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    Clinical Trial Results:
    A Phase 2a, randomized, double-blinded, placebo-controlled study to evaluate the antiviral activity, safety, and pharmacokinetics of repeated doses of orally administered JNJ-53718678 against Respiratory Syncytial Virus (RSV) infection in the virus challenge model in healthy adult subjects.

    Summary
    EudraCT number
    		 2014-005041-41
    Trial protocol
    		 GB  
    Global end of trial date
    02 Oct 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Nov 2016
    First version publication date
    11 Nov 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    53718678RSV2001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02387606
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Janssen Sciences Ireland UC
    Sponsor organisation address
    Eastgate Village, Eastgate Little Island, Co. Cork, Ireland,
    Public contact
    Clinical Registry Group, Janssen Research and Development, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Janssen Research and Development, ClinicalTrialsEU@its.jnj.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
    02 Oct 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Oct 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to evaluate the antiviral effect (nasal wash respiratory syncytial virus [RSV] area under the viral load-time curve [VL AUC] by quantitative reverse transcriptase-polymerase chain reaction [qRT-PCR]) assay of repeated oral dosing of JNJ-53718678 compared to placebo in healthy adult subjects infected through inoculation with RSV-A Memphis 37b virus.
    Protection of trial subjects
    Safety assessments included adverse event (AE) analysis, clinical laboratory tests, electrocardiogram (ECG), vital sign assessments, and physical examination. Special events of interest were the coagulation system (prothrombin [PT] and activated partial thromboplastin time [aPTT]) as well as liver/gall bladder toxicities (alanine aminotransferase [ALT], aspartate aminotransferase [AST], bilirubin).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 May 2015
    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: 66
    Worldwide total number of subjects
    66
    EEA total number of subjects
    66
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    66
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted from 11 May 2015 to 02 October 2015.

    Pre-assignment
    Screening details
    		 Total 69 subjects were inoculated out of which 66 subjects were randomised and dosed in this study.

    Period 1
    Period 1 title
    Overall (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Placebo was administered as oral solution once daily for 7 days.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo was administered as oral solution once daily

    Arm title
    		 JNJ-53718678 75 milligram (mg) once daily
    Arm description
    		 JNJ-53718678 75 mg was administered as 7.5 milliliter (ml) once daily as oral solution for 7 days in cohort 2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    JNJ-53718678 75 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    JNJ-53718678 75 mg was administered as 7.5 ml as oral solution once daily for 7 days

    Arm title
    		 JNJ-53718678 200 mg once daily
    Arm description
    		 JNJ-53718678 200 mg was administered as 20 ml oral solution once daily for 7 days in both cohort 1 and cohort 2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    JNJ-53718678 200 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    JNJ-53718678 200 mg was administered as 20 ml oral solution once daily for 7 days in both cohort 1 and cohort 2.

    Arm title
    		 JNJ-53718678 500 mg once daily
    Arm description
    		 JNJ-53718678 500 mg was administered as 50 ml oral solution once daily for 7 days in both cohort 1 and cohort 2
    Arm type
    		 Experimental

    Investigational medicinal product name
    JNJ-53718678 500 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    JNJ-53718678 500 mg was administered as 50 ml oral solution once daily for 7 days in both cohort 1 and cohort 2

    Number of subjects in period 1
    		Placebo JNJ-53718678 75 milligram (mg) once daily JNJ-53718678 200 mg once daily JNJ-53718678 500 mg once daily
    Started
    16
    15
    17
    18
    Completed
    15
    13
    16
    17
    Not completed
    1
    2
    1
    1
         Adverse event, non-fatal
    1
    1
    1
    -
         Other
    -
    1
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo was administered as oral solution once daily for 7 days.

    Reporting group title
    JNJ-53718678 75 milligram (mg) once daily
    Reporting group description
    		 JNJ-53718678 75 mg was administered as 7.5 milliliter (ml) once daily as oral solution for 7 days in cohort 2.

    Reporting group title
    JNJ-53718678 200 mg once daily
    Reporting group description
    		 JNJ-53718678 200 mg was administered as 20 ml oral solution once daily for 7 days in both cohort 1 and cohort 2.

