from peak viral shedding was calculated as the number of days between time of maximum viral load and first time when virus became undetectable.
    End point type
    Secondary
    End point timeframe
    Day 1 to day 28
    End point values
    		 ITT-I MDT-637 BD ITT-I MDT-637 TDS ITT-I Placebo
    Number of subjects analysed
    32
    31
    34
    Units: days
        median (confidence interval 95%)
    14.75 (6.5 to 19)
    7 (4.5 to 17.5)
    7.25 (5.5 to 19)
    Statistical analysis title
    		 Time to Resolve: MDT-637 TDS to Placebo
    Statistical analysis description
    Kaplan-Meier Estimates for Time to Resolution from Peak Viral Shedding By Quantitative Polymerase Chain Reaction Assay
    Comparison groups
    ITT-I MDT-637 TDS v ITT-I Placebo
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9607 [28]
    Method
    		 Logrank
    Confidence interval
    Notes
    [28] - Comparison was performed at the 0.05 significance level.
    Statistical analysis title
    		 Time to Resolve: MDT-637 BD to Placebo
    Statistical analysis description
    Kaplan-Meier Estimates for Time to Resolution from Peak Viral Shedding By Quantitative Polymerase Chain Reaction Assay
    Comparison groups
    ITT-I Placebo v ITT-I MDT-637 BD
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3501 [29]
    Method
    		 Logrank
    Confidence interval
    Notes
    [29] - Comparison was performed at the 0.05 significance level.
    Statistical analysis title
    		 Time to Resolve: MDT-637 TDS to MDT-637 BD
    Statistical analysis description
    Kaplan-Meier Estimates for Time to Resolution from Peak Viral Shedding By Quantitative Polymerase Chain Reaction Assay
    Comparison groups
    ITT-I MDT-637 BD v ITT-I MDT-637 TDS
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3238 [30]
    Method
    		 Logrank
    Confidence interval
    Notes
    [30] - Comparison was performed at the 0.05 significance level.

    Secondary: Total Mucus Weight by Study Phase

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    End point title
    		 Total Mucus Weight by Study Phase
    End point description
    Subjects were given pre-weighed packets of paper tissues (handkerchiefs). Subjects stored each tissue used for nose blowing or sneezing in an airtight plastic bag. Bags of used tissues were collected daily (24-hour collection) and new bags were distributed. All paper tissues used by each subject were collected for each 24-hour period throughout the quarantine period, to determine the total weight of mucus produced
    End point type
    Secondary
    End point timeframe
    After viral challenge: Day 1 up to day 5 Dosing phase: When PRC positive or Day 5 at latest, to Day 12
    End point values
    		 ITT-I MDT-637 BD ITT-I MDT-637 TDS ITT-I Placebo
    Number of subjects analysed
    32
    31
    35
    Units: grams
    arithmetic mean (standard deviation)
        After viral challenge
    29.35 ± 30.173
    26.88 ± 26.451
    30.24 ± 40.929
        Dosing phase
    27.48 ± 29.995
    25.46 ± 25.836
    27.49 ± 39.683
    No statistical analyses for this end point

    Secondary: Total Number of Tissues Used by Study Phase

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    End point title
    		 Total Number of Tissues Used by Study Phase
    End point description
    Subjects were given pre-weighed packets of paper tissues (handkerchiefs). Subjects stored each tissue used for nose blowing or sneezing in an airtight plastic bag. All paper tissues used by each subject were collected for each 24-hour period throughout the quarantine period, to determine the total weight of mucus produced, and the total number of tissues used.
    End point type
    Secondary
    End point timeframe
    After viral challenge: Day 1 up to day 5 Dosing phase: When PRC positive or Day 5 at latest, to Day 12
    End point values
    		 ITT-I MDT-637 BD ITT-I MDT-637 TDS ITT-I Placebo
    Number of subjects analysed
    32
    31
    35
    Units: number of tissues
    arithmetic mean (standard deviation)
        After viral challenge
    58.9 ± 57.65
    65.3 ± 68.35
    54.6 ± 59.4
        Dosing phase
    54.6 ± 56.2
    61.3 ± 66.01
    48.9 ± 57.64
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Grade 2 or Worse Symptoms At Any Day Post Inoculation

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    End point title
    		 Percentage of Subjects With Grade 2 or Worse Symptoms At Any Day Post Inoculation
    End point description
    Subjects were asked to assess challenge virus-related signs and symptoms, and associated severity at scheduled times throughout the quarantine period, and to record the signs and symptoms in the subject diary card. The symptoms that the subjects were asked to assess were: runny nose, stuffy nose, sneezing, sore throat, earache, malaise (tiredness), cough, shortness of breath, headache, and muscle and/or joint pain. For each symptom, subjects were asked to check the rating that best described how they felt since completing the last diary card, using the following categories: Grade 0 indicated no symptoms. Grade 1 meant symptoms were just noticeable. Grade 2 symptoms indicated 'It's clearly bothersome from time to time, but it doesn't stop me from participating in activities', Grade 3 indicated 'It's quite bothersome, most or all of the time, and it stops me from participating in activities'.
    End point type
    Secondary
    End point timeframe
    Day 1 to day 12
    End point values
    		 ITT-I MDT-637 BD ITT-I MDT-637 TDS ITT-I Placebo
    Number of subjects analysed
    32
    31
    35
    Units: percentage of subjects
        number (not applicable)
    71.9
    71
    74.3
    No statistical analyses for this end point

    Secondary: Duration of Grade 2 or Worse Symptoms

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    End point title
    		 Duration of Grade 2 or Worse Symptoms
    End point description
    The duration of Grade 2 or worse symptoms was calculated as number of days elapsed from the date of first occurrence of any Grade >2 symptom to the date of last occurrence of any Grade >2 symptom as recorded by subjects in the Symptom Diary Cards.
    End point type
    Secondary
    End point timeframe
    Day 1 to day 12
    End point values
    		 ITT-I MDT-637 BD ITT-I MDT-637 TDS ITT-I Placebo
    Number of subjects analysed
    23 [31]
    22 [32]
    26 [33]
    Units: days
        arithmetic mean (standard deviation)
    3.7 ± 1.99
    5 ± 2.8
    5.5 ± 3.34
    Notes
    [31] - Subjects with grade 2 or worse clinical symptoms
    [32] - Subjects with grade 2 or worse clinical symptoms
    [33] - Subjects with grade 2 or worse clinical symptoms
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Grade 1 or Worse Symptoms At Any Day During the Dose Phase

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    End point title
    		 Percentage of Subjects With Grade 1 or Worse Symptoms At Any Day During the Dose Phase
    End point description
    Subjects were asked to assess challenge virus-related signs and symptoms, and associated severity at scheduled times throughout the quarantine period, and to record the signs and symptoms in the subject diary card. Symptoms were: runny nose, stuffy nose, sneezing, sore throat, earache, malaise (tiredness), cough, shortness of breath, headache, and muscle and/or joint pain. Ratings since completing the previous card were: 0="I have NO symptoms"; 1="Just noticeable"; 2="It's clearly bothersome from time to time, but it doesn't stop me from participating in activities"; 3="It's quite bothersome, most or all of the time and it stops me from participating in activities".
    End point type
    Secondary
    End point timeframe
    Dose phase: When PRC positive or Day 5 at latest, to Day 12
    End point values
    		 ITT-I MDT-637 BD ITT-I MDT-637 TDS ITT-I Placebo
    Number of subjects analysed
    32
    31
    35
    Units: percentage of subjects
        number (not applicable)
    90.6
    96.8
    97.1
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Grade 1 or Worse of Three Symptom Categories (Upper Respiratory Tract, Lower Respiratory Tract, Systemic Symptoms) At Any Day Post Inoculation

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    End point title
    		 Percentage of Subjects With Grade 1 or Worse of Three Symptom Categories (Upper Respiratory Tract, Lower Respiratory Tract, Systemic Symptoms) At Any Day Post Inoculation
    End point description
    The percentage of subjects with Grade ≥1 symptom score was calculated for upper respiratory tract (URTI) symptoms, lower respiratory tract symptoms and systemic symptoms ( ie, malaise and muscle and/or joint aches). The numerator for the proportion was the number of subjects who experienced URTI (or other category) symptoms at any time during post inoculation. The denominator was the number of subjects with at least one record in the symptom diary card post inoculation. The proportion was then multiplied by 100 to create the percentage.
    End point type
    Secondary
    End point timeframe
    Day 1 to day 12
    End point values
    		 ITT-I MDT-637 BD ITT-I MDT-637 TDS ITT-I Placebo
    Number of subjects analysed
    32
    31
    35
    Units: percentage of subjects
    number (not applicable)
        Upper respiratory tract
    96.9
    96.8
    97.1
        Lower respiratory tract
    65.6
    48.4
    54.3
        Systemic symptoms
    75
    83.9
    85.7
    No statistical analyses for this end point

    Secondary: Time to Peak Symptoms Recorded on the Symptom Diary Card

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    End point title
    		 Time to Peak Symptoms Recorded on the Symptom Diary Card
    End point description
    Time to peak of each reported symptom was calculated as the number of days between administration of virus inoculum and time when the symptom reached its maximum severity. If the duration of maximum was several days, the earliest occurrence was used in the calculations.
    End point type
    Secondary
    End point timeframe
    Day 1 to day 12
    End point values
    		 ITT-I MDT-637 BD ITT-I MDT-637 TDS ITT-I Placebo
    Number of subjects analysed
    32 [34]
    31 [35]
    35 [36]
    Units: days
    median (confidence interval 95%)
        Runny nose (n=24, 24, 24)
    6 (5 to 7)
    7 (5 to 7)
    6 (5 to 6)
        Stuffy nose (n=29, 29, 34)
    5 (5 to 6)
    6 (5 to 7)
    6 (5 to 6)
        Sneezing (n=24, 25, 25)
    5 (4 to 6)
    6 (6 to 7)
    6 (4 to 6)
        Sore throat (n=24, 27, 31)
    5 (5 to 6)
    5 (4 to 6)
    5 (4 to 6)
        Earache (n=8, 7, 10)
    6.5 (1 to 9)
    5 (2 to 7)
    5.5 (4 to 7)
        Cough (n=20, 15, 17)
    5 (4 to 7)
    6 (4 to 7)
    6 (2 to 7)
        Shortness of breath (n=5, 3, 6)
    5 (5 to 6)
    2 (2 to 6)
    6 (4 to 11)
        Malaise (n=19, 18, 20)
    5 (3 to 6)
    6 (5 to 7)
    6 (3 to 7)
        Headache (n=18, 22, 26)
    6 (5 to 7)
    5.5 (5 to 6)
    5.5 (3 to 6)
        Muscle and/or joint ache (n=7, 14, 11)
    4 (2 to 5)
    4.5 (2 to 6)
    4 (1 to 6)
    Notes
    [34] - Population counts for each symptom follow the symptom name.
    [35] - Population counts for each symptom follow the symptom name.
    [36] - Population counts for each symptom follow the symptom name.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Pyrexia At Any Day Post Inoculation

