<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04502966</url>
  </required_header>
  <id_info>
    <org_study_id>DAIT ITN084AD</org_study_id>
    <secondary_id>NIAID CRMS ID#: 38629</secondary_id>
    <secondary_id>2018-003456-20</secondary_id>
    <nct_id>NCT04502966</nct_id>
  </id_info>
  <brief_title>Grass Pollen Immunotherapy Plus Dupilumab for Tolerance Induction</brief_title>
  <acronym>GRADUATE</acronym>
  <official_title>Grass Pollen Sublingual Tablet Immunotherapy Plus Dupilumab for Induction of Tolerance in Adults With Moderate to Severe Seasonal Allergic Rhinitis (ITN084AD)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Institute of Allergy and Infectious Diseases (NIAID)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Immune Tolerance Network (ITN)</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>ALK-Abelló A/S</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Regeneron Pharmaceuticals</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>PPD</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Rho Federal Systems Division, Inc.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>National Institute of Allergy and Infectious Diseases (NIAID)</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The primary objective of this study is to assess whether the combination of grass allergen&#xD;
      sublingual immunotherapy (SLIT) and dupilumab for 2 years is more effective than double&#xD;
      placebo in suppressing the nasal allergen challenge (NAC) response to grass pollen at 1 year&#xD;
      after completion of study medication.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a double-blind (masked) placebo-controlled trial in adults (N=108 subjects will be&#xD;
      enrolled) with moderate to severe seasonal allergic rhinitis and allergic sensitization to&#xD;
      grass pollen. Eligible participants who demonstrate a positive response defined by a Total&#xD;
      Nasal Symptom Score [TNSS] ≥ 5 (Scale 0-12 in response to a Nasal Allergen Challenge [NAC]&#xD;
      with grass pollen extract), will be randomized to one of the following 3 groups in a 1:1:1&#xD;
      ratio:&#xD;
&#xD;
        -  Grass allergen sublingual immunotherapy (SLIT) + dupilumab (n=36)&#xD;
&#xD;
        -  Grass allergen SLIT +dupilumab placebo (n=36)&#xD;
&#xD;
        -  Grass allergen SLIT placebo + dupilumab placebo (n=36)&#xD;
&#xD;
      Grazax® is a sublingual grass allergen immunotherapy product approved for clinical use in the&#xD;
      United Kingdom and will be used as SLIT in this study. Grazax (and its matching placebo) will&#xD;
      be self-administered daily by participants for a duration of two years.&#xD;
&#xD;
      Dupixent®is the brand name for dupilumab and is a monoclonal antibody against the interleukin&#xD;
      4 (IL-4) receptor. Dupilumab (and its matching placebo) will be administered every two weeks&#xD;
      by subcutaneous injection through for a duration of two years, administered by study&#xD;
      personnel. The treatment phase of two years will be followed by an observation phase of 1&#xD;
      year.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">November 9, 2020</start_date>
  <completion_date type="Anticipated">January 2025</completion_date>
  <primary_completion_date type="Anticipated">January 2025</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>TNSS Area Under Curve (AUC) Post Nasal Allergen Challenge (NAC) Over the First Hour After the Challenge (0-1 Hour (hr): A Comparison between the Grazax® +Dupixent® and the Grazax® Placebo +Dupixent® Placebo Treatment Arms</measure>
    <time_frame>0 to 1 hour of the NAC at Year 3, One Year After Completion of Treatment</time_frame>
    <description>NAC (TNSS Area-under-Curve [AUC 0-1hr]), comparing the TNSS AUC 0-1 hr between the referenced treatment arms: a clinical tolerance outcome measure.&#xD;
The Total Nasal Symptom Score (TNSS) is a participant-reported composite symptom assessment of 4 symptoms (rhinorrhea, nasal congestion, nasal itching and sneezing), each scored on a scale from 0 to 3 where 0 = none, 3 = severe. TNSS total score is calculated as the sum of the response for all 4 individual nasal symptom scores and can range from a minimum score of 0 to a maximum score of 12: a higher score indicates more severe symptoms.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>TNSS Area Under Curve (AUC) Post Nasal Allergen Challenge (NAC) Over the First Hour After the Challenge (0-1 Hour (hr): A Comparison between the Grazax® +Dupixent® and Grazax® + Dupixent® Placebo Treatment Arms</measure>
    <time_frame>0 to 1 hour of the NAC at Year 3, One Year After Completion of Treatment</time_frame>
    <description>NAC (TNSS Area-under-Curve [AUC 0-1hr]), comparing the TNSS AUC 0-1 hr between the referenced treatment arms: a clinical tolerance outcome measure.&#xD;
The Total Nasal Symptom Score (TNSS) is a participant-reported composite symptom assessment of 4 symptoms (rhinorrhea, nasal congestion, nasal itching and sneezing), each scored on a scale from 0 to 3 where 0 = none, 3 = severe. TNSS total score is calculated as the sum of the response for all 4 individual nasal symptom scores and can range from a minimum score of 0 to a maximum score of 12: a higher score indicates more severe symptoms.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Peak Nasal Inspiratory Flow (PNIF) (Delta PNIF Area Under the Curve [AUC] 0-1 hr): A Comparison Between Treatment Arms</measure>
    <time_frame>0 to 1 hour of the NAC at Year 3, One Year After Completion of Treatment</time_frame>
    <description>The following analyses will performed as an assessment of clinical tolerance:&#xD;
Comparison between Grazax® +Dupixent® and Grazax® Placebo +Dupixent® Placebo treatment arms, and&#xD;
Comparison between Grazax® +Dupixent® and the Grazax® + Dupixent® Placebo treatment arms&#xD;
PNIF is defined as the speed of inspiration of air in Liters per minute when breathing into the lungs through the nose. Lower scores indicate less ability to breathe air into the lungs due to more severe nasal symptoms.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>TNSS Area Under Curve (AUC) Post Nasal Allergen Challenge (NAC) Over the First Hour After the Challenge (0-1 Hour (hr): A Comparison between the Grazax® +Dupixent® and the Grazax® Placebo +Dupixent® Placebo Treatment Arms</measure>
    <time_frame>0 to 1 hour of the NAC at Year 1 and Year 2</time_frame>
    <description>NAC (TNSS Area-under-Curve [AUC 0-1hr]), comparing the TNSS AUC 0-1 hr between the referenced treatment arms: a desensitization to grass pollen outcome measure.&#xD;
The Total Nasal Symptom Score (TNSS) is a participant-reported composite symptom assessment of 4 symptoms (rhinorrhea, nasal congestion, nasal itching and sneezing), each scored on a scale from 0 to 3 where 0 = none, 3 = severe. TNSS total score is calculated as the sum of the response for all 4 individual nasal symptom scores and can range from a minimum score of 0 to a maximum score of 12: a higher score indicates more severe symptoms.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Peak Nasal Inspiratory Flow (PNIF) (Delta PNIF Area Under the Curve [AUC] 0-1 hr): A Comparison between the Grazax® +Dupixent® and the Grazax® Placebo +Dupixent® Placebo Treatment Arms</measure>
    <time_frame>0 to 1 hour of the NAC at Year 1 and Year 2</time_frame>
    <description>PNIF is defined as the speed of inspiration of air in Liters per minute when breathing into the lungs through the nose. Lower scores indicate less ability to breathe air into the lungs due to more severe nasal symptoms.&#xD;
This assessment is a desensitization to grass pollen outcome measure.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Frequency, Severity, and Relatedness of Adverse Events (AEs) byTreatment Arm</measure>
    <time_frame>Week 0 to Year 3</time_frame>
    <description>The number, severity, and relatedness of local and systemic AEs and Serious AEs will be summarized by treatment arm. AEs will be classified by grade according to the National Cancer Institute's (NCI's) Common Toxicity Criteria for Adverse Events (CTCAE) version 5.0, November 27, 2017).&#xD;
Reference: Safety and Seasonal Symptom outcome measure.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Weekly Seasonal Symptoms Score (Visual analogue scale [VAS] 0-10 cms): A Comparison Between the Grazax® +Dupixent® and Grazax® Placebo +Dupixent® Placebo Treatment Arms</measure>
    <time_frame>Year 3</time_frame>
    <description>A participant-reported (self-administered) seasonal symptoms outcome measure on a Likert scale (0 to 10 cms, 0=No Symptoms, 10=Worst possible symptoms), a quality of life measure reflecting the quality of life impact of rhinitis (&quot;hay fever&quot;) symptoms experienced during the span of the &quot;last week.&quot;</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Weekly Rhinitis Quality of Life Scores Using the Juniper Mini-Rhinoconjunctivitis Quality of Life Questionnaire: A Comparison Between the Grazax® +Dupixent® and Grazax® Placebo +Dupixent® Placebo Treatment Arms</measure>
