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    Clinical Trial Results:
    A Phase 2b, Randomized, Double-Blind, Placebo-Controlled Multi-Center Study Evaluating Antiviral Effects, Pharmacokinetics, Safety, and Tolerability of GS-5806 in Hematopoietic Cell Transplant (HCT) Recipients with Respiratory Syncytial Virus (RSV) Infection of the Lower Respiratory Tract

    Summary
    EudraCT number
    2014-002475-29
    Trial protocol
    NL   DE  
    Global end of trial date
    17 Apr 2017

    Results information
    Results version number
    v1
    This version publication date
    12 Apr 2018
    First version publication date
    12 Apr 2018
    Other versions
    v2

    Trial information

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    Trial identification
    Sponsor protocol code
    GS-US-218-1502
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02254421
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Gilead Sciences
    Sponsor organisation address
    333 Lakeside Drive, Foster City, CA, United States, 94404
    Public contact
    Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@gilead.com
    Scientific contact
    Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@gilead.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
    17 Apr 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Apr 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Apr 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the effect of presatovir on respiratory syncytial virus (RSV) viral load in autologous or allogeneic hematopoietic cell transplant (HCT) recipients with an acute RSV lower respiratory tract infection (LRTI).
    Protection of trial subjects
    The protocol and consent/assent forms were submitted by each investigator to a duly constituted Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for review and approval before study initiation. All revisions to the consent/assent forms (if applicable) after initial IEC/IRB approval were submitted by the investigator to the IEC/IRB for review and approval before implementation in accordance with regulatory requirements. This study was conducted in accordance with recognized international scientific and ethical standards, including but not limited to the International Conference on Harmonization guideline for Good Clinical Practice (ICH GCP) and the original principles embodied in the Declaration of Helsinki.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    31 Jan 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Sweden: 1
    Country: Number of subjects enrolled
    France: 4
    Country: Number of subjects enrolled
    United States: 48
    Country: Number of subjects enrolled
    Korea, Republic of: 4
    Country: Number of subjects enrolled
    Switzerland: 3
    Worldwide total number of subjects
    60
    EEA total number of subjects
    5
    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)
    47
    From 65 to 84 years
    13
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Participants were enrolled at study sites in Asia Pacific, Europe, and the United States. The first participant was screened on 31 January 2015. The last study visit occurred on 17 April 2017.

    Pre-assignment
    Screening details
    71 participants were screened.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Presatovir
    Arm description
    Presatovir on Days 1, 5, 9, 13, and 17
    Arm type
    Experimental

    Investigational medicinal product name
    Presatovir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use, Nasogastric use
    Dosage and administration details
    Presatovir 200 mg (4 x 50 mg tablets) administered orally or via nasogastric tube

    Arm title
    Placebo
    Arm description
    Placebo on Days 1, 5, 9, 13, and 17
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Nasogastric use , Oral use
    Dosage and administration details
    Placebo administered orally or via nasogastric tube

    Number of subjects in period 1 [1]
    Presatovir Placebo
    Started
    30
    29
    Completed
    29
    26
    Not completed
    1
    3
         Death
    -
    2
         Withdrew consent
    1
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 1 participant from the Presatovir group who was enrolled but not treated is not included in the subject disposition table.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Presatovir
    Reporting group description
    Presatovir on Days 1, 5, 9, 13, and 17

    Reporting group title
    Placebo
    Reporting group description
    Placebo on Days 1, 5, 9, 13, and 17

    Reporting group values
    Presatovir Placebo Total
    Number of subjects
    30 29 59
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    50.5 ± 16.27 54.4 ± 12.59 -
    Gender categorical
    Units: Subjects
        Female
    9 6 15
        Male
    21 23 44
    Race
    Units: Subjects
        American Indian or Alaska Native
    1 1 2
        Asian
    4 3 7
        Black or African American
    1 2 3
        White
    23 18 41
        Not Permitted
    1 5 6
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    5 6 11
        Not Hispanic or Latino
    23 18 41
        Not Permitted
    2 5 7
    Stratification Factor: Supplemental O2 Requirement at Time of Randomization
    Units: Subjects
        Supplemental O2 Requirement ≤ 2 L/min
    19 19 38
        Supplemental O2 Requirement > 2 L/min
    11 10 21
    Stratification Factor: Treatment of Current RSV Infection with Ribavirin
    Units: Subjects
        Yes
    12 11 23
        No
    18 18 36
    Nasal Viral Load
    Units: log10 copies/mL
        arithmetic mean (standard deviation)
    6.22 ± 1.365 6.02 ± 1.574 -
    Oxygen Saturation
    Oxygen saturation is a measure of how much oxygen the blood is carrying as a percentage of the maximum it could carry.
    Units: percent saturation
        arithmetic mean (standard deviation)
    94 ± 3.8 93 ± 5.1 -