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    End point title
    		 Percentage of Subjects with Pyrexia At Any Day Post Inoculation
    End point description
    Pyrexia was defined as a temperature of >37.9°C or two SDs greater than the average of the 3 last non-missing assessments prior to the virus inoculum. A subject was considered to have a febrile illness post-challenge if he/she had any occurrence of a temperature of ≥37.9°C (confirmed by a repeat measurement as ≥37.9°C within 20 to 60 minutes) between day 0 and the last day of receiving study drug.
    End point type
    Secondary
    End point timeframe
    Day 0 to day 12
    End point values
    		 ITT-I MDT-637 BD ITT-I MDT-637 TDS ITT-I Placebo
    Number of subjects analysed
    32
    31
    35
    Units: percentage of subjects
        number (not applicable)
    28.1
    22.6
    20
    No statistical analyses for this end point

    Secondary: Mean Duration of Pyrexia

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    End point title
    		 Mean Duration of Pyrexia
    End point description
    Mean duration of pyrexia was defined as the number of hours with pyrexia.
    End point type
    Secondary
    End point timeframe
    Day 0 to day 12
    End point values
    		 ITT-I MDT-637 BD ITT-I MDT-637 TDS ITT-I Placebo
    Number of subjects analysed
    9 [37]
    7 [38]
    7 [39]
    Units: hours
        arithmetic mean (standard deviation)
    23.639 ± 19.9069
    24.667 ± 35.1291
    16.324 ± 8.1769
    Notes
    [37] - Subjects with pyrexia
    [38] - Subjects with pyrexia
    [39] - Subjects with pyrexia
    No statistical analyses for this end point

    Secondary: Area Under the Curve of Temperature During the Dosing Phase

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    End point title
    		 Area Under the Curve of Temperature During the Dosing Phase
    End point description
    The AUC of temperature during the dosing phase included all time points and was calculated by a linear trapezoidal method.
    End point type
    Secondary
    End point timeframe
    Dosing phase: When PRC positive or Day 5 at latest, to Day 12
    End point values
    		 ITT-I MDT-637 BD ITT-I MDT-637 TDS ITT-I Placebo
    Number of subjects analysed
    32
    31
    35
    Units: °C*days
        arithmetic mean (standard deviation)
    298.6 ± 26.812
    300.18 ± 30.899
    294.16 ± 30.846
    No statistical analyses for this end point

    Secondary: Percentage of Successful Doses As Observed by Study Staff

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    End point title
    		 Percentage of Successful Doses As Observed by Study Staff
    End point description
    Treatment compliance was calculated as the number of successful doses taken as observed by study staff taken by the planned number of doses and multiplied by 100%.
    End point type
    Secondary
    End point timeframe
    Dosing phase: When PRC positive or Day 5 at latest, to Day 12
    End point values
    		 MDT-637 BD MDT-637 TDS Placebo
    Number of subjects analysed
    48 [40]
    48 [41]
    47 [42]
    Units: percentage of total doses
        number (not applicable)
    100
    100
    100
    Notes
    [40] - Intent to treat population
    [41] - Intent to treat population
    [42] - Intent to treat population
    No statistical analyses for this end point

    Secondary: Summary of Adverse Events

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    End point title
    		 Summary of Adverse Events
    End point description
    An adverse event was defined in the protocol as any untoward medical occurrence in a clinical study subject to which study drug (active or placebo) had been administered, including occurrences that were not necessarily caused by or related to that product. Treatment-emergent AEs are those that started after the first dose of study drug. AE severity was rated as mild (mild level of discomfort and did not interfere with regular activities), moderate, severe (significant level of discomfort and prevented regular activities) or life-threatening. The investigator determined whether there was a reasonable possibility of treatment relation. A serious adverse event was an adverse event that resulted in any of the following outcomes or actions:  Death  Life threatening  Required inpatient hospitalization/prolongation of hospitalization  Resulted in persistent or significant disability/incapacity  Congenital anomaly/birth defect An other important medical event
    End point type
    Secondary
    End point timeframe
    Day 0 to day 12
    End point values
    		 MDT-637 BD MDT-637 TDS Placebo
    Number of subjects analysed
    48 [43]
    48 [44]
    47 [45]
    Units: subjects
        1+ AE
    31
    32
    34
        1+ treatment-emergent AE (TEAE)
    25
    30
    30
        Mild TEAE
    22
    24
    24
        Moderate TEAE
    2
    5
    6
        Severe TEAE
    1
    1
    0
        Related TEAE
    6
    9
    11
        TEAE related to challenge virus
    11
    8
    14
        TEAE related to challenge virus + study drug
    4
    6
    8
        TEAE related to study procedure/assessment
    6
    5
    9
        TEAE related to concomitant med
    5
    5
    8
        TEAE related to device
    0
    0
    0
        Adverse device effect
    0
    0
    0
        Device deficiency
    0
    0
    0
        Serious TEAE
    0
    0
    0
    Notes
    [43] - Safety population
    [44] - Safety population
    [45] - Safety population
    No statistical analyses for this end point