    <time_frame>Year 3</time_frame>
    <description>The Juniper Mini-Rhinoconjunctivitis Quality of Life Questionnaire [MiniRQLQ], is a participant-reported (self-administered) questionnaire that consists of 14 questions grouped into 5 domains. Each question is scored on a scale of 0 (not troubled with symptoms) to 6 (extremely troubled with symptoms) and describes nose/eye symptoms experienced &quot;during the last week.&quot;</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Global Rhinitis Evaluation Scores: A Comparison Between the Grazax® +Dupixent® and Grazax® Placebo +Dupixent® Placebo Treatment Arms</measure>
    <time_frame>Year 3</time_frame>
    <description>Participants are asked, as part of their Year 3 visit, to describe their allergic rhinitis (&quot;hay fever&quot;). This administered set of questions is comprised of 6 questions, focusing on nasal and eye symptoms [0=No symptoms, 3=Severe] and a single question regarding the change in current rhinitis/hay fever compared to the years prior to initiating study treatment (Much better:+3, Much worse: -3).&#xD;
Reference: A clinical tolerance outcome measure.</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">120</enrollment>
  <condition>Allergic Rhinoconjunctivitis</condition>
  <condition>Grass Pollen Allergy</condition>
  <arm_group>
    <arm_group_label>Grazax® +Dupixent®</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants randomized to this assignment will receive the following during the initial 2-year period of the trial:&#xD;
Once daily tablet of Grazax® sublingual immunotherapy and&#xD;
Dupixent® administered every other week (e.g., biweekly) by subcutaneous injection</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Grazax® + Dupixent® Placebo</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants randomized to this assignment will receive the following during the initial 2-year period of the trial:&#xD;
Once daily tablet of Grazax® sublingual immunotherapy and&#xD;
Placebo for Dupixent® administered every other week (e.g., biweekly) by subcutaneous injection</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Grazax® Placebo +Dupixent® Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Participants randomized to this assignment will receive the following during the initial 2-year period of the trial:&#xD;
Once daily tablet of placebo for Grazax® sublingual immunotherapy and&#xD;
Placebo for Dupixent® administered every other week (e.g., biweekly) by subcutaneous injection</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Dupixent®</intervention_name>
    <description>An initial dose of 600 mg (two 300 mg injections), followed by 300 mg administered every other week (biweekly), by subcutaneous injection.</description>
    <arm_group_label>Grazax® +Dupixent®</arm_group_label>
    <other_name>dupilumab</other_name>
    <other_name>monoclonal antibody against the IL-4 receptor</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Grazax®</intervention_name>
    <description>One Grazax® tablet daily, by sublingual administration.&#xD;
Grazax® is formulated as a freeze-dried oral lyophilisate/orally disintegrating tablet for oromucosal use. The active pharmaceutical ingredient is a standardized allergen extract derived from extraction and purification of grass pollen from timothy grass (Phleum pratense). The biological activity of the allergen is expressed in Standardized Quality Tablet units (SQ-T) units. The Grazax® dosage is one oral lyophilisate (75,000 Standardized Quality Tablet units (SQ-T) or approximately 2800 Bioequivalent allergy units (BAU), a measure of Phleum pratense SQ total biological potency defined by the FDA.</description>
    <arm_group_label>Grazax® + Dupixent® Placebo</arm_group_label>
    <arm_group_label>Grazax® +Dupixent®</arm_group_label>
    <other_name>grass pollen allergen sublingual immunotherapy (SLIT)</other_name>
    <other_name>timothy grass (Phleum pratense) sublingual immunotherapy (SLIT)</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Dupixent® Placebo</intervention_name>
    <description>Two subcutaneous injections of Placebo (for Dupilumab) as a loading dose followed by a single injection administered every other week.&#xD;
Dupixent® placebo is a subcutaneous injection whose composition is identical to the active Dupixent®, with the exception of the active pharmaceutical ingredient.</description>
    <arm_group_label>Grazax® + Dupixent® Placebo</arm_group_label>
    <arm_group_label>Grazax® Placebo +Dupixent® Placebo</arm_group_label>
    <other_name>placebo</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Grazax® Placebo</intervention_name>
    <description>One tablet of Placebo (for Grazax®) daily, by sublingual administration.&#xD;
Grazax® placebo is a tablet whose composition is identical to the active Grazax® tablet with the only exception being exclusion of the active pharmaceutical ingredient, Phleum pratense Standardized Quality Tablet (SQ-T) units.</description>
    <arm_group_label>Grazax® Placebo +Dupixent® Placebo</arm_group_label>
    <other_name>placebo</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Participant must be able to understand and provide informed consent&#xD;
&#xD;
          -  A clinical history of grass pollen-induced allergic rhinoconjunctivitis for at least 2&#xD;
             years, with peak symptoms in May, June, or July&#xD;
&#xD;
          -  A clinical history of moderate to severe rhinoconjunctivitis symptoms for at least 2&#xD;
             years, interfering with usual daily activities or with sleep as defined according to&#xD;
             the Allergic Rhinitis and Its Impact on Asthma (ARIA) classification of rhinitis&#xD;
&#xD;
          -  A clinical history of inadequately controlled rhinoconjunctivitis symptoms, despite&#xD;
             treatment with antihistamines and/or nasal corticosteroids during the grass pollen&#xD;
             season, for at least 2 years&#xD;
&#xD;
          -  Positive skin prick test response at screening, defined as wheal diameter ≥3 mm to&#xD;
             Phleum pratense&#xD;
&#xD;
          -  Positive specific immunoglobulin E (IgE) at screening, defined as IgE class 2 (e.g., ≥&#xD;
             0.7 kilounits per liter [kU/L]) against Phleum pratense&#xD;
&#xD;
          -  A positive response to nasal allergen challenge (NAC) with Phleum pratense defined as&#xD;
             a Total Nasal Symptom Score (TNSS) ≥5 points (out of a a maximum possibility 12&#xD;
             points)&#xD;
&#xD;
          -  A woman of childbearing potential (WOCBP), regardless of birth control history, must:&#xD;
&#xD;
               -  have a negative serum pregnancy test at screening,&#xD;
&#xD;
               -  not be breast-feeding or lactating, and ---is required to consistently use one of&#xD;
                  the following highly effective methods of contraception throughout the study:&#xD;
&#xD;
                    -  hormonal (e.g. oral, transdermal, intravaginal, implant, or injection),&#xD;
&#xD;
                    -  intrauterine device (IUD) or system (IUS),&#xD;
&#xD;
                    -  vasectomized partner,&#xD;
&#xD;
                    -  bilateral tubal occlusion, or&#xD;
&#xD;
                    -  sexual abstinence.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Inability or unwillingness of the Subject to give written informed consent or to&#xD;
             comply with study protocol requirements&#xD;
&#xD;
          -  Prebronchodilator forced expiratory volume (FEV1) &lt;70% of predicted value at either&#xD;
             Screening Visit or Baseline (Visit 0) Visit&#xD;
&#xD;
          -  A clinical history of asthma requiring regular inhaled corticosteroids for &gt;4 weeks&#xD;
             per year, outside of the grass pollen season&#xD;
&#xD;
          -  A clinical history of moderate to severe allergic rhinitis, as defined according to&#xD;
             the Allergic Rhinitis and Its Impact on Asthma (ARIA) classification of rhinitis,&#xD;
             caused by either:&#xD;
&#xD;
               -  An allergen to which the Subject is regularly exposed, or&#xD;
&#xD;
               -  Tree pollen during tree pollen season, treated with regular antihistamine or&#xD;
                  intranasal corticosteroids&#xD;
&#xD;
          -  History of emergency visit or hospital admission for asthma in the previous 12 months&#xD;
&#xD;
          -  History of chronic obstructive pulmonary disease&#xD;
&#xD;
          -  History of recurrent acute sinusitis, defined as 2 episodes per year for the last 2&#xD;
             years, all of which required antibiotic treatment&#xD;
&#xD;
          -  History of chronic sinusitis, defined as a sinus symptoms lasting greater than 12&#xD;
             weeks, that includes 2 or more major factors or 1 major factor and 2 minor factors.&#xD;
&#xD;
               -  Major factors are defined as:&#xD;
&#xD;
                    -  Facial pain or pressure,&#xD;
&#xD;
                    -  Nasal obstruction or blockage,&#xD;
&#xD;
                    -  Nasal discharge or purulence or discolored postnasal discharge,&#xD;
&#xD;
                    -  Purulence in nasal cavity, or&#xD;
&#xD;
                    -  Impaired or loss of smell.&#xD;
&#xD;
               -  Minor factors are defined as:&#xD;
&#xD;
                    -  Headache,&#xD;
&#xD;
                    -  Fever,&#xD;
&#xD;
                    -  Halitosis,&#xD;
&#xD;
                    -  Fatigue,&#xD;
&#xD;
                    -  Dental pain,&#xD;
&#xD;
                    -  Cough, and/or&#xD;
&#xD;
                    -  Ear pain, pressure, or fullness.&#xD;
&#xD;
          -  History of systemic disease affecting the immune system, such as autoimmune diseases,&#xD;
             immune complex disease or immunodeficiency&#xD;
&#xD;
          -  At randomization: Current symptoms of, or treatment for:&#xD;
&#xD;
               -  Upper respiratory tract infection,&#xD;
&#xD;
               -  Acute sinusitis,&#xD;
&#xD;
               -  Acute otitis media, or&#xD;
&#xD;
               -  Other relevant infectious process ---Note: 1.) Serous otitis media is not an&#xD;
                  exclusion criterion and 2.) Participants may be re-evaluated for eligibility&#xD;
                  after symptoms resolve.&#xD;
&#xD;
          -  A past history of any malignant disease in the previous 5 years&#xD;
&#xD;
          -  Any tobacco smoking within the last 6 months, or a history of greater than or equal to&#xD;
             10 pack years of cigarette use.&#xD;
&#xD;
          -  Any vaping or electronic cigarette use within the last 6 months&#xD;
&#xD;
          -  Previous immunotherapy with grass pollen allergen within the previous 5 years&#xD;
&#xD;
          -  Previous treatment by dupilumab (Dupixent®)&#xD;
&#xD;
          -  Previous Grade 4 anaphylaxis (World Allergy Organization grading criteria), due to any&#xD;
             cause&#xD;
&#xD;
          -  History of anti-IgE, anti-IL-5, anti-IL-5 receptor, anti-IL-4/IL-13 receptor, or other&#xD;
             monoclonal antibody treatment&#xD;
&#xD;
          -  Use of tricyclic antidepressants or monoamine oxidase inhibitors&#xD;
&#xD;
          -  Ongoing systemic immunosuppressive treatment&#xD;
&#xD;
          -  History of intolerance to the study therapy, rescue medications, or their excipients&#xD;
&#xD;
          -  For women of childbearing age a positive serum or urine pregnancy test with&#xD;
             sensitivity of less than 50 milli-international units per milliliter [mIU/ml] within&#xD;
             72 hours before the scheduled start of study therapy&#xD;
&#xD;
          -  The use of any investigational drug within 30 days of the Screening Visit&#xD;
&#xD;
          -  The presence of any medical condition that the investigator deems incompatible with&#xD;
             participation in the trial&#xD;
&#xD;
          -  Past or current medical problems or findings from physical examination or laboratory&#xD;
             testing that are not listed above, which, in the opinion of the investigator, may pose&#xD;
             additional risks from participation in the study, may interfere with the participant's&#xD;
             ability to comply with study requirements or may impact the quality or interpretation&#xD;
             of the data obtained from the study&#xD;
&#xD;
          -  Eosinophilic esophagitis or a diagnosis of any hypereosinophilic syndrome, and/or&#xD;
&#xD;
          -  Administration of live attenuated vaccines within four weeks of dupilumab or dupilumab&#xD;
             placebo injections, before the first injection and throughout the treatment period.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Stephen R. Durham, MD</last_name>
    <role>Study Chair</role>
    <affiliation>Allergy and Clinical Immunology Section at NHLI,Imperial College London</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Royal Brompton Hospital</name>
      <address>
        <city>London</city>
        <zip>SW36HP</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <link>
    <url>https://www.niaid.nih.gov/</url>
    <description>National Institute of Allergy and Infectious Diseases (NIAID)</description>
  </link>
