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.

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.

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.

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.

Participants received once daily tablet of placebo for sublingual immunotherapy and placebo for dupilumab administered every other week (e.g., biweekly) by subcutaneous injection. The treatment period was 2 years.

Total of all reporting groups

The wheal size to timothy grass pollen (Phleum pratense) subtracts out the wheal size from negative control.

The timothy grass pollen specific IgE (Phleum pratense) was measured at screening.

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.

Modified intent-to-treat population included all randomized participants who received at least one dose of study treatment, subset to participants with post-baseline TNSS data.

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.

Modified intent-to-treat population included all randomized participants who received at least one dose of study treatment, subset to participants with post-baseline PNIF data.

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.

Modified intent-to-treat population included all randomized participants who received at least one dose of study treatment, subset to participants with post-baseline TNSS data.

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.

Modified intent-to-treat population included all randomized participants who received at least one dose of study treatment, subset to participants with post-baseline early skin test response data.

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.

Modified intent-to-treat population included all randomized participants who received at least one dose of study treatment, subset to participants with post-baseline late skin test response data.

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.

Modified intent-to-treat population included all randomized participants who received at least one dose of study treatment, subset to participants with post-baseline skin prick test titration data.

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.

Modified intent-to-treat population included all randomized participants who received at least one dose of study treatment, subset to participants with post-baseline CSMS data (after multiple imputation).

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.

Modified intent-to-treat population included all randomized participants who received at least one dose of study treatment, subset to participants with post-baseline VAS data (after multiple imputation).

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.

Modified intent-to-treat population included all randomized participants who received at least one dose of study treatment, subset to participants with post-baseline WMS data (after multiple imputation).

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.

Modified intent-to-treat population included all randomized participants who received at least one dose of study treatment, subset to participants with post-baseline MiniRQLQ data (after multiple imputation).

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.

Modified intent-to-treat population included all randomized participants who received at least one dose of study treatment, subset to participants with baseline and post-baseline MRSUI data.

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.

Modified intent-to-treat population included all randomized participants who received at least one dose of study treatment, subset to participants with post-baseline Global Evaluation No. 1 data.

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.

Modified intent-to-treat population included all randomized participants who received at least one dose of study treatment, subset to participants with post-baseline Global Evaluation No. 2 data.

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.

Safety population included all randomized participants who received at least one dose of study treatment.

Participants received once daily tablet of sublingual immunotherapy and placebo for dupilumab administered every other week (e.g., biweekly) by subcutaneous injection. The treatment period was 2 years.

Participants received once daily tablet of placebo for sublingual immunotherapy and placebo for dupilumab administered every other week (e.g., biweekly) by subcutaneous injection. The treatment period was 2 years.

Participants who were randomized but did not initiate study treatment.

Participants who were consented but did not meet inclusion/exclