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    Clinical Trial Results:
    A Phase III, Randomized, Placebo-Controlled Clinical Trial to Study the Efficacy and Safety of MK-3641, a Ragweed (Ambrosia artemisiifolia) Sublingual Immunotherapy Tablet, in Children With a History of Ragweed-Induced Rhinoconjunctivitis With or Without Asthma

    Summary
    EudraCT number
    		 2014-004341-27
    Trial protocol
    		 HU   HR   Outside EU/EEA  
    Global end of trial date
    19 Nov 2018

    Results information
    Results version number
    		 v2(current)
    This version publication date
    06 Sep 2019
    First version publication date
    31 May 2019
    Other versions
    		 v1
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    3641-008
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02478398
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, United States, 07330
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001881-PIP01-15
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    19 Nov 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Nov 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Nov 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to assess the efficacy and safety of MK-3641 (short ragweed [Ambrosia artemisiifolia] extract, MK-3641, SCH 039641, RAGWITEK™) sublingual immunotherapy tablets in children aged 5 to 17 years with ragweed-induced allergic rhinitis/rhinoconjunctivitis with or without asthma. The primary hypothesis of this study is that administration of MK-3641 sublingual immunotherapy tablets to children 5 to 17 years of age, compared with placebo, will result in a significant reduction in the combination of rhinoconjunctivitis symptoms and medication use over the peak ragweed season (RS).
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    		 Only those participants with ragweed pollen-induced rhinoconjunctivitis with or without controlled asthma were eligible for participation in this study. Participants with asthma may have used as-needed short-acting beta2-agonists (SABAs) and/or low or medium daily doses of inhaled corticosteroids (ICS).
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Jul 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
    Canada: 246
    Country: Number of subjects enrolled
    Croatia: 79
    Country: Number of subjects enrolled
    Hungary: 145
    Country: Number of subjects enrolled
    Serbia: 161
    Country: Number of subjects enrolled
    Ukraine: 185
    Country: Number of subjects enrolled
    United States: 209
    Worldwide total number of subjects
    1025
    EEA total number of subjects
    224
    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)
    410
    Adolescents (12-17 years)
    606
    Adults (18-64 years)
    9
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Participants who were 17 years old at screening and who turned 18 years old prior to randomization were permitted to continue in the study.

    Period 1
    Period 1 title
    Randomization
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Short ragweed pollen allergen extract
    Arm description
    		 Participants randomized to short ragweed pollen allergen extract sublingual tablet, to be administered once daily (QD) for up to 35 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Short ragweed pollen allergen extract
    Investigational medicinal product code
    Other name
    SCH 03 9641 (MK-3641)
    Pharmaceutical forms
    Tablet
    Routes of administration
    Sublingual use
    Dosage and administration details
    One short ragweed pollen allergen extract sublingual tablet, administered once daily (QD) for up to 35 weeks.

    Investigational medicinal product name
    Loratadine
    Investigational medicinal product code
    Other name
    Rescue therapy
    Pharmaceutical forms
    Syrup, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Loratadine syrup 1 mg/mL, administered as needed for rhinoconjunctivitis symptoms as 5 mL QD for 5-year-old participants and 10 mL QD for 6- to 17-year-old participants, or loratadine tablet (5 mg or 10 mg) administered as one 5 mg tablet QD for 5-year-old participants and one 10 mg tablet QD for 6- to 17-year-old participants

    Investigational medicinal product name
    Olopatadine
    Investigational medicinal product code
    Other name
    Rescue therapy
    Pharmaceutical forms
    Eye drops
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    Olopatadine ophthalmic solution 0.1%, administered as needed for rhinoconjunctivitis symptoms as one drop in each affected eye twice daily

    Investigational medicinal product name
    Mometasone
    Investigational medicinal product code
    Other name
    Rescue therapy
    Pharmaceutical forms
    Nasal spray
    Routes of administration
    Intranasal use
    Dosage and administration details
    Mometasone furoate nasal spray 50 mcg, administered as needed for rhinoconjunctivitis symptoms as one spray in each nostril QD for 5- to 11- year old participants and or as two sprays in each nostril for 12- to 17-year-old participants