    End points

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    End points reporting groups
    Reporting group title
    Presatovir
    Reporting group description
    Presatovir on Days 1, 5, 9, 13, and 17

    Reporting group title
    Placebo
    Reporting group description
    Placebo on Days 1, 5, 9, 13, and 17

    Primary: Time-weighted Average Change in Nasal Respiratory Syncytial Viral (RSV) Load From Baseline to Day 9

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    End point title
    Time-weighted Average Change in Nasal Respiratory Syncytial Viral (RSV) Load From Baseline to Day 9
    End point description
    The time-weighted average change, often referred to as the DAVG, provides the average viral burden change from baseline. The mean values presented were calculated using the ANCOVA model and are adjusted for baseline value and stratification factors. The Full Analysis Set included all randomized participants who received at least 1 full dose of study drug and had an RSV viral load greater than or equal to the lower limit of quantification of the RT-qPCR assay in the Day 1 nasal sample, as determined by RT-qPCR at the central lab.
    End point type
    Primary
    End point timeframe
    Baseline to Day 9
    End point values
    Presatovir Placebo
    Number of subjects analysed
    29
    28
    Units: log10 copies/mL
        arithmetic mean (standard error)
    -1.00 ± 0.215
    -0.97 ± 0.218
    Statistical analysis title
    Statistical Analysis - Presatovir vs Placebo
    Comparison groups
    Placebo v Presatovir
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.94 [1]
    Method
    ANCOVA
    Parameter type
    Treatment difference
    Point estimate
    -0.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.62
         upper limit
    0.57
    Notes
    [1] - P-value was calculated from the ANCOVA model including baseline values and stratification factors.

    Secondary: Number of Supplemental O2-Free Days Through Day 28

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    End point title
    Number of Supplemental O2-Free Days Through Day 28
    End point description
    The Full Analysis Set includes all randomized participants who received at least 1 full dose of study drug and had an RSV viral load greater than or equal to the lower limit of quantification of the RT-qPCR assay in the Day 1 nasal sample, as determined by RT-qPCR at the central lab.
    End point type
    Secondary
    End point timeframe
    Up to Day 28
    End point values
    Presatovir Placebo
    Number of subjects analysed
    29
    28
    Units: days
        median (inter-quartile range (Q1-Q3))
    26 (10 to 28)
    28 (9 to 28)
    Statistical analysis title
    Statistical Analysis - Presatovir vs Placebo
    Comparison groups
    Presatovir v Placebo
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.84 [2]
    Method
    Negative Binomial Model
    Confidence interval
    Notes
    [2] - P-value was calculated from the negative binomial model with stratification factors as covariates.

    Secondary: Percentage of Participants Developing Respiratory Failure Requiring Mechanical Ventilation Through Day 28

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    End point title
    Percentage of Participants Developing Respiratory Failure Requiring Mechanical Ventilation Through Day 28
    End point description
    The Full Analysis Set includes all randomized participants who received at least 1 full dose of study drug and had an RSV viral load greater than or equal to the lower limit of quantification of the RT-qPCR assay in the Day 1 nasal sample, as determined by RT-qPCR at the central lab.
    End point type
    Secondary
    End point timeframe
    Up to Day 28
    End point values
    Presatovir Placebo
    Number of subjects analysed
    29
    28
    Units: percentage of participants
        number (confidence interval 95%)
    10.3 (2.2 to 27.4)
    10.7 (2.3 to 28.2)
    Statistical analysis title
    Statistical Analysis - Presatovir vs Placebo
    Comparison groups
    Presatovir v Placebo
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.98 [3]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [3] - P-value was calculated from the Cochran-Mantel-Haenszel (CMH) test stratified by stratification factors.

    Secondary: Percentage of All-Cause Mortality Among Participants Through Day 28

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    End point title
    Percentage of All-Cause Mortality Among Participants Through Day 28
    End point description
    The Full Analysis Set includes all randomized participants who received at least 1 full dose of study drug and had an RSV viral load greater than or equal to the lower limit of quantification of the RT-qPCR assay in the Day 1 nasal sample, as determined by RT-qPCR at the central lab.
    End point type
    Secondary
    End point timeframe
    Up to Day 28
    End point values
    Presatovir Placebo
    Number of subjects analysed
    29
    28
    Units: percentage of participants
        number (confidence interval 95%)
    0.0 (0.0 to 11.9)
    7.1 (0.9 to 23.5)
    Statistical analysis title
    Statistical Analysis - Presatovir vs Placebo
    Comparison groups
    Presatovir v Placebo
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.19 [4]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [4] - P-value was calculated from the CMH test stratified by stratification factors.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Day 28
    Adverse event reporting additional description
    Safety Analysis Set: participants who received at least 1 full dose of study drug.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Presatovir
    Reporting group description
    Presatovir on Days 1, 5, 9, 13, and 17

    Reporting group title
    Placebo
    Reporting group description
    Placebo on Days 1, 5, 9, 13, and 17

    Serious adverse events
    Presatovir Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 30 (23.33%)
    7 / 29 (24.14%)
         number of deaths (all causes)
    0
    4
         number of deaths resulting from adverse events
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute leukaemia
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 29 (6.90%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute respiratory failure
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Graft versus host disease
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Altered state of consciousness
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    3 / 30 (10.00%)
    2 / 29 (6.90%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Presatovir Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 30 (63.33%)
    17 / 29 (58.62%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 29 (3.45%)
         occurrences all number
    2
    1
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 30 (6.67%)
    3 / 29 (10.34%)
         occurrences all number
    2
    4
    Oedema peripheral
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 29 (6.90%)
         occurrences all number
    1
    2
    Fatigue
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    0
    2
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 29 (0.00%)
         occurrences all number
    3
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 29 (6.90%)
         occurrences all number
    1
    2
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 30 (10.00%)
    1 / 29 (3.45%)
         occurrences all number
    3
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 29 (3.45%)
         occurrences all number
    2
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 29 (0.00%)
         occurrences all number
    2
    0
    Troponin T increased
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    0
    2
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    0
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 30 (3.33%)
    3 / 29 (10.34%)
         occurrences all number
    1
    3
    Thrombocytopenia
         subjects affected / exposed
    1 / 30 (3.33%)
    3 / 29 (10.34%)
         occurrences all number
    1
    3
    Lymphopenia
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 29 (6.90%)
         occurrences all number
    1
    2
    Neutropenia
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 30 (0.00%)
    3 / 29 (10.34%)
         occurrences all number
    0
    3
    Epistaxis
         subjects affected / exposed
    3 / 30 (10.00%)
    0 / 29 (0.00%)
         occurrences all number
    3
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 30 (6.67%)
    3 / 29 (10.34%)
         occurrences all number
    2
    4
    Dizziness
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    0
    2
    Eye disorders
    Visual impairment
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    0
    2
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 30 (10.00%)
    3 / 29 (10.34%)
         occurrences all number
    3
    3
    Nausea
         subjects affected / exposed
    3 / 30 (10.00%)
    1 / 29 (3.45%)
         occurrences all number
    3
    1
    Dry mouth
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 29 (3.45%)
         occurrences all number
    2
    1
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    0
    2
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 29 (6.90%)
         occurrences all number
    1
    2
    Pruritus
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 29 (0.00%)
         occurrences all number
    2
    0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    0
    2
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    3 / 30 (10.00%)
    1 / 29 (3.45%)
         occurrences all number
    3
    1
    Infections and infestations
    Acute sinusitis
         subjects affected / exposed
    3 / 30 (10.00%)
    0 / 29 (0.00%)
         occurrences all number
    3
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 Jul 2014
    ● An optional extended viral monitoring section was created and appropriate text was included throughout the protocol to describe the study procedures during this period. In addition, planned analyses of the optional extended viral monitoring data were added to applicable sections of the protocol. ● The discontinuation criteria section was revised such that all Grade 3 or 4 adverse events (AEs) or serious adverse events (SAEs) must have been reviewed with the Gilead Sciences (Gilead) medical monitor to assess whether to continue study drug administration, to ensure that any Grade 3 or 4 AEs/SAEs that were associated with graft-versus-host disease (GVHD) or veno-occlusive disease were reviewed. ● Updated study drug instructions to recommend that subjects avoid direct UV exposure for the duration of exposure to presatovir (ie, 8 days following study drug administration), as the potential risk of phototoxicity was unknown and presatovir should have been almost completely eliminated within 8 days. ● The concomitant medications section was updated to address potential drug-drug interactions for presatovir and to clarify the need for safety monitoring consistent with the prescribing information for other agents when given concomitantly with presatovir, as presatovir affects transporters and has the potential to affect exposures of other drugs that depend on the same transporters. ● Appendix 5 was updated to provide additional information regarding pregnancy precautions and contraceptive requirements. ● The terminology of relevant endpoints was updated from daily averages to time-weighted averages as this term, along with time-weighted average change, is often used in literature. The definitions and calculations of the endpoints remained the same. ● Inclusion Criterion 2 was updated to < 48 hours prior to screening for clarity. ● Inclusion Criterion 7 was removed for consistency with Exclusion Criterion 3