    Secondary: Maximum Observed Plasma Drug Concentration (Cmax)

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    End point title
    		 Maximum Observed Plasma Drug Concentration (Cmax)
    End point description
    Blood samples to determine the pharmacokinetic profile of MDT-637 in plasma of subjects inoculated with RSV-A were taken only in the subjects who participated in quarantine 2, and were linked to the morning dose.
    End point type
    Secondary
    End point timeframe
    Days 6 and 12 (dose days 2 and 7): predose (0 hours -15 minutes), 0.5, 1, 2, 3, 4, 6, 12, 12.5, 13, 14, 16, 18, and 24 hours
    End point values
    		 PK MDT-637 BD PK MDT-637 TDS PK Placebo
    Number of subjects analysed
    10 [46]
    9 [47]
    0 [48]
    Units: pg/mL
    arithmetic mean (standard deviation)
        Dose day 2
    22.1 ± 5.9
    33.6 ± 10.6
    ±
        Dose day 7
    25.6 ± 9.4
    34.7 ± 9
    ±
    Notes
    [46] - Subjects from quarantine 2 only
    [47] - Subjects from quarantine 2 only
    [48] - Placebo-treated subjects do not have MDT-637 PK results reported.
    No statistical analyses for this end point

    Secondary: Time To Maximum Observed Drug Concentration (Tmax)

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    End point title
    		 Time To Maximum Observed Drug Concentration (Tmax)
    End point description
    Blood samples to determine the pharmacokinetic profile of MDT-637 in plasma of subjects inoculated with RSV-A were taken only in the subjects who participated in quarantine 2, and were linked to the morning dose.
    End point type
    Secondary
    End point timeframe
    Days 6 and 12 (dose days 2 and 7): predose (0 hours -15 minutes), 0.5, 1, 2, 3, 4, 6, 12, 12.5, 13, 14, 16, 18, and 24 hours
    End point values
    		 PK MDT-637 BD PK MDT-637 TDS PK Placebo
    Number of subjects analysed
    10 [49]
    9 [50]
    0 [51]
    Units: hour
    arithmetic mean (standard deviation)
        Dose day 2
    15.5 ± 1.7
    13.6 ± 1.1
    ±
        Dose day 7
    7.7 ± 7.1
    13.4 ± 4.8
    ±
    Notes
    [49] - Subjects from quarantine 2 only
    [50] - Subjects from quarantine 2 only
    [51] - Placebo-treated subjects do not have MDT-637 PK results reported.
    No statistical analyses for this end point

    Secondary: Area Under The Plasma-Concentration-Time Curve From Time 0 To The Time Of The Last Measurable Drug Concentration (AUC0-t)