  <link>
    <url>https://www.niaid.nih.gov/about/dait</url>
    <description>Division of Allergy, Immunology, and Transplantation (DAIT)</description>
  </link>
  <link>
    <url>http://www.immunetolerance.org</url>
    <description>Immune Tolerance Network (ITN)</description>
  </link>
  <verification_date>July 2023</verification_date>
  <study_first_submitted>August 4, 2020</study_first_submitted>
  <study_first_submitted_qc>August 4, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">August 6, 2020</study_first_posted>
  <last_update_submitted>July 11, 2023</last_update_submitted>
  <last_update_submitted_qc>July 11, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">July 13, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>immunotherapy</keyword>
  <keyword>nasal allergen challenge (NAC)</keyword>
  <keyword>total nasal symptom score (TNSS)</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Rhinitis, Allergic, Seasonal</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Immunomodulating Agents</mesh_term>
    <mesh_term>Immunologic Factors</mesh_term>
    <mesh_term>Antibodies, Monoclonal</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04502966
org study id: DAIT ITN084AD
secondary id: NIAID CRMS ID#: 38629
secondary id: 2018-003456-20
nct id: NCT04502966
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The primary objective of this study is to assess whether the combination of grass allergen
      sublingual immunotherapy (SLIT) and dupilumab for 2 years is more effective than double
      placebo in suppressing the nasal allergen challenge (NAC) response to grass pollen at 1 year
      after completion of study medication.
This is a double-blind (masked) placebo-controlled trial in adults (N=108 subjects will be
      enrolled) with moderate to severe seasonal allergic rhinitis and allergic sensitization to
      grass pollen. Eligible participants who demonstrate a positive response defined by a Total
      Nasal Symptom Score [TNSS] ≥ 5 (Scale 0-12 in response to a Nasal Allergen Challenge [NAC]
      with grass pollen extract), will be randomized to one of the following 3 groups in a 1:1:1
      ratio:

        -  Grass allergen sublingual immunotherapy (SLIT) + dupilumab (n=36)

        -  Grass allergen SLIT +dupilumab placebo (n=36)

        -  Grass allergen SLIT placebo + dupilumab placebo (n=36)

      Grazax® is a sublingual grass allergen immunotherapy product approved for clinical use in the
      United Kingdom and will be used as SLIT in this study. Grazax (and its matching placebo) will
      be self-administered daily by participants for a duration of two years.

      Dupixent®is the brand name for dupilumab and is a monoclonal antibody against the interleukin
      4 (IL-4) receptor. Dupilumab (and its matching placebo) will be administered every two weeks
      by subcutaneous injection through for a duration of two years, administered by study
      personnel. The treatment phase of two years will be followed by an observation phase of 1
      year.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
measure: TNSS Area Under Curve (AUC) Post Nasal Allergen Challenge (NAC) Over the First Hour After the Challenge (0-1 Hour (hr): A Comparison between the Grazax® +Dupixent® and the Grazax® Placebo +Dupixent® Placebo Treatment Arms
time frame: 0 to 1 hour of the NAC at Year 3, One Year After Completion of Treatment
description: NAC (TNSS Area-under-Curve [AUC 0-1hr]), comparing the TNSS AUC 0-1 hr between the referenced treatment arms: a clinical tolerance outcome measure.
The Total Nasal Symptom Score (TNSS) is a participant-reported composite symptom assessment of 4 symptoms (rhinorrhea, nasal congestion, nasal itching and sneezing), each scored on a scale from 0 to 3 where 0 = none, 3 = severe. TNSS total score is calculated as the sum of the response for all 4 individual nasal symptom scores and can range from a minimum score of 0 to a maximum score of 12: a higher score indicates more severe symptoms.
measure: TNSS Area Under Curve (AUC) Post Nasal Allergen Challenge (NAC) Over the First Hour After the Challenge (0-1 Hour (hr): A Comparison between the Grazax® +Dupixent® and Grazax® + Dupixent® Placebo Treatment Arms
time frame: 0 to 1 hour of the NAC at Year 3, One Year After Completion of Treatment
description: NAC (TNSS Area-under-Curve [AUC 0-1hr]), comparing the TNSS AUC 0-1 hr between the referenced treatment arms: a clinical tolerance outcome measure.