    Reporting group title
    JNJ-53718678 500 mg once daily
    Reporting group description
    		 JNJ-53718678 500 mg was administered as 50 ml oral solution once daily for 7 days in both cohort 1 and cohort 2

    Reporting group values
    		 Placebo JNJ-53718678 75 milligram (mg) once daily JNJ-53718678 200 mg once daily JNJ-53718678 500 mg once daily Total
    Number of subjects
    		 16 15 17 18 66
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 16 15 17 18 66
        From 65 to 84 years
    		 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    		 24.3 ± 4.06 24 ± 5.55 21.7 ± 2.52 22.1 ± 2.8 -
    Title for Gender
    Units: subjects
        Male
    		 16 15 17 18 66

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo was administered as oral solution once daily for 7 days.

    Reporting group title
    JNJ-53718678 75 milligram (mg) once daily
    Reporting group description
    		 JNJ-53718678 75 mg was administered as 7.5 milliliter (ml) once daily as oral solution for 7 days in cohort 2.

    Reporting group title
    JNJ-53718678 200 mg once daily
    Reporting group description
    		 JNJ-53718678 200 mg was administered as 20 ml oral solution once daily for 7 days in both cohort 1 and cohort 2.

    Reporting group title
    JNJ-53718678 500 mg once daily
    Reporting group description
    		 JNJ-53718678 500 mg was administered as 50 ml oral solution once daily for 7 days in both cohort 1 and cohort 2

    Primary: Area Under the Viral Load-time Curve (VL AUC) Over Time Measured With Quantitative Reverse Transcriptase –Polymerase Chain Reaction (qRT-PCR) Assay

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    End point title
    		 Area Under the Viral Load-time Curve (VL AUC) Over Time Measured With Quantitative Reverse Transcriptase –Polymerase Chain Reaction (qRT-PCR) Assay
    End point description
    VL for RSV-A Memphis 37b was determined by quantitative reverse transcriptase -polymerase chain reaction (qRT-PCR) assay of nasal wash. The VL AUC was calculated based on the viral load values measured 2 times per day, starting with the last value prior to first dosing, and ending with the last available value before discharge (day 13). Here, intent-to-treat-infected (ITT-I) population was defined as all subjects who were challenged by virus inoculation with a positive viral load value (measured with qRT-PCR assay) immediately prior to first dosing or with 2 or more positive viral load values (measured with qRT-PCR assay) after the first administration of study medication and who received at least one dose of JNJ-53718678 or placebo.
    End point type
    Primary
    End point timeframe
    Baseline up to discharge (Day 13)
    End point values
    		 Placebo JNJ-53718678 75 milligram (mg) once daily JNJ-53718678 200 mg once daily JNJ-53718678 500 mg once daily
    Number of subjects analysed
    12
    9
    12
    12
    Units: log10 PFUe*hour per ml
        least squares mean (confidence interval 95%)
    432.8 (272.4 to 593.2)
    240.3 (42.3 to 438.4)
    203.8 (96.7 to 310.8)
    253.8 (135.4 to 372.2)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v JNJ-53718678 75 milligram (mg) once daily
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.105
    Method
    		 Least Squares Estimates
    Parameter type
    		 Mean difference (net)
    Point estimate
    -192.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -429.6
         upper limit
    		 44.7
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    JNJ-53718678 200 mg once daily v Placebo
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0167
    Method
    		 Least Squares Estimates
    Parameter type
    		 Mean difference (net)
    Point estimate
    -229
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -411.8
         upper limit
    		 -46.2
    Statistical analysis title
    		 Statistical Analysis 3
    Comparison groups
    Placebo v JNJ-53718678 500 mg once daily
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0629
    Method
    		 Least Squares Estimates
    Parameter type
    		 Mean difference (net)
    Point estimate
    -179
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -368.6
         upper limit
    		 10.6

    Secondary: Area Under Curve of Viral Load From Time 0 to 7 Days After First Dose Measured With qRT-PCR Assay