    Investigational medicinal product name
    Epinephrine
    Investigational medicinal product code
    Other name
    Rescue therapy
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Self-injectable epinephrine, administered as needed for severe allergic reactions at suggested doses of 15-30 kg for participants weighing 33-66 pounds (0.15 mg) or ≥30 kg for participants weighing ≥66 pounds (0.3 mg). Epinephrine was only provided in countries/study sites where it was a regulatory requirement.

    Investigational medicinal product name
    Albuterol/Salbutamol
    Investigational medicinal product code
    Other name
    Rescue therapy
    Pharmaceutical forms
    Pressurised inhalation
    Routes of administration
    Inhalation use
    Dosage and administration details
    Albuterol metered-dose inhaler (90 mcg/puff); salbutamol metered-dose inhaler (100 mcg/puff) administered as needed as asthma rescue medication for those participants with asthma

    Arm title
    		 Placebo
    Arm description
    		 Participants randomized to placebo sublingual tablet, to be administered QD for up to 35 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Sublingual use
    Dosage and administration details
    One placebo sublingual tablet, administered QD for up to 35 weeks

    Investigational medicinal product name
    Loratadine
    Investigational medicinal product code
    Other name
    Rescue therapy
    Pharmaceutical forms
    Syrup, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Loratadine syrup 1 mg/mL, administered as needed for rhinoconjunctivitis symptoms as 5 mL QD for 5-year-old participants and 10 mL QD for 6- to 17-year-old participants, or loratadine tablet (5 mg or 10 mg) administered as one 5 mg tablet QD for 5-year-old participants and one 10 mg tablet QD for 6- to 17-year-old participants

    Investigational medicinal product name
    Olopatadine
    Investigational medicinal product code
    Other name
    Rescue therapy
    Pharmaceutical forms
    Eye drops
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    Olopatadine ophthalmic solution 0.1%, administered as needed for rhinoconjunctivitis symptoms as one drop in each affected eye twice daily

    Investigational medicinal product name
    Mometasone
    Investigational medicinal product code
    Other name
    Rescue therapy
    Pharmaceutical forms
    Nasal spray
    Routes of administration
    Intranasal use
    Dosage and administration details
    Mometasone furoate nasal spray 50 mcg, administered as needed for rhinoconjunctivitis symptoms as one spray in each nostril QD for 5- to 11- year old participants and or as two sprays in each nostril for 12- to 17-year-old participants

    Investigational medicinal product name
    Epinephrine
    Investigational medicinal product code
    Other name
    Rescue therapy
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Self-injectable epinephrine, administered as needed for severe allergic reactions at suggested doses of 15-30 kg for participants weighing 33-66 pounds (0.15 mg) or ≥30 kg for participants weighing ≥66 pounds (0.3 mg). Epinephrine was only provided in countries/study sites where it was a regulatory requirement.

    Investigational medicinal product name
    Albuterol/Salbutamol
    Investigational medicinal product code
    Other name
    Rescue therapy
    Pharmaceutical forms
    Pressurised inhalation
    Routes of administration
    Inhalation use
    Dosage and administration details
    Albuterol metered-dose inhaler (90 mcg/puff); salbutamol metered-dose inhaler (100 mcg/puff) administered as needed as asthma rescue medication for those participants with asthma

    Number of subjects in period 1
    		Short ragweed pollen allergen extract Placebo
    Started
    513
    512
    Completed
    512
    510
    Not completed
    1
    2
         Withdrawal By Parent/Guardian
    -
    2
         Protocol deviation
    1
    -
    Period 2
    Period 2 title
    Treatment
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    A double-blind/masking technique was used. Short ragweed pollen allergen extract and placebo were packaged identically so blind/masking was maintained. The participant/parent/guardian and the investigator were unaware of the group assignments.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Short ragweed pollen allergen extract
    Arm description
    		 One short ragweed pollen allergen extract sublingual tablet, once daily (QD) for up to 35 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Short ragweed pollen allergen extract
    Investigational medicinal product code
    Other name
    SCH 03 9641 (MK-3641)
    Pharmaceutical forms
    Tablet
    Routes of administration
    Sublingual use
    Dosage and administration details
    One short ragweed pollen allergen extract sublingual tablet, administered once daily (QD) for up to 35 weeks.