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    End point title
    		 Area Under The Plasma-Concentration-Time Curve From Time 0 To The Time Of The Last Measurable Drug Concentration (AUC0-t)
    End point description
    Blood samples to determine the pharmacokinetic profile of MDT-637 in plasma of subjects inoculated with RSV-A were taken only in the subjects who participated in quarantine 2, and were linked to the morning dose.
    End point type
    Secondary
    End point timeframe
    Days 6 and 12 (dose days 2 and 7): predose (0 hours -15 minutes), 0.5, 1, 2, 3, 4, 6, 12, 12.5, 13, 14, 16, 18, and 24 hours
    End point values
    		 PK MDT-637 BD PK MDT-637 TDS PK Placebo
    Number of subjects analysed
    10 [52]
    9 [53]
    0 [54]
    Units: hour*pg/mL
    arithmetic mean (standard deviation)
        Dose day 2
    388 ± 113
    599 ± 190
    ±
        Dose day 7
    473 ± 207
    614 ± 149
    ±
    Notes
    [52] - Subjects from quarantine 2 only
    [53] - Subjects from quarantine 2 only
    [54] - Placebo-treated subjects do not have MDT-637 PK results reported.
    No statistical analyses for this end point

    Secondary: Area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞)

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    End point title
    		 Area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞)
    End point description
    Blood samples to determine the pharmacokinetic profile of MDT-637 in plasma of subjects inoculated with RSV-A were taken only in the subjects who participated in quarantine 2, and were linked to the morning dose. Results are not reported because different dosing schedules and the same sampling times for the two MDT treatments meant that results for derived pharmacokinetic variables would not be comparable.
    End point type
    Secondary
    End point timeframe
    Days 6 and 12 (dose days 2 and 7): predose (0 hours -15 minutes), 0.5, 1, 2, 3, 4, 6, 12, 12.5, 13, 14, 16, 18, and 24 hours
    End point values
    		 PK MDT-637 BD PK MDT-637 TDS PK Placebo
    Number of subjects analysed
    0 [55]
    0 [56]
    0 [57]
    Units: h*pg/mL
    arithmetic mean (standard deviation)
        Dose day 2
    ±
    ±
    ±
        Dose day 7
    ±
    ±
    ±
    Notes
    [55] - Different dosing schedules for the two MDT arms meant results for derived PK were not comparable.
    [56] - Different dosing schedules for the two MDT arms meant results for derived PK were not comparable.
    [57] - Placebo-treated subjects do not have MDT-637 PK results reported.
    No statistical analyses for this end point

    Secondary: Elimination half life (t½)

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    End point title
    		 Elimination half life (t½)
    End point description
    Blood samples to determine the pharmacokinetic profile of MDT-637 in plasma of subjects inoculated with RSV-A were taken only in the subjects who participated in quarantine 2, and were linked to the morning dose. Results are not reported because different dosing schedules and the same sampling times for the two MDT treatments meant that results for derived pharmacokinetic variables would not be comparable.
    End point type
    Secondary
    End point timeframe
    Days 6 and 12 (dose days 2 and 7): predose (0 hours -15 minutes), 0.5, 1, 2, 3, 4, 6, 12, 12.5, 13, 14, 16, 18, and 24 hours
    End point values
    		 PK MDT-637 BD PK MDT-637 TDS PK Placebo
    Number of subjects analysed
    0 [58]
    0 [59]
    0 [60]
    Units: hour
    arithmetic mean (standard deviation)
        Dose day 2
    ±
    ±
    ±
        Dose day 7
    ±
    ±
    ±
    Notes
    [58] - Different dosing schedules for the two MDT arms meant results for derived PK were not comparable
    [59] - Different dosing schedules for the two MDT arms meant results for derived PK were not comparable
    [60] - Placebo-treated subjects do not have MDT-637 PK results reported.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Dosing phase: When PRC positive or Day 5 at latest, to Day 12
    Adverse event reporting additional description
    The symptoms that were recorded on the diary cards were presumed to represent challenge virus infection consequent to challenge, and were not to be captured as adverse events unless they met one of the criteria for a serious adverse event. However, this was not followed consistently as there were no SAEs but there were TEAEs with those symptoms.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    MDT-637 BD
    Reporting group description
    		 MDT-637 administered twice a day (BD) via dry-powder, aerosol inhaler at a dose of approximately 132 mcg with daily administration at 0800 and 2000 hours. Placebo administered via the same dry-powder aerosol inhaler at 1400 hours. Dosing commenced on Days 2, 3, 4 or 5, post-inoculum dependent on a positive non-qPCR nasal wash result for the presence of the challenge virus. The total dose was up to 21 consecutive doses (14 active, 7 placebo) dispensed over 7 days.