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    End point title
    		 Area Under Curve of Viral Load From Time 0 to 7 Days After First Dose Measured With qRT-PCR Assay
    End point description
    VL for RSV-A Memphis 37b was determined by quantitative reverse transcriptase -polymerase chain reaction (qRT-PCR) assay of nasal wash. The VL AUC was calculated based on the viral load values measured 2 times per day, starting with the last value prior to first dosing, and ending with the last available value on dosing day 7. Here, intent-to-treat-infected (ITT-I) population was defined as all subjects who were challenged by virus inoculation with a positive viral load value (measured with qRT-PCR assay) immediately prior to first dosing or with 2 or more positive viral load values (measured with qRT-PCR assay) after the first administration of study medication and who received at least one dose of JNJ-53718678 or placebo.
    End point type
    Secondary
    End point timeframe
    Baseline through day 7 of dose.
    End point values
    		 Placebo JNJ-53718678 75 milligram (mg) once daily JNJ-53718678 200 mg once daily JNJ-53718678 500 mg once daily
    Number of subjects analysed
    12
    9
    12
    12
    Units: log10 PFUe * hour per ml
        least squares mean (confidence interval 95%)
    390.5 (265.7 to 515.4)
    205.5 (61.3 to 349.7)
    192.9 (68 to 317.7)
    268.1 (143.2 to 392.9)
    No statistical analyses for this end point

    Secondary: Area Under Curve of Viral Load-Time From Time 0 to 24 Hours After First Dose Measured With qRT-PCR Assay

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    End point title
    		 Area Under Curve of Viral Load-Time From Time 0 to 24 Hours After First Dose Measured With qRT-PCR Assay
    End point description
    VL for RSV-A Memphis 37b was determined by quantitative reverse transcriptase -polymerase chain reaction (qRT-PCR) assay of nasal wash. The VL AUC was calculated based on the viral load values measured 2 times per day, starting with the last value prior to first dosing, and ending with the value 24 hours after start of dosing. Here, intent-to-treat-infected (ITT-I) population was defined as all subjects who were challenged by virus inoculation with a positive viral load value (measured with qRT-PCR assay) immediately prior to first dosing or with 2 or more positive viral load values (measured with qRT-PCR assay) after the first administration of study medication and who received at least one dose of JNJ-53718678 or placebo.
    End point type
    Secondary
    End point timeframe
    Baseline to 24 hours after first dose
    End point values
    		 Placebo JNJ-53718678 75 milligram (mg) once daily JNJ-53718678 200 mg once daily JNJ-53718678 500 mg once daily
    Number of subjects analysed
    12
    9
    12
    12
    Units: log10 PFUe*hour per ml
        least squares mean (confidence interval 95%)
    43 (25.4 to 60.5)
    35.8 (15.4 to 56.1)
    54.5 (36.9 to 72.1)
    65 (47.4 to 82.6)
    No statistical analyses for this end point

    Secondary: Area Under Curve of Viral Load-Time From Time 0 to 48 Hours After First Dose Measured With qRT-PCR Assay

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    End point title
    		 Area Under Curve of Viral Load-Time From Time 0 to 48 Hours After First Dose Measured With qRT-PCR Assay
    End point description
    VL for RSV-A Memphis 37b was determined by quantitative reverse transcriptase -polymerase chain reaction (qRT-PCR) assay of nasal wash. The VL AUC was calculated based on the viral load values measured 2 times per day, starting with the last value prior to first dosing, and ending with the value 48 hours after start of dosing. Here, intent-to-treat-infected (ITT-I) population was defined as all subjects who were challenged by virus inoculation with a positive viral load value (measured with qRT-PCR assay) immediately prior to first dosing or with 2 or more positive viral load values (measured with qRT-PCR assay) after the first administration of study medication and who received at least one dose of JNJ-53718678 or placebo.
    End point type
    Secondary
    End point timeframe
    Baseline to 48 hours after first dose
    End point values
    		 Placebo JNJ-53718678 75 milligram (mg) once daily JNJ-53718678 200 mg once daily JNJ-53718678 500 mg once daily
    Number of subjects analysed
    12
    9
    12
    12
    Units: log10 PFUe*hour per ml
        least squares mean (confidence interval 95%)
    112.2 (71.7 to 152.7)
    83.5 (36.8 to 130.3)
    100.9 (60.4 to 141.4)
    125.9 (85.4 to 166.4)
    No statistical analyses for this end point

    Secondary: Peak Viral Load Measured With qRT-PCR Assay

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    End point title
    		 Peak Viral Load Measured With qRT-PCR Assay
    End point description
    Peak viral load is defined as the maximum viral load value from baseline up to discharge. Here, intent-to-treat-infected (ITT-I) population was defined as all subjects who were challenged by virus inoculation with a positive viral load value (measured with qRT-PCR assay) immediately prior to first dosing or with 2 or more positive viral load values (measured with qRT-PCR assay) after the first administration of study medication and who received at least one dose of JNJ-53718678 or placebo.
    End point type
    Secondary
    End point timeframe
    Baseline up to discharge (Day 13)
    End point values
    		 Placebo JNJ-53718678 75 milligram (mg) once daily JNJ-53718678 200 mg once daily JNJ-53718678 500 mg once daily
    Number of subjects analysed
    12
    9
    12
    12
    Units: log10 PFUe
        least squares mean (confidence interval 95%)
    4.7 (3.7 to 5.7)
    3.2 (2 to 4.3)
    3.4 (2.4 to 4.4)
    4 (3 to 5)
    No statistical analyses for this end point