    Investigational medicinal product name
    Loratadine
    Investigational medicinal product code
    Other name
    Rescue therapy
    Pharmaceutical forms
    Syrup, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Loratadine syrup 1 mg/mL, administered as needed for rhinoconjunctivitis symptoms as 5 mL QD for 5-year-old participants and 10 mL QD for 6- to 17-year-old participants, or loratadine tablet (5 mg or 10 mg) administered as needed for rhinoconjunctivitis symptoms as one 5 mg tablet QD for 5-year-old participants and one 10 mg tablet QD for 6- to 17-year-old participants

    Investigational medicinal product name
    Olopatadine
    Investigational medicinal product code
    Other name
    Rescue therapy
    Pharmaceutical forms
    Eye drops
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    Olopatadine ophthalmic solution 0.1%, administered as needed for rhinoconjunctivitis symptoms as one drop in each affected eye twice daily

    Investigational medicinal product name
    Mometasone
    Investigational medicinal product code
    Other name
    Rescue therapy
    Pharmaceutical forms
    Nasal spray
    Routes of administration
    Intranasal use
    Dosage and administration details
    Mometasone furoate nasal spray 50 mcg, administered as needed for rhinoconjunctivitis symptoms as one spray in each nostril QD for 5- to 11- year old participants and or as two sprays in each nostril for 12- to 17-year-old participants

    Investigational medicinal product name
    Epinephrine
    Investigational medicinal product code
    Other name
    Rescue therapy
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Self-injectable epinephrine, administered as needed for severe allergic reactions at suggested doses of 15-30 kg for participants weighing 33-66 pounds (0.15 mg) or ≥30 kg for participants weighing ≥66 pounds (0.3 mg). Epinephrine was only provided in countries/study sites where it was a regulatory requirement.

    Investigational medicinal product name
    Albuterol/Salbutamol
    Investigational medicinal product code
    Other name
    Rescue therapy
    Pharmaceutical forms
    Pressurised inhalation
    Routes of administration
    Inhalation use
    Dosage and administration details
    Albuterol metered-dose inhaler (90 mcg/puff); salbutamol metered-dose inhaler (100 mcg/puff) administered as needed as asthma rescue medication for those participants with asthma

    Arm title
    		 Placebo
    Arm description
    		 Participants received one placebo sublingual tablet, QD for up to 35 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Sublingual use
    Dosage and administration details
    One placebo sublingual tablet, administered QD for up to 28 weeks

    Investigational medicinal product name
    Loratadine
    Investigational medicinal product code
    Other name
    Rescue therapy
    Pharmaceutical forms
    Syrup, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Loratadine syrup 1 mg/mL, administered as needed for rhinoconjunctivitis symptoms as 5 mL QD for 5-year-old participants and 10 mL QD for 6- to 17-year-old participants, or loratadine tablet (5 mg or 10 mg) administered as one 5 mg tablet QD for 5-year-old participants and one 10 mg tablet QD for 6- to 17-year-old participants

    Investigational medicinal product name
    Olopatadine
    Investigational medicinal product code
    Other name
    Rescue therapy
    Pharmaceutical forms
    Eye drops
    Routes of administration
    Ophthalmic use
    Dosage and administration details
    Olopatadine ophthalmic solution 0.1%, administered as needed for rhinoconjunctivitis symptoms as one drop in each affected eye twice daily