The Total Nasal Symptom Score (TNSS) is a participant-reported composite symptom assessment of 4 symptoms (rhinorrhea, nasal congestion, nasal itching and sneezing), each scored on a scale from 0 to 3 where 0 = none, 3 = severe. TNSS total score is calculated as the sum of the response for all 4 individual nasal symptom scores and can range from a minimum score of 0 to a maximum score of 12: a higher score indicates more severe symptoms.
measure: Peak Nasal Inspiratory Flow (PNIF) (Delta PNIF Area Under the Curve [AUC] 0-1 hr): A Comparison Between Treatment Arms
time frame: 0 to 1 hour of the NAC at Year 3, One Year After Completion of Treatment
description: The following analyses will performed as an assessment of clinical tolerance:
Comparison between Grazax® +Dupixent® and Grazax® Placebo +Dupixent® Placebo treatment arms, and
Comparison between Grazax® +Dupixent® and the Grazax® + Dupixent® Placebo treatment arms
PNIF is defined as the speed of inspiration of air in Liters per minute when breathing into the lungs through the nose. Lower scores indicate less ability to breathe air into the lungs due to more severe nasal symptoms.
measure: TNSS Area Under Curve (AUC) Post Nasal Allergen Challenge (NAC) Over the First Hour After the Challenge (0-1 Hour (hr): A Comparison between the Grazax® +Dupixent® and the Grazax® Placebo +Dupixent® Placebo Treatment Arms
time frame: 0 to 1 hour of the NAC at Year 1 and Year 2
description: NAC (TNSS Area-under-Curve [AUC 0-1hr]), comparing the TNSS AUC 0-1 hr between the referenced treatment arms: a desensitization to grass pollen outcome measure.
The Total Nasal Symptom Score (TNSS) is a participant-reported composite symptom assessment of 4 symptoms (rhinorrhea, nasal congestion, nasal itching and sneezing), each scored on a scale from 0 to 3 where 0 = none, 3 = severe. TNSS total score is calculated as the sum of the response for all 4 individual nasal symptom scores and can range from a minimum score of 0 to a maximum score of 12: a higher score indicates more severe symptoms.
measure: Peak Nasal Inspiratory Flow (PNIF) (Delta PNIF Area Under the Curve [AUC] 0-1 hr): A Comparison between the Grazax® +Dupixent® and the Grazax® Placebo +Dupixent® Placebo Treatment Arms
time frame: 0 to 1 hour of the NAC at Year 1 and Year 2
description: PNIF is defined as the speed of inspiration of air in Liters per minute when breathing into the lungs through the nose. Lower scores indicate less ability to breathe air into the lungs due to more severe nasal symptoms.
This assessment is a desensitization to grass pollen outcome measure.
measure: Frequency, Severity, and Relatedness of Adverse Events (AEs) byTreatment Arm
time frame: Week 0 to Year 3
description: The number, severity, and relatedness of local and systemic AEs and Serious AEs will be summarized by treatment arm. AEs will be classified by grade according to the National Cancer Institute's (NCI's) Common Toxicity Criteria for Adverse Events (CTCAE) version 5.0, November 27, 2017).
Reference: Safety and Seasonal Symptom outcome measure.
measure: Weekly Seasonal Symptoms Score (Visual analogue scale [VAS] 0-10 cms): A Comparison Between the Grazax® +Dupixent® and Grazax® Placebo +Dupixent® Placebo Treatment Arms
time frame: Year 3
description: A participant-reported (self-administered) seasonal symptoms outcome measure on a Likert scale (0 to 10 cms, 0=No Symptoms, 10=Worst possible symptoms), a quality of life measure reflecting the quality of life impact of rhinitis ("hay fever") symptoms experienced during the span of the "last week."
measure: Weekly Rhinitis Quality of Life Scores Using the Juniper Mini-Rhinoconjunctivitis Quality of Life Questionnaire: A Comparison Between the Grazax® +Dupixent® and Grazax® Placebo +Dupixent® Placebo Treatment Arms
time frame: Year 3
description: The Juniper Mini-Rhinoconjunctivitis Quality of Life Questionnaire [MiniRQLQ], is a participant-reported (self-administered) questionnaire that consists of 14 questions grouped into 5 domains. Each question is scored on a scale of 0 (not troubled with symptoms) to 6 (extremely troubled with symptoms) and describes nose/eye symptoms experienced "during the last week."
measure: Global Rhinitis Evaluation Scores: A Comparison Between the Grazax® +Dupixent® and Grazax® Placebo +Dupixent® Placebo Treatment Arms
time frame: Year 3
description: Participants are asked, as part of their Year 3 visit, to describe their allergic rhinitis ("hay fever"). This administered set of questions is comprised of 6 questions, focusing on nasal and eye symptoms [0=No symptoms, 3=Severe] and a single question regarding the change in current rhinitis/hay fever compared to the years prior to initiating study treatment (Much better:+3, Much worse: -3).