    Secondary: Overall Total Clinical Symptom Score

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    End point title
    		 Overall Total Clinical Symptom Score
    End point description
    Total (i.e sum) clinical symptom score was assessed using a composite of 10 self-reported symptoms on the Symptom Diary Card (SDC). Every Symptom Score ranges from 0 to 3. The overall total Clinical Symptom Score is the sum of all total Clinical Symptom Scores across all days. Here, intent-to-treat-infected (ITT-I) population was defined as all subjects who were challenged by virus inoculation with a positive viral load value (measured with qRT-PCR assay) immediately prior to first dosing or with 2 or more positive viral load values (measured with qRT-PCR assay) after the first administration of study medication and who received at least one dose of JNJ-53718678 or placebo.
    End point type
    Secondary
    End point timeframe
    Baseline up to discharge (Day 13)
    End point values
    		 Placebo JNJ-53718678 75 milligram (mg) once daily JNJ-53718678 200 mg once daily JNJ-53718678 500 mg once daily
    Number of subjects analysed
    12
    9
    12
    12
    Units: Units on a scale
        least squares mean (confidence interval 95%)
    36.6 (20.4 to 52.8)
    6.4 (-12.3 to 25.2)
    23.1 (6.9 to 39.3)
    14.8 (-1.4 to 31.1)
    No statistical analyses for this end point

    Secondary: Peak Total Clinical Symptom Score

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    End point title
    		 Peak Total Clinical Symptom Score
    End point description
    The peak total symptom score was the maximum of the total symptom score values for 1 subject. Here, intent-to-treat-infected (ITT-I) population was defined as all subjects who were challenged by virus inoculation with a positive viral load value (measured with qRT-PCR assay) immediately prior to first dosing or with 2 or more positive viral load values (measured with qRT-PCR assay) after the first administration of study medication and who received at least one dose of JNJ-53718678 or placebo.
    End point type
    Secondary
    End point timeframe
    Baseline up to discharge (Day 13)
    End point values
    		 Placebo JNJ-53718678 75 milligram (mg) once daily JNJ-53718678 200 mg once daily JNJ-53718678 500 mg once daily
    Number of subjects analysed
    12
    9
    12
    12
    Units: Units on a scale
        least squares mean (confidence interval 95%)
    5 (2.9 to 7.1)
    1.3 (-1 to 3.7)
    2.6 (0.5 to 4.6)
    1.9 (-0.1 to 4)
    No statistical analyses for this end point

    Secondary: Number of Tissues Used

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    End point title
    		 Number of Tissues Used
    End point description
    Here, intent-to-treat-infected (ITT-I) population was defined as all subjects who were challenged by virus inoculation with a positive viral load value (measured with qRT-PCR assay) immediately prior to first dosing or with 2 or more positive viral load values (measured with qRT-PCR assay) after the first administration of study medication and who received at least one dose of JNJ-53718678 or placebo.
    End point type
    Secondary
    End point timeframe
    Baseline up to discharge (Day 13)
    End point values
    		 Placebo JNJ-53718678 75 milligram (mg) once daily JNJ-53718678 200 mg once daily JNJ-53718678 500 mg once daily
    Number of subjects analysed
    12
    9
    12
    12
    Units: Number
        arithmetic mean (standard deviation)
    25.3 ± 25.99
    14.9 ± 28.31
    6.8 ± 6.31
    11.3 ± 8.41
    No statistical analyses for this end point