    Investigational medicinal product name
    Mometasone
    Investigational medicinal product code
    Other name
    Rescue therapy
    Pharmaceutical forms
    Nasal spray
    Routes of administration
    Intranasal use
    Dosage and administration details
    Mometasone furoate nasal spray 50 mcg, administered as needed for rhinoconjunctivitis symptoms as one spray in each nostril QD for 5- to 11- year old participants and or as two sprays in each nostril for 12- to 17-year-old participants

    Investigational medicinal product name
    Epinephrine
    Investigational medicinal product code
    Other name
    Rescue therapy
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Self-injectable epinephrine, administered as needed for severe allergic reactions at suggested doses of 15-30 kg for participants weighing 33-66 pounds (0.15 mg) or ≥30 kg for participants weighing ≥66 pounds (0.3 mg). Epinephrine was only provided in countries/study sites where it was a regulatory requirement.

    Investigational medicinal product name
    Albuterol/Salbutamol
    Investigational medicinal product code
    Other name
    Rescue therapy
    Pharmaceutical forms
    Pressurised inhalation
    Routes of administration
    Inhalation use
    Dosage and administration details
    Albuterol metered-dose inhaler (90 mcg/puff); salbutamol metered-dose inhaler (100 mcg/puff) administered as needed as asthma rescue medication for those participants with asthma

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Period 2 was defined as the Baseline period for the study.
    Number of subjects in period 2 [2]
    		Short ragweed pollen allergen extract Placebo
    Started
    512
    510
    Completed
    461
    491
    Not completed
    51
    19
         Withdrawal By Participant
    10
    4
         Adverse event, non-fatal
    20
    5
         Withdrawal By Parent/Guardian
    9
    4
         Non-Compliance With Study Drug
    5
    1
         Lost to follow-up
    5
    4
         Protocol deviation
    2
    1
    Notes
    [2] - 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: The number of participants globally enrolled was greater than the number of participants who received treatment and entered the baseline period. Period 2 was the Baseline period.

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Short ragweed pollen allergen extract
    Reporting group description
    		 One short ragweed pollen allergen extract sublingual tablet, once daily (QD) for up to 35 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received one placebo sublingual tablet, QD for up to 35 weeks.

    Reporting group values
    		 Short ragweed pollen allergen extract Placebo Total
    Number of subjects
    		 512 510 1022
    Age Categorical
    Units: Subjects
        < 12 years
    		 206 204 410
        ≥ 12 years
    		 306 306 612
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 12.1 ( 3.2 ) 12.2 ( 3.1 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 188 191 379
        Male
    		 324 319 643
    Race
    Units: Subjects
        White
    		 473 477 950
        Black or African American
    		 18 14 32
        Asian
    		 4 6 10
        Native Hawaiian or Other Pacific Islander
    		 3 2 5
        American Indian or Alaska Native
    		 1 0 1
        Multiple
    		 13 11 24
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 15 21 36
        Not Hispanic or Latino
    		 490 483 973
        Not Reported
    		 4 5 9
        Unknown
    		 3 1 4
    Baseline Asthma Status
    Units: Subjects
        Yes
    		 219 217 436
        No
    		 293 293 586

    End points

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    End points reporting groups
    Reporting group title
    Short ragweed pollen allergen extract
    Reporting group description
    		 Participants randomized to short ragweed pollen allergen extract sublingual tablet, to be administered once daily (QD) for up to 35 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants randomized to placebo sublingual tablet, to be administered QD for up to 35 weeks.
    Reporting group title
    Short ragweed pollen allergen extract
    Reporting group description
    		 One short ragweed pollen allergen extract sublingual tablet, once daily (QD) for up to 35 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received one placebo sublingual tablet, QD for up to 35 weeks.

    Subject analysis set title
    Short ragweed pollen allergen extract
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants randomized to short ragweed pollen allergen extract sublingual tablet, to be administered once daily (QD) for up to 35 weeks.

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants randomized to placebo sublingual tablet, to be administered once daily (QD) for up to 35 weeks.

