Grass Pollen Immunotherapy Plus Dupilumab for Tolerance Induction

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Grass Pollen Sublingual Tablet Immunotherapy Plus Dupilumab for Induction of Tolerance in Adults With Moderate to Severe Seasonal Allergic Rhinitis (ITN084AD)

Conditions
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Allergic Rhinoconjunctivitis, Grass Pollen Allergy

Intervention / Treatment
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* Biological: Dupixent®
* Biological: Grazax®
* Drug: Dupixent® Placebo
* Drug: Grazax® Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant must be able to understand and provide informed consent A clinical history of grass pollen-induced allergic rhinoconjunctivitis for at least 2 years, with peak symptoms in May, June, or July A clinical history of moderate to severe rhinoconjunctivitis symptoms for at least 2 years, interfering with usual daily activities or with sleep as defined according to the Allergic Rhinitis and Its Impact on Asthma (ARIA) classification of rhinitis A clinical history of inadequately controlled rhinoconjunctivitis symptoms, despite treatment with antihistamines and/or nasal corticosteroids during the grass pollen season, for at least 2 years Positive skin prick test response at screening, defined as wheal diameter ≥3 mm to Phleum pratense Positive specific immunoglobulin E (IgE) at screening, defined as IgE class 2 (e.g., ≥ 0.7 kilounits per liter [kU/L]) against Phleum pratense A positive response to nasal allergen challenge (NAC) with Phleum pratense defined as a Total Nasal Symptom Score (TNSS) ≥5 points (out of a a maximum possibility 12 points) A woman of childbearing potential (WOCBP), regardless of birth control history, must: have a negative serum pregnancy test at screening, not be breast-feeding or lactating, and ---is required to consistently use one of the following highly effective methods of contraception throughout the study: hormonal (e.g. oral, transdermal, intravaginal, implant, or injection), intrauterine device (IUD) or system (IUS), vasectomized partner, bilateral tubal occlusion, or sexual abstinence. Exclusion Criteria: Inability or unwillingness of the Subject to give written informed consent or to comply with study protocol requirements Prebronchodilator forced expiratory volume (FEV1) <70% of predicted value at either Screening Visit or Baseline (Visit 0) Visit A clinical history of asthma requiring regular inhaled corticosteroids for >4 weeks per year, outside of the grass pollen season A clinical history of moderate to severe allergic rhinitis, as defined according to the Allergic Rhinitis and Its Impact on Asthma (ARIA) classification of rhinitis, caused by either: An allergen to which the Subject is regularly exposed, or Tree pollen during tree pollen season, treated with regular antihistamine or intranasal corticosteroids History of emergency visit or hospital admission for asthma in the previous 12 months History of chronic obstructive pulmonary disease History of recurrent acute sinusitis, defined as 2 episodes per year for the last 2 years, all of which required antibiotic treatment History of chronic sinusitis, defined as a sinus symptoms lasting greater than 12 weeks, that includes 2 or more major factors or 1 major factor and 2 minor factors. Major factors are defined as: Facial pain or pressure, Nasal obstruction or blockage, Nasal discharge or purulence or discolored postnasal discharge, Purulence in nasal cavity, or Impaired or loss of smell. Minor factors are defined as: Headache, Fever, Halitosis, Fatigue, Dental pain, Cough, and/or Ear pain, pressure, or fullness. History of systemic disease affecting the immune system, such as autoimmune diseases, immune complex disease or immunodeficiency At randomization: Current symptoms of, or treatment for: Upper respiratory tract infection, Acute sinusitis, Acute otitis media, or Other relevant infectious process ---Note: 1.) Serous otitis media is not an exclusion criterion and 2.) Participants may be re-evaluated for eligibility after symptoms resolve. A past history of any malignant disease in the previous 5 years Any tobacco smoking within the last 6 months, or a history of greater than or equal to 10 pack years of cigarette use. Any vaping or electronic cigarette use within the last 6 months Previous immunotherapy with grass pollen allergen within the previous 5 years Previous treatment by dupilumab (Dupixent®) Previous Grade 4 anaphylaxis (World Allergy Organization grading criteria), due to any cause History of anti-IgE, anti-IL-5, anti-IL-5 receptor, anti-IL-4/IL-13 receptor, or other monoclonal antibody treatment Use of tricyclic antidepressants or monoamine oxidase inhibitors Ongoing systemic immunosuppressive treatment History of intolerance to the study therapy, rescue medications, or their excipients For women of childbearing age a positive serum or urine pregnancy test with sensitivity of less than 50 milli-international units per milliliter [mIU/ml] within 72 hours before the scheduled start of study therapy The use of any investigational drug within 30 days of the Screening Visit The presence of any medical condition that the investigator deems incompatible with participation in the trial Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements or may impact the quality or interpretation of the data obtained from the study Eosinophilic esophagitis or a diagnosis of any hypereosinophilic syndrome, and/or Administration of live attenuated vaccines within four weeks of dupilumab or dupilumab placebo injections, before the first injection and throughout the treatment period.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Grazax® +Dupixent®<br>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 | Biological: Dupixent®<br>* An initial dose of 600 mg (two 300 mg injections), followed by 300 mg administered every other week (biweekly), by subcutaneous injection.<br>* Other names: monoclonal antibody against the IL-4 receptor;Biological: Grazax®<br>* 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.<br>* Other names: timothy grass (Phleum pratense) sublingual immunotherapy (SLIT);|
| Experimental: Grazax® + Dupixent® Placebo<br>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 | Biological: Grazax®<br>* 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.<br>* Other names: timothy grass (Phleum pratense) sublingual immunotherapy (SLIT);Drug: Dupixent® Placebo<br>* 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.<br>* Other names: placebo;|
| Placebo Comparator: Grazax® Placebo +Dupixent® Placebo<br>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 | Drug: Dupixent® Placebo<br>* 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.<br>* Other names: placebo;Drug: Grazax® Placebo<br>* 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.<br>* Other names: placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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. | 0 to 1 hour of the NAC at Year 3, One Year After Completion of Treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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. | 0 to 1 hour of the NAC at Year 3, One Year After Completion of Treatment | 
| Peak Nasal Inspiratory Flow (PNIF) (Delta PNIF Area Under the Curve [AUC] 0-1 hr): A Comparison Between Treatment Arms | 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. | 0 to 1 hour of the NAC at Year 3, One Year After Completion of Treatment | 
| 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 | 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. | 0 to 1 hour of the NAC at Year 1 and Year 2 | 
| 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 | 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. | 0 to 1 hour of the NAC at Year 1 and Year 2 | 
| Frequency, Severity, and Relatedness of Adverse Events (AEs) byTreatment Arm | 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. | Week 0 to Year 3 | 
| Weekly Seasonal Symptoms Score (Visual analogue scale [VAS] 0-10 cms): A Comparison Between the Grazax® +Dupixent® and Grazax® Placebo +Dupixent® Placebo Treatment Arms | 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. | Year 3 | 
| 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 | 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. | Year 3 | 
| Global Rhinitis Evaluation Scores: A Comparison Between the Grazax® +Dupixent® and Grazax® Placebo +Dupixent® Placebo Treatment Arms | 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. | Year 3 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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immunotherapy, nasal allergen challenge (NAC), total nasal symptom score (TNSS)