Grass Pollen Immunotherapy Plus Dupilumab for Tolerance Induction

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

Sponsors

Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Collaborator: Immune Tolerance Network (ITN)
ALK-Abelló A/S
Regeneron Pharmaceuticals
PPD
Rho Federal Systems Division, Inc.

Source National Institute of Allergy and Infectious Diseases (NIAID)
Brief Summary

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

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.

Overall Status Not yet recruiting
Start Date September 2020
Completion Date September 2024
Primary Completion Date September 2024
Phase Phase 2
Study Type Interventional
Primary Outcome
Measure 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 0 to 1 hour of the NAC at Year 3, One Year After Completion of Treatment
Secondary Outcome
Measure 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 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 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 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 0 to 1 hour of the NAC at Year 1 and Year 2
Frequency, Severity, and Relatedness of Adverse Events (AEs) byTreatment Arm 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 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 Year 3
Global Rhinitis Evaluation Scores: A Comparison Between the Grazax® +Dupixent® and Grazax® Placebo +Dupixent® Placebo Treatment Arms Year 3
Enrollment 108
Condition
Intervention

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®

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.

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.

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

Eligibility

Criteria:

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.

Gender: All

Minimum Age: 18 Years

Maximum Age: 65 Years

Healthy Volunteers: No

Overall Official
Last Name Role Affiliation
Stephen R. Durham, MD Study Chair Allergy and Clinical Immunology Section at NHLI,Imperial College London
Location
Facility: Contact: Investigator: Royal Brompton Hospital Lisa K. Curry 0330 1284407 [email protected] Stephen R. Durham, MD Principal Investigator
Location Countries

United Kingdom

Verification Date

August 2020

Responsible Party

Type: Sponsor

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 3
Arm Group

Label: Grazax® +Dupixent®

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

Label: Grazax® + Dupixent® Placebo

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

Label: Grazax® Placebo +Dupixent® Placebo

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

Acronym GRADUATE
Study Design Info

Allocation: Randomized

Intervention Model: Parallel Assignment

Primary Purpose: Treatment

Masking: Triple (Participant, Care Provider, Investigator)

Source: ClinicalTrials.gov