    Primary: Total Combined Score (TCS) During the Peak Ragweed Season (RS)

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    End point title
    		 Total Combined Score (TCS) During the Peak Ragweed Season (RS)
    End point description
    TCS is daily symptom score (DSS) plus daily medication score (DMS), assessed in the peak RS (15 consecutive RS days with the highest 15-day average pollen count). The rhinoconjunctivitis (RC) DSS assesses 6 allergy symptoms measured on a scale of 0 to 3 (0=no symptoms, 3=severe symptoms; score range: 0-18). Lower DSS indicates less RC symptoms. The RC DMS is based on use of RC rescue medications (loratadine, olopatadine, mometasone), with different rescue medications being assigned different scores/dose unit (score range: 0-20). Lower DMS indicates less RC medication use. Summed RC DSS+DMS ranged from 0 to 38; a lower score indicates less RC symptoms and medication use. Components that contribute to DSS and DMS endpoints are collected in an e-diary completed by the participant/parent/guardian. Evaluation is based on average TCS during peak RS. The analysis population includes all treated participants w/ ≥1 e-diary entry for the specified measurement and timeframe.
    End point type
    Primary
    End point timeframe
    The 15-day period during the ragweed season with the highest moving pollen average
    End point values
    		 Short ragweed pollen allergen extract Placebo
    Number of subjects analysed
    460
    487
    Units: Score on a scale
        least squares mean (confidence interval 95%)
    4.39 (3.85 to 4.94)
    7.12 (6.57 to 7.67)
    Statistical analysis title
    		 Comparison of MK-3641 vs Placebo
    Statistical analysis description
    Model included fixed effects of treatment, baseline asthma status, age group, pollen season, and pollen region nested within pollen season
    Comparison groups
    Placebo v Short ragweed pollen allergen extract
    Number of subjects included in analysis
    947
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.45
         upper limit
    		 -2

    Secondary: Average TCS During the Entire RS

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    End point title
    		 Average TCS During the Entire RS
    End point description
    TCS is DSS plus DMS, assessed during the entire RS. This starts from the first day of 3 consecutive days w/ ragweed pollen counts ≥10 grains/m^3 through the last day of the last occurrence of 3 consecutive days w/ ragweed pollen counts ≥10 grains/m^3. Duration of entire RS is up to 13 weeks; this duration varies by site/region. The RC DSS assesses 6 allergy symptoms measured on a scale of 0 to 3 (range: 0-18). A lower DSS indicates less RC symptoms. The RC DMS is based on use of RC rescue medications (loratadine, olopatadine, mometasone) w/ different scores/dose unit (range: 0-20). A lower DMS indicates less RC medication use. The sum of RC DSS+DMS ranges from 0 to 38, w/ a lower score indicating less RC symptoms and medication use. Components contributing to the TCS for the entire RS are collected in an e-diary completed by the participant/parent/guardian. The analysis pop. includes all treated participants w/ ≥1 e-diary entry for the specified measurement and timeframe.
    End point type
    Secondary
    End point timeframe
    Up to 13 weeks
    End point values
    		 Short ragweed pollen allergen extract Placebo
    Number of subjects analysed
    466
    491
    Units: Score on a scale
        least squares mean (confidence interval 95%)
    3.88 (3.44 to 4.33)
    5.75 (5.30 to 6.20)
    Statistical analysis title
    		 Comparison of MK-3641 vs Placebo
    Statistical analysis description
    Model included fixed effects of treatment, baseline asthma status, age group, pollen season, and pollen region nested within pollen season
    Comparison groups
    Short ragweed pollen allergen extract v Placebo
    Number of subjects included in analysis
    957
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANOVA
    Parameter type
    		 Difference in LS Mean
    Point estimate
    -1.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.46
         upper limit
    		 -1.27