    Secondary: Weight of Mucus

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    End point title
    		 Weight of Mucus
    End point description
    Here, intent-to-treat-infected (ITT-I) population was defined as all subjects who were challenged by virus inoculation with a positive viral load value (measured with qRT-PCR assay) immediately prior to first dosing or with 2 or more positive viral load values (measured with qRT-PCR assay) after the first administration of study medication and who received at least one dose of JNJ-53718678 or placebo.
    End point type
    Secondary
    End point timeframe
    Baseline up to discharge (Day 13)
    End point values
    		 Placebo JNJ-53718678 75 milligram (mg) once daily JNJ-53718678 200 mg once daily JNJ-53718678 500 mg once daily
    Number of subjects analysed
    12
    9
    12
    12
    Units: Grams
        arithmetic mean (standard deviation)
    10.111 ± 14.9639
    7.014 ± 15.5249
    2.994 ± 3.7404
    4.798 ± 5.1623
    No statistical analyses for this end point

    Secondary: Area Under Curve of Viral Load Over Time Measured With Plaque Assay

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    End point title
    		 Area Under Curve of Viral Load Over Time Measured With Plaque Assay
    End point description
    VL for RSV-A Memphis 37b was determined by plaque forming unit (PFU) assay of nasal wash. The VL AUC was calculated based on the VL values measured 2 times per day, starting with the last value prior to first dosing, and ending with the last available value before discharge (day 13). Here, intent-to-treat-infected (ITT-I) population was defined as all subjects who were challenged by virus inoculation with a positive viral load value (measured with qRT-PCR assay) immediately prior to first dosing or with 2 or more positive viral load values (measured with qRT-PCR assay) after the first administration of study medication and who received at least one dose of JNJ-53718678 or placebo.
    End point type
    Secondary
    End point timeframe
    Baseline up to discharge (Day 13)
    End point values
    		 Placebo JNJ-53718678 75 milligram (mg) once daily JNJ-53718678 200 mg once daily JNJ-53718678 500 mg once daily
    Number of subjects analysed
    12
    9
    12
    12
    Units: log10 PFU*hour per ml
        least squares mean (confidence interval 95%)
    282.1 (183.2 to 380.9)
    206.6 (92.4 to 320.7)
    150.6 (51.7 to 249.5)
    256 (157.1 to 354.9)
    No statistical analyses for this end point

    Secondary: Area Under Curve of Viral Load-Time From Time 0 to 24 Hours After First Dose Measured With Plaque Assay

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    End point title
    		 Area Under Curve of Viral Load-Time From Time 0 to 24 Hours After First Dose Measured With Plaque Assay
    End point description
    VL for RSV-A Memphis 37b was determined by plaque forming unit (PFU) assay of nasal wash. The VL AUC was calculated based on the VL values measured 2 times per day, starting with the last available value prior to first dosing, and ending with the value 24 hours after start of dosing. Here, intent-to-treat-infected (ITT-I) population was defined as all subjects who were challenged by virus inoculation with a positive viral load value (measured with qRT-PCR assay) immediately prior to first dosing or with 2 or more positive viral load values (measured with qRT-PCR assay) after the first administration of study medication and who received at least one dose of JNJ-53718678 or placebo.
    End point type
    Secondary
    End point timeframe
    Baseline up to 24 hours after first dose
    End point values
    		 Placebo JNJ-53718678 75 milligram (mg) once daily JNJ-53718678 200 mg once daily JNJ-53718678 500 mg once daily
    Number of subjects analysed
    12
    9
    12
    12
    Units: log10 PFU*hour per ml
        least squares mean (confidence interval 95%)
    20.4 (4 to 36.8)
    27 (8 to 45.9)
    27.3 (10.9 to 43.8)
    48.5 (32.1 to 64.9)
    No statistical analyses for this end point

    Secondary: Area Under Curve of Viral Load-Time From Time 0 to 48 Hours After First Dose Measured With Plaque Assay

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    End point title
    		 Area Under Curve of Viral Load-Time From Time 0 to 48 Hours After First Dose Measured With Plaque Assay
    End point description
    VL for RSV-A Memphis 37b was determined by plaque forming unit (PFU) assay of nasal wash. The VL AUC was calculated based on the VL values measured 2 times per day, starting with the last value prior to first dosing, and ending with the last available value prior to first dosing, and ending with the value 48 hours after start of dosing. Here, intent-to-treat-infected (ITT-I) population was defined as all subjects who were challenged by virus inoculation with a positive viral load value (measured with qRT-PCR assay) immediately prior to first dosing or with 2 or more positive viral load values (measured with qRT-PCR assay) after the first administration of study medication and who received at least one dose of JNJ-53718678 or placebo.
    End point type
    Secondary
    End point timeframe
    Baseline up to 48 hours after first dose
    End point values
    		 Placebo JNJ-53718678 75 milligram (mg) once daily JNJ-53718678 200 mg once daily JNJ-53718678 500 mg once daily
    Number of subjects analysed
    12
    9
    12
    12
    Units: log10 PFUe*hour per ml
        least squares mean (confidence interval 95%)
    72.7 (37.5 to 108)
    63.5 (22.8 to 104.2)
    59 (23.8 to 94.3)
    103.6 (68.4 to 138.8)
    No statistical analyses for this end point

