Trial Outcomes & Findings for Grass Pollen Immunotherapy Plus Dupilumab for Tolerance Induction (NCT NCT04502966)

A single site consented 199 participants for evaluation of eligibility criteria. 111 participants were determined to be eligible, underwent a baseline assessment, and were randomized into the study. After randomization, 108 participants initiated study treatment.

199 potential participants signed an informed consent before undergoing any study procedures. After the informed consent was signed and participants were determined to meet eligibility criteria, the eligible participants underwent a baseline assessment and were subsequently randomized into the study. A total of 111 were determined eligible and were randomized.

Grass Pollen Immunotherapy Plus Dupilumab for Tolerance Induction

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 at Year 3, one year after completion of treatment. 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. The primary treatment comparison is between SLIT/Dupilumab and Double-Placebo.

NAC (TNSS Area-under-Curve \[AUC 0-1hr\]), comparing the referenced treatment arms at years 1 and 2 while on study treatment for clinical desensitization. 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. The following treatment comparisons are of secondary outcome interest: * Comparison between SLIT/Dupilumab and Double-Placebo * Comparison between SLIT/Dupilumab versus SLIT/Dupilumab Placebo Both treatment comparisons are key secondary endpoints at Year 2 and therefore multiplicity adjustments are considered; however, at Year 1 the same comparisons are not adjusted for multiplicity.

PNIF is defined as the maximum effort 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 congestion. The following treatment comparison is of secondary outcome interest, where Year 3 is a clinical tolerance outcome measure, and Years 1 and 2 are clinical desensitization outcome measures: • Comparison between SLIT/Dupilumab and Double-Placebo According to the SAP, this treatment comparison at Year 3 is a key secondary endpoint and therefore a multiplicity adjustment is considered; however, at Years 1 and 2 the comparisons are not adjusted for multiplicity.

The NAC 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. The following treatment comparison is of secondary outcome interest, where Year 3 is a clinical tolerance outcome measure, and Years 1 and 2 are clinical desensitization outcome measures: • Comparison between SLIT/Dupilumab and Double-Placebo According to the SAP, this treatment comparison at Year 3 is a key secondary endpoint and therefore a multiplicity adjustment is considered; however at Years 1 and 2 the comparisons are not adjusted for multiplicity.

An intradermal skin test will be performed in duplicate (left and right arm) using Timothy grass pollen, with an early phase read-out after 15 minutes (with a +/- 3 minute window). A 10 BU test concentration will be used. The average of left and right arm wheal sizes will be used for analysis. A higher wheal size indicates a more severe reaction. The following treatment comparison is of secondary outcome interest, where Year 3 is a clinical tolerance outcome measure, and Years 1 and 2 are clinical desensitization outcome measures: • Comparison between SLIT/Dupilumab and Double-Placebo According to the SAP, this treatment comparison at Year 3 is a key secondary endpoint and therefore a multiplicity adjustment is considered; however at Years 1 and 2 the comparisons are not adjusted for multiplicity.

An intradermal skin test will be performed in duplicate (left and right arm) using Timothy grass pollen, with a late phase read-out after 6.5 hours (with a +/- 30 minute window) post initial injection. A 10 BU test concentration will be used. The average of left and right arm induration sizes will be used for analysis. A higher induration indicates a more severe reaction. The following treatment comparison is of secondary outcome interest, where Year 3 is a clinical tolerance outcome measure, and Years 1 and 2 are clinical desensitization outcome measures: • Comparison between SLIT/Dupilumab and Double-Placebo According to the SAP, this treatment comparison at Year 3 is a key secondary endpoint and therefore a multiplicity adjustment is considered; however, at Years 1 and 2 the comparisons are not adjusted for multiplicity.

A skin prick test endpoint titration response assessment will be performed in left and right arms using increasing concentrations of Timothy grass pollen (0.001 to 10 HEP U/mL). The average of left and right arm wheal sizes will be analyzed. The PC5 is defined as the minimum concentration (on base-10 log scale) for which an average wheal size is ≥5mm, based on linear interpolation. A smaller PC5 indicates a more severe reaction. Geometric means were back-transformed to original HEP U/mL scale from log10 values. The following treatment comparison is of secondary outcome interest, where Year 3 is a clinical tolerance outcome measure, and Years 1 and 2 are clinical desensitization outcome measures: • Comparison between SLIT/Dupilumab and Double-Placebo According to the SAP, this treatment comparison at Year 3 is a key secondary endpoint and therefore a multiplicity adjustment is considered; however, at Years 1 and 2 the comparisons are not adjusted for multiplicity.

A participant-reported seasonal symptoms outcome calculated as average of: a) weekly Visual Analogue Scale (VAS) score and b) weekly medication score (WMS), each assessed for the 7 days prior to the assessment. VAS (0=No Symptoms, 10=Worst possible symptoms) and WMS (0 = medications not used this week, 10 = medications on 5 or more days this week). Weekly Seasonal CSMS ranges from 0-10, with 10 being the highest severity. The average score per participant was calculated across the "in-season" weeks per year. The following treatment comparison is of secondary outcome interest, where Year 3 is a clinical tolerance outcome measure, and Years 1 and 2 are clinical desensitization outcome measures: • Comparison between SLIT/Dupilumab and Double-Placebo This treatment comparison at Year 3 is a key secondary endpoint and therefore a multiplicity adjustment is considered; however at Years 1 and 2 the comparisons are not adjusted for multiplicity.