    Secondary: Average Rhinoconjunctivitis (RC) DSS During the Peak RS

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    End point title
    		 Average Rhinoconjunctivitis (RC) DSS During the Peak RS
    End point description
    The DSS consists of a total of 6 rhinoconjunctivitis symptoms: 4 rhinitis symptoms (runny nose, stuffy nose, sneezing, itchy nose) and 2 conjunctivitis symptoms (itchy eyes, watery eyes). The components that contribute to the DSS endpoint are collected in an e-diary completed by the participant/parent/guardian. The RC DSS is measured on a 4-point scale from 0 to 3 as follows: 0 (no sign/symptom evident) to 3 (sign/symptom that is hard to tolerate; may cause interference with activities of daily living and/or sleeping). The maximum DSS is 18 points if a participant experiences all 6 symptoms with an intensity of 3 for each symptom. The minimum DSS is 0 points if a participant experiences no symptoms. A lower DSS means symptoms are less severe. The evaluation is based on the average DSS during the peak RS. The analysis population includes all treated participants w/ ≥1 e-diary entry for the specified measurement and timeframe.
    End point type
    Secondary
    End point timeframe
    The 15-day period during the ragweed season with the highest moving pollen average
    End point values
    		 Short ragweed pollen allergen extract Placebo
    Number of subjects analysed
    468
    494
    Units: Score on a scale
        least squares mean (confidence interval 95%)
    2.55 (2.24 to 2.86)
    3.95 (3.63 to 4.26)
    Statistical analysis title
    		 Comparison of MK-3641 vs Placebo
    Statistical analysis description
    Model included fixed effects of treatment, baseline asthma status, age group, pollen season, and pollen region nested within pollen season
    Comparison groups
    Short ragweed pollen allergen extract v Placebo
    Number of subjects included in analysis
    962
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.81
         upper limit
    		 -0.99

    Secondary: Average Rhinoconjunctivitis (RC) DMS During the Peak RS

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    End point title
    		 Average Rhinoconjunctivitis (RC) DMS During the Peak RS
    End point description
    This DMS endpoint consists of a total of scores for use of RC medications: loratadine syrup or tablets (6 points), olopatadine (6 points), and mometasone (8 points). The score range of the RC DMS is 0-20 points, and a lower DMS means that less medication is used. The method used for analysis of the RC DMS is a zero-inflated log-normal model, which takes the average RC DMS during the peak RS as the response and adjusts for the same terms as in the ANOVA model. The components that contribute to the DMS endpoint are collected in an e-diary completed by the participant/parent/guardian. The analysis population includes all treated participants w/ ≥1 e-diary entry for the specified measurement and timeframe.
    End point type
    Secondary
    End point timeframe
    The 15-day period during the ragweed season with the highest moving pollen average
    End point values
    		 Short ragweed pollen allergen extract Placebo
    Number of subjects analysed
    460
    487
    Units: Score on a scale
        arithmetic mean (confidence interval 95%)
    2.01 (1.57 to 2.46)
    3.85 (3.14 to 4.57)
    Statistical analysis title
    		 Comparison of MK-3641 vs Placebo
    Statistical analysis description
    Model included fixed effects of treatment, baseline asthma, age group, pollen season, and pollen region nested within pollen season
    Comparison groups
    Short ragweed pollen allergen extract v Placebo
    Number of subjects included in analysis
    947
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Zero-Inflated Log-Normal Model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.6
         upper limit
    		 -1.08

    Secondary: Percentage of Participants Reporting Pre-specified Local Application Site Reactions

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    End point title
    		 Percentage of Participants Reporting Pre-specified Local Application Site Reactions
    End point description
    Pre-specified local application site reactions, irrespective of causality, included AEs related to lip swelling/edema, mouth swelling/edema, palatal swelling/edema, swollen tongue/edema, oropharyngeal swelling/edema, pharyngeal edema/throat tightness, oral pruritus, throat irritation, tongue pruritus, and ear pruritus. The safety population was all participants as treated. One participant was randomized to placebo but received short ragweed pollen allergen extract for one day and is included in the short ragweed pollen allergen extract arm.
    End point type
    Secondary
    End point timeframe
    Up to 35 weeks
    End point values
    		 Short ragweed pollen allergen extract Placebo
    Number of subjects analysed
    513
    509
    Units: Percentage of participants
        number (not applicable)
    64.52
    26.92
    Statistical analysis title
    		 Difference in %
    Comparison groups
    Short ragweed pollen allergen extract v Placebo
    Number of subjects included in analysis
    1022
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Difference in % estimates
    Point estimate
    37.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 31.82
         upper limit
    		 43.12