    22 Sep 2014
    ● Exclusion Criterion 2 (washout period for strong cytochrome P450 enzyme [CYP] inducers) was extended from 1 to 2 weeks to reflect a more conservative washout period. ● Pregnancy testing was added at all dosing visits for females of childbearing potential for consistency with Appendix 5: Pregnancy Precautions, Definition for Female of Childbearing Potential, and Contraceptive Requirement. ● Male contraceptive and sperm donation requirements were extended from 30 to 90 days after last dose of study drug for consistency with the investigator’s brochure (IB). ● Inclusion Criterion 6 (contraceptive requirements) was modified in alignment with changes made to contraceptive requirements in Appendix 5.
    21 Oct 2014
    ● Removal of double-barrier method as contraceptive method to ensure all contraception is in accordance with the ICH M3 guidance that birth control methods need to be highly effective (ie, < 1% failure rate).
    30 Jun 2015
    ● Reproductive toxicology data in the protocol background was updated to reflect the definitive rat and rabbit studies. ● Exclusion Criterion 8 was removed as the intent of the criterion is covered in Exclusion Criterion 13 ● Exclusion Criteria 16 and 17 (aspartate aminotransferase [AST]/alanine aminotransferase [ALT] and total bilirubin [TBIL] requirements), discontinuation criteria, and safety labs were updated to include hepatic monitoring consistent with Canadian regulations. ● Study drug administration information updated to allow for nasogastric (NG) tube administration, and removal of the need for fasting or avoidance of direct UV exposure per new stability and phototoxicity data of GS-5806-02. ● Study drug discontinuation criteria updated to include extra hepatic monitoring and Hy’s law in accordance with Canadian regulations. ● Secondary and exploratory endpoints and analyses updated ● Induced sputum removed as collection of this sample is not standard practice. ● Section 1.2.2 was updated for consistency with the IB. ● A new Inclusion Criterion 1 was added to clarify age ranges allowed in the study. ● Exclusion Criterion 2 (CYP restrictions) and Section 5.4: Prior and Concomitant Medications were updated to further exclude moderate CYP inducers, as DDI results indicated that moderate CYP inducers moderately decrease presatovir exposure. ● Exclusion Criterion 8 (other respiratory viruses) was updated to exclude coronaviruses due to severe clinical disease now known to be associated with Middle East respiratory syndrome. ●Exclusion Criterion 14 (allergy to sulfa drugs) was updated to clarify that the criterion applies to sulfa reactions that are of most concern. ● Hepatic monitoring and statistical texts were updated for clarity
    30 Nov 2015
    ● Section 1.2.4.4: Ongoing Studies was added to provide consistency among protocols in the presatovir program. ● Inclusion Criteria 4 (documented RSV) and Section 6.11.1: Nasal Samples, Virology, and Antibody Titer were updated to clarify that spontaneous sputum is not allowed. ● Screening RSV testing was updated to allow for standard clinical practice procedures surrounding RSV diagnosis confirmation and in meeting study inclusion criteria. ● Electrocardiograms (ECGs), troponin testing, and collection of standard of care clinical data for central review were added. ● The prior and concomitant medications section was updated to attribute part of cyclosporine effect as a weak CYP3A inhibitor, to clarify that presatovir is not expected to alter PK of concomitant medications that are substrates of major CYP enzymes or drug transporters, and to note that the potential effect of strong- and moderate-CYP3A inhibitors on presatovir PK are under investigation. ● Vital signs and O2 saturation measurement were added to Visits 3 and 5, if not home visits, and study-specific assessments were added to all study visits for consistency. ● The O2 saturation measurement procedure was updated for consistency across the presatovir program and to allow subjects to remain on chronic O2 for standards in clinical care.
    28 Mar 2016
    ● Screening procedures were modified such that subjects who were not tested for RSV as standard of care could consent to the study and be tested for RSV during the screening visit. ● Visit 3 was made optional if the subject was not hospitalized at the time of visit to reduce the visit burden during the first 9 days of the study. ● The number of sites was increased in order to accelerate enrollment. ● Sweden-specific requirements for obtaining consent via legal guardian were added to the inclusion criteria. ● Section 6.1.1: Visit 1: Screening Visit was updated to allow subjects who screen failed out of GS-US-218-0108 due to presence of LRTI to screen into GS-US-218-1502 and vice versa. ● Administrative clarifications were made to Section 8: Statistical Considerations.

    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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