A participant-reported (self-administered) seasonal symptoms outcome measure on a Likert scale (0 to 10 cm, 0=No Symptoms, 10=Worst possible symptoms), a quality of life measure reflecting the impact of rhinitis ("hay fever") symptoms experienced during the 7 days prior to the assessment. The average score per participant was calculated across the "in-season" weeks per year. The following treatment comparison is of secondary outcome interest, where Year 3 is a clinical tolerance outcome measure, and Years 1 and 2 are clinical desensitization outcome measures: • Comparison between SLIT/Dupilumab and Double-Placebo According to the SAP, no comparisons at any year are adjusted for multiplicity for this outcome.

A participant-reported (self-administered) seasonal symptoms medications score based on the use of antihistamines (oral and/or eyedrop) and intranasal corticosteroids, assessed for the 7 days prior to the assessment. The WMS has a score ranging from 0 to 10 (0 = medications not used this week, 10 = medications on 5 or more days this week). The average score per participant was calculated across the "in-season" weeks per year. The following treatment comparison is of secondary outcome interest, where Year 3 is a clinical tolerance outcome measure, and Years 1 and 2 are clinical desensitization outcome measures: • Comparison between SLIT/Dupilumab and Double-Placebo According to the SAP, no comparisons at any year are adjusted for multiplicity for this outcome.

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 for the 7 days prior to the assessment. A total score was calculated as average of all questions. The average total score per participant was calculated across the "in-season" weeks per year. The following treatment comparison is of secondary outcome interest, where Year 3 is a clinical tolerance outcome measure, and Years 1 and 2 are clinical desensitization outcome measures: • Comparison between SLIT/Dupilumab and Double-Placebo According to the SAP, this treatment comparison at Year 3 is a key secondary endpoint and therefore a multiplicity adjustment is considered; however at Years 1 and 2 the comparisons are not adjusted for multiplicity.

The Modified Rhinitis Symptom Utility Index (MRSUI) questionnaire consists of 10 questions regarding symptoms experienced during the prior 2 weeks from the nose, eyes, and throat, specifically how frequently the symptoms occurred and how bothersome they were. The total MRSUI score will be calculated as the sum of the numeric responses to all 10 questions. The total MRSUI score ranges from 0-25, with 25 being the worst outcome. The following treatment comparison is of secondary outcome interest, where Year 3 is a clinical tolerance outcome measure, and Years 1 and 2 are clinical desensitization outcome measures: • Comparison between SLIT/Dupilumab and Double-Placebo According to the SAP, this treatment comparison at Year 3 is a key secondary endpoint and therefore a multiplicity adjustment is considered; however at Years 1 and 2 the comparisons are not adjusted for multiplicity.

Participants are asked to describe their allergic rhinitis ("hay fever"). This administered questionnaire is comprised of 6 questions, focusing on nasal and eye symptoms \[0=No symptoms, 3=Severe\]. The total Global Evaluation No. 1 score will be calculated as the total sum of the numeric responses to all 6 questions. Higher scores indicate a worse outcome/severity, where the minimum score is 0 and maximum score is 18. The following treatment comparison is of secondary outcome interest, where Year 3 is a clinical tolerance outcome measure, and Years 1 and 2 are clinical desensitization outcome measures: • Comparison between SLIT/Dupilumab and Double-Placebo According to the SAP, this treatment comparison at Year 3 is a key secondary endpoint and therefore a multiplicity adjustment is considered; however, at Years 1 and 2 the comparisons are not adjusted for multiplicity.

For the Global Evaluation No. 2 questionnaire, participants are asked 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). The following treatment comparison is of secondary outcome interest, where Year 3 is a clinical tolerance outcome measure, and Years 1 and 2 are clinical desensitization outcome measures: • Comparison between SLIT/Dupilumab and Double-Placebo According to the SAP, this treatment comparison at Year 3 is a key secondary endpoint and therefore a multiplicity adjustment is considered; however at Years 1 and 2 the comparisons are not adjusted for multiplicity.

The number and percentage of participants with at least one treatment-emergent AE in the following categories will be summarized by treatment arm: 1. any AE related to any study drug 2. any severe (Grade 3 or higher) AE Only treatment-emergent AEs will be summarized. All AEs, including local, systemic, and serious AEs will be considered. For grading severity, the protocol-specified grading criteria will be used which depends on the type of AE: * Grading Table for Local Reactions to SLIT (Grades 1-4) * Grading Table for Local Reactions to Allergen Skin Testing (Grades 1-3) * Grading Table for NAC Procedure for Local Reactions (Grades 1-4) * WAO Subcutaneous Immunotherapy Systemic Reaction Grading System (Grades 1-5) for any immediate (0-1hr) systemic allergic reaction * National Cancer Institute's (NCI's) Common Toxicity Criteria for Adverse Events (CTCAE) v5.0 (November 27, 2017; Grades 1-5) for all remaining AEs.