    Secondary: Percentage of Participants Reporting Anaphylaxis and/or Systemic Allergic Reactions

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    End point title
    		 Percentage of Participants Reporting Anaphylaxis and/or Systemic Allergic Reactions
    End point description
    For the purposes of this study, systemic allergic reactions are allergic reactions that occur away from the site of study drug application (allergic reactions other than local application site reactions). Anaphylaxis is a severe allergic reaction that typically involves more than one body system. The safety population was all participants as treated. One participant was randomized to placebo but received short ragweed pollen allergen extract for one day and is included in the short ragweed pollen allergen extract arm.
    End point type
    Secondary
    End point timeframe
    Up to 35 weeks
    End point values
    		 Short ragweed pollen allergen extract Placebo
    Number of subjects analysed
    513 [1]
    509 [2]
    Units: Percentage of participants
        number (not applicable)
    0.58
    0.20
    Notes
    [1] - No participants reported anaphylaxis. All reported events were systemic allergic reactions.
    [2] - No participants reported anaphylaxis. All reported events were systemic allergic reactions.
    Statistical analysis title
    		 Difference in %
    Comparison groups
    Short ragweed pollen allergen extract v Placebo
    Number of subjects included in analysis
    1022
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.32
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Difference in % estimates
    Point estimate
    0.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.57
         upper limit
    		 1.53

    Secondary: Percentage of Participants Treated with Epinephrine

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    End point title
    		 Percentage of Participants Treated with Epinephrine
    End point description
    Self-injectable epinephrine was provided to each participant/parent/guardian at randomization in countries where it is a regulatory requirement, and was to be available around the time treatment is administered at home. Self-injectable epinephrine was intended for immediate self-administration for an anaphylactic reaction, including symptoms/signs of upper airway obstruction. Instances of treatment with forms of epinephrine other than systemic epinephrine (e.g., inhaled racepinephrine) were counted as use of epinephrine. The safety population was all participants as treated. One participant was randomized to placebo but received short ragweed pollen allergen extract for one day and is included in the short ragweed pollen allergen extract arm.
    End point type
    Secondary
    End point timeframe
    Up to 35 weeks
    End point values
    		 Short ragweed pollen allergen extract Placebo
    Number of subjects analysed
    513 [3]
    509
    Units: Percentage of participants
        number (not applicable)
    0.19
    0.20
    Notes
    [3] - Participant in this arm received inhaled racepinephrine
    Statistical analysis title
    		 Difference in %
    Comparison groups
    Short ragweed pollen allergen extract v Placebo
    Number of subjects included in analysis
    1022
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.996
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Difference in % estimates
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.92
         upper limit
    		 0.92

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 35 weeks
    Adverse event reporting additional description
    An AE is any physical or clinical change or disease experienced by the participant any time during the study, whether or not considered related to use of the study drug. The safety population was all participants as treated. 1 participant was randomized to pbo but received short ragweed pollen allergen extract for 1 day and is included in that arm.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants who received placebo sublingual tablet, administered once daily (QD) for up to 35 weeks.

    Reporting group title
    Short ragweed pollen allergen extract
    Reporting group description
    		 Participants who received short ragweed pollen allergen extract sublingual tablet, administered once daily (QD) for up to 35 weeks.