    Secondary: Peak Viral Load Measured With Plaque Assay

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    End point title
    		 Peak Viral Load Measured With Plaque Assay
    End point description
    Here, intent-to-treat-infected (ITT-I) population was defined as all subjects who were challenged by virus inoculation with a positive viral load value (measured with qRT-PCR assay) immediately prior to first dosing or with 2 or more positive viral load values (measured with qRT-PCR assay) after the first administration of study medication and who received at least one dose of JNJ-53718678 or placebo.
    End point type
    Secondary
    End point timeframe
    Baseline up to discharge (Day 13)
    End point values
    		 Placebo JNJ-53718678 75 milligram (mg) once daily JNJ-53718678 200 mg once daily JNJ-53718678 500 mg once daily
    Number of subjects analysed
    12
    9
    12
    12
    Units: log10 PFU
        least squares mean (confidence interval 95%)
    4.2 (3.3 to 5.2)
    2.7 (1.6 to 3.8)
    2.9 (2 to 3.9)
    3.7 (2.7 to 4.6)
    No statistical analyses for this end point

    Secondary: Area Under Curve of Viral Load From Time 0 to 7 Days After First Dose Measured With Plaque Assay

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    End point title
    		 Area Under Curve of Viral Load From Time 0 to 7 Days After First Dose Measured With Plaque Assay
    End point description
    VL for RSV-A Memphis 37b was determined by plaque forming unit (PFU) assay of nasal wash. The VL AUC was calculated based on the VL values measured 2 times per day, starting with the last value prior to first dosing, and ending with the last available value 7 days after start of dosing. Here, intent-to-treat-infected (ITT-I) population was defined as all subjects who were challenged by virus inoculation with a positive viral load value (measured with qRT-PCR assay) immediately prior to first dosing or with 2 or more positive viral load values (measured with qRT-PCR assay) after the first administration of study medication and who received at least one dose of JNJ-53718678 or placebo.
    End point type
    Secondary
    End point timeframe
    Baseline through 7 days after first dose
    End point values
    		 Placebo JNJ-53718678 75 milligram (mg) once daily JNJ-53718678 200 mg once daily JNJ-53718678 500 mg once daily
    Number of subjects analysed
    12
    9
    12
    12
    Units: log10 PFU*hour per ml
        least squares mean (confidence interval 95%)
    265 (174.8 to 355.2)
    170.3 (66.2 to 274.5)
    130.9 (40.7 to 221.1)
    215 (124.8 to 305.2)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline through Day 28
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 JNJ-53718678 500 mg was administered as 50 ml oral solution once daily for 7 days in both cohort 1 and cohort 2

    Reporting group title
    JNJ-53718678 75 mg qd
    Reporting group description
    		 JNJ-53718678 75 mg is administered as 7.5 milliliter (ml) once daily as oral solution for 7 days in cohort 2

    Reporting group title
    JNJ-53718678 200 mg qd
    Reporting group description
    		 JNJ-53718678 200 mg was administered as 20 ml oral solution once daily for 7 days in both cohort 1 and cohort 2

    Reporting group title
    JNJ-53718678 500 mg qd
    Reporting group description
    		 JNJ-53718678 500 mg was administered as 50 ml oral solution once daily for 7 days in both cohort 1 and cohort 2