Reference: A clinical tolerance outcome measure.
arm group label: Grazax® +Dupixent®
arm group type: Experimental
description: Participants randomized to this assignment will receive the following during the initial 2-year period of the trial:
Once daily tablet of Grazax® sublingual immunotherapy and
Dupixent® administered every other week (e.g., biweekly) by subcutaneous injection
arm group label: Grazax® + Dupixent® Placebo
arm group type: Experimental
description: Participants randomized to this assignment will receive the following during the initial 2-year period of the trial:
Once daily tablet of Grazax® sublingual immunotherapy and
Placebo for Dupixent® administered every other week (e.g., biweekly) by subcutaneous injection
arm group label: Grazax® Placebo +Dupixent® Placebo
arm group type: Placebo Comparator
description: Participants randomized to this assignment will receive the following during the initial 2-year period of the trial:
Once daily tablet of placebo for Grazax® sublingual immunotherapy and
Placebo for Dupixent® administered every other week (e.g., biweekly) by subcutaneous injection
intervention type: Biological
intervention name: Dupixent®
description: An initial dose of 600 mg (two 300 mg injections), followed by 300 mg administered every other week (biweekly), by subcutaneous injection.
arm group label: Grazax® +Dupixent®
other name: dupilumab
other name: monoclonal antibody against the IL-4 receptor
intervention type: Biological
intervention name: Grazax®
description: One Grazax® tablet daily, by sublingual administration.
Grazax® is formulated as a freeze-dried oral lyophilisate/orally disintegrating tablet for oromucosal use. The active pharmaceutical ingredient is a standardized allergen extract derived from extraction and purification of grass pollen from timothy grass (Phleum pratense). The biological activity of the allergen is expressed in Standardized Quality Tablet units (SQ-T) units. The Grazax® dosage is one oral lyophilisate (75,000 Standardized Quality Tablet units (SQ-T) or approximately 2800 Bioequivalent allergy units (BAU), a measure of Phleum pratense SQ total biological potency defined by the FDA.
arm group label: Grazax® + Dupixent® Placebo
arm group label: Grazax® +Dupixent®
other name: grass pollen allergen sublingual immunotherapy (SLIT)
other name: timothy grass (Phleum pratense) sublingual immunotherapy (SLIT)
intervention type: Drug
intervention name: Dupixent® Placebo
description: Two subcutaneous injections of Placebo (for Dupilumab) as a loading dose followed by a single injection administered every other week.
Dupixent® placebo is a subcutaneous injection whose composition is identical to the active Dupixent®, with the exception of the active pharmaceutical ingredient.
arm group label: Grazax® + Dupixent® Placebo
arm group label: Grazax® Placebo +Dupixent® Placebo
other name: placebo
intervention type: Drug
intervention name: Grazax® Placebo
description: One tablet of Placebo (for Grazax®) daily, by sublingual administration.
Grazax® placebo is a tablet whose composition is identical to the active Grazax® tablet with the only exception being exclusion of the active pharmaceutical ingredient, Phleum pratense Standardized Quality Tablet (SQ-T) units.
arm group label: Grazax® Placebo +Dupixent® Placebo
other name: placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Stephen R. Durham, MD
role: Study Chair
affiliation: Allergy and Clinical Immunology Section at NHLI,Imperial College London
facility: 
country: United Kingdom
url: https://www.niaid.nih.gov/
description: National Institute of Allergy and Infectious Diseases (NIAID)
url: https://www.niaid.nih.gov/about/dait
description: Division of Allergy, Immunology, and Transplantation (DAIT)
url: http://www.immunetolerance.org
description: Immune Tolerance Network (ITN)
responsible party type: Sponsor
mesh term: Rhinitis, Allergic, Seasonal
mesh term: Immunomodulating Agents
mesh term: Immunologic Factors
mesh term: Antibodies, Monoclonal