    Serious adverse events
    		 Placebo Short ragweed pollen allergen extract
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 509 (1.77%)
    7 / 513 (1.36%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Concussion
         subjects affected / exposed
    0 / 509 (0.00%)
    1 / 513 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue injury
         subjects affected / exposed
    1 / 509 (0.20%)
    0 / 513 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 509 (0.00%)
    1 / 513 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 509 (0.20%)
    1 / 513 (0.19%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 509 (0.20%)
    0 / 513 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral pruritus
         subjects affected / exposed
    0 / 509 (0.00%)
    1 / 513 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    3 / 509 (0.59%)
    0 / 513 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Conduct disorder
         subjects affected / exposed
    1 / 509 (0.20%)
    0 / 513 (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
    Campylobacter gastroenteritis
         subjects affected / exposed
    0 / 509 (0.00%)
    1 / 513 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    0 / 509 (0.00%)
    1 / 513 (0.19%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 509 (0.20%)
    0 / 513 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 509 (0.20%)
    0 / 513 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal viral inection
         subjects affected / exposed
    0 / 509 (0.00%)
    1 / 513 (0.19%)
         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
    		 Placebo Short ragweed pollen allergen extract
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    233 / 509 (45.78%)
    370 / 513 (72.12%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    49 / 509 (9.63%)
    45 / 513 (8.77%)
         occurrences all number
    67
    100
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    20 / 509 (3.93%)
    29 / 513 (5.65%)
         occurrences all number
    23
    33
    Ear and labyrinth disorders
    Ear pruritus
         subjects affected / exposed
    35 / 509 (6.88%)
    177 / 513 (34.50%)
         occurrences all number
    65
    750
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    30 / 509 (5.89%)
    54 / 513 (10.53%)
         occurrences all number
    53
    119
    Diarrhoea
         subjects affected / exposed
    21 / 509 (4.13%)
    26 / 513 (5.07%)
         occurrences all number
    29
    55
    Enlarged uvula
         subjects affected / exposed
    2 / 509 (0.39%)
    33 / 513 (6.43%)
         occurrences all number
    2
    65
    Glossodynia
         subjects affected / exposed
    13 / 509 (2.55%)
    64 / 513 (12.48%)
         occurrences all number
    29
    171
    Lip swelling
         subjects affected / exposed
    7 / 509 (1.38%)
    66 / 513 (12.87%)
         occurrences all number
    14
    165
    Nausea
         subjects affected / exposed
    43 / 509 (8.45%)
    70 / 513 (13.65%)
         occurrences all number
    69
    167
    Oral pain
         subjects affected / exposed
    16 / 509 (3.14%)
    64 / 513 (12.48%)
         occurrences all number
    29
    151
    Oral pruritus
         subjects affected / exposed
    62 / 509 (12.18%)
    247 / 513 (48.15%)
         occurrences all number
    131
    1115
    Stomatitis
         subjects affected / exposed
    6 / 509 (1.18%)
    34 / 513 (6.63%)
         occurrences all number
    13
    89
    Swollen tongue
         subjects affected / exposed
    4 / 509 (0.79%)
    56 / 513 (10.92%)
         occurrences all number
    5
    132
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    30 / 509 (5.89%)
    30 / 513 (5.85%)
         occurrences all number
    53
    39
    Oropharyngeal pain
         subjects affected / exposed
    29 / 509 (5.70%)
    25 / 513 (4.87%)
         occurrences all number
    44
    56
    Pharyngeal oedema
         subjects affected / exposed
    8 / 509 (1.57%)
    58 / 513 (11.31%)
         occurrences all number
    14
    138
    Throat irritation
         subjects affected / exposed
    98 / 509 (19.25%)
    254 / 513 (49.51%)
         occurrences all number
    223
    1048
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    36 / 509 (7.07%)
    38 / 513 (7.41%)
         occurrences all number
    50
    50

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Sep 2016
    The asthma DSS will be completed daily beginning with Visit 4 by all participants in the study, and decreased blood volume is to be taken at screening
    11 Sep 2018
    Addition of “severe asthma exacerbation” to the list of discontinuation criteria.

    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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