    Reporting group title
    MDT-637 TDS
    Reporting group description
    		 MDT-637 administered three times a day (TDS) via dry-powder, aerosol inhaler at a dose of approximately 132 mcg with daily administration at 0800, 1400 and 2000 hours. Dosing commenced on Days 2, 3, 4 or 5, post-inoculum dependent on a positive non-qPCR nasal wash result for the presence of the challenge virus. The total dose was up to 21 consecutive doses dispensed over 7 days.

    Reporting group title
    Placebo
    Reporting group description
    		 Inhalation grade lactose administered three times a day via dry-powder, aerosol inhaler at 0800, 1400 and 2000 hours. Placebo Dosing commenced on Days 2, 3, 4 or 5, post-inoculum dependent on a positive non-qPCR nasal wash result for the presence of the challenge virus. The total dose was up to 21 consecutive doses dispensed over 7 days.

    Serious adverse events
    		 MDT-637 BD MDT-637 TDS Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 48 (0.00%)
    0 / 47 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 MDT-637 BD MDT-637 TDS Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 48 (33.33%)
    12 / 48 (25.00%)
    19 / 47 (40.43%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 48 (8.33%)
    5 / 48 (10.42%)
    5 / 47 (10.64%)
         occurrences all number
    4
    5
    5
    Spirometry abnormal
         subjects affected / exposed
    2 / 48 (4.17%)
    2 / 48 (4.17%)
    3 / 47 (6.38%)
         occurrences all number
    2
    3
    3
    Forced expiratory volume decreased
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 48 (2.08%)
    4 / 47 (8.51%)
         occurrences all number
    0
    1
    5
    Injury, poisoning and procedural complications
    Procedural haemorrhage
         subjects affected / exposed
    3 / 48 (6.25%)
    2 / 48 (4.17%)
    2 / 47 (4.26%)
         occurrences all number
    3
    2
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 48 (6.25%)
    2 / 48 (4.17%)
    7 / 47 (14.89%)
         occurrences all number
    3
    2
    7
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    2 / 48 (4.17%)
    1 / 48 (2.08%)
    3 / 47 (6.38%)
         occurrences all number
    2
    1
    5
    Cough
         subjects affected / exposed
    3 / 48 (6.25%)
    0 / 48 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    3
    0
    1
    Nasal congestion
         subjects affected / exposed
    3 / 48 (6.25%)
    1 / 48 (2.08%)
    0 / 47 (0.00%)
         occurrences all number
    3
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Jul 2013
    Amendment 1 (dated 10 July 2013) to the protocol was issued before any subjects were enrolled into the study. The following major procedural changes (not all-inclusive) were made to the protocol:  - The following secondary objectives were added: antiviral effect (as defined by reduction in log AUC viral load by TCID50), and performance and safety of the inhaler device.  - The inclusion and exclusion criteria were clarified  - The study procedures were clarified
    11 Sep 2013
    Amendment 2 (dated 11 September 2013) to the protocol was issued after screening had started but before any subjects entered quarantine. The following major procedural changes (not all-inclusive) were made to the protocol:  - The BD dosing regimen was added  - Further information was added on the background to the product, the use of the facemask and device, risk-benefit assessment, and definitions and reporting requirements of any adverse reactions to the EP1C inhaler device.  - The sponsor was changed from MicroDose to Teva, which resulted in a change of pharmacovigilance reporting procedures.

    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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