    Serious adverse events
    		 Placebo JNJ-53718678 75 mg qd JNJ-53718678 200 mg qd JNJ-53718678 500 mg qd
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Placebo JNJ-53718678 75 mg qd JNJ-53718678 200 mg qd JNJ-53718678 500 mg qd
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 16 (56.25%)
    8 / 15 (53.33%)
    13 / 17 (76.47%)
    13 / 18 (72.22%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 17 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    1
    General disorders and administration site conditions
    Vessel Puncture Site Bruise
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 15 (13.33%)
    6 / 17 (35.29%)
    1 / 18 (5.56%)
         occurrences all number
    0
    2
    7
    1
    Investigations
    Activated Partial Thromboplastin Time Prolonged
         subjects affected / exposed
    2 / 16 (12.50%)
    2 / 15 (13.33%)
    1 / 17 (5.88%)
    0 / 18 (0.00%)
         occurrences all number
    2
    2
    1
    0
    Alanine Aminotransferase Increased
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Bilirubin Conjugated Increased
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blood Cholesterol Increased
         subjects affected / exposed
    0 / 16 (0.00%)
    4 / 15 (26.67%)
    0 / 17 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    4
    0
    1
    Blood Creatinine Increased
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 17 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    1
    Blood Fibrinogen Decreased
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Electrocardiogram Pr Prolongation
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    C-Reactive Protein Increased
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Electrocardiogram QRS Complex Prolonged
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Low Density Lipoprotein Increased
         subjects affected / exposed
    0 / 16 (0.00%)
    3 / 15 (20.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Electrocardiogram Change
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    1 / 17 (5.88%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Neutrophil Count Decreased
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 17 (5.88%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Spirometry Abnormal
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 17 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    1
    0
    0
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Limb Injury
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 17 (5.88%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 17 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    1
    Palpitations
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 17 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    1
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 17 (5.88%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Eye disorders
    Ocular Hyperaemia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    4 / 16 (25.00%)
    0 / 15 (0.00%)
    3 / 17 (17.65%)
    9 / 18 (50.00%)
         occurrences all number
    4
    0
    3
    10
    Abdominal Pain
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 17 (5.88%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Toothache
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Dermatitis Contact
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 17 (5.88%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Dermatitis Allergic
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 17 (5.88%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Erythema
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    2 / 17 (11.76%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Rash Erythematous
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 17 (5.88%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Rash Macular
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 17 (5.88%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Urticaria
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 17 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 17 (5.88%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Groin Pain
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 17 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    1
    Musculoskeletal Chest Pain
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 17 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    1
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 17 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Jun 2015
    Amendment was created to make the time window for start of dosing after a positive RSV-detection test in Cohort 2 flexible, in line with other dosing decisions for Cohort 2 which were also determined based upon the emerging data from Cohort 1. In addition, some updates occured: for consistency between the protocol body text and the Time and Events Schedule, the Time and Events Schedule was updated to indicate that (1) nasal wash samples for the RSV positivity assay were collected from Study Day 2 onwards and that (2) the SDC also had to be completed on Study Day 1. To make the differences between Cohort 1 and Cohort 2 clearer, the time and events schedule was split up in 2 separate tables (1 for each cohort). Due to a company name change, Retroscreen Virology Limited was replaced by hVIVO. For consistency within the protocol, the limit for the PR-interval was changed from <220 millisecound (msec) to <210 msec, in line with the determination of values greater than or equal to (>=) 210 msec as “abnormally high”. Minor errors were corrected.
    28 Aug 2015
    The protocol was updated to include a third cohort of 8 or 12 subjects (randomized 3:1 to JNJ-53718678 75 mg or placebo, respectively), depending on the combined infection rate for Cohort 1 and Cohort 2, to supplement the number of subjects dosed with 75 mg in Cohort 2 with the purpose of having overall an approximately equal number of infected subjects (in the ITT-I population which was used for the efficacy analysis) on each dose level evaluated (ie, JNJ-53718678 75 mg, 200 mg, and 500 mg). As a result of the decision on the doses in Cohort 2, for Cohorts 1 and 2 combined, 18 subjects were planned to be randomized to either the JNJ-53718678 200-mg or 500-mg dose level, whereas only 12 subjects were planned to be randomized to the JNJ-53718678 75-mg dose. In line with the decisions for Cohort 2, the duration of dosing in Cohort 3 was to be 7 days, the dosing regimen qd, and the start of treatment approximately 12 hours after positive PCR or in the morning of Day 6 for non-infected subjects, while the assessment schedule was to be the same as for Cohort 1. In view of the addition of Cohort 3, the final analysis including data from all cohorts was to be performed after completion of Cohort 3. However, in view of further development activities, an unblinded interim analysis on the combined data from Cohort 1 and Cohort 2 was planned after completion of Cohort 2. It was clarified that additional subjects could be recruited in case of a dropout after receiving the first dose of study for reasons other than safety. If a subject dropped out of the study due to safety concerns, no additional subject could be recruited to replace this subject. Cohort 3 was not performed and the final analysis was performed after completion of cohort 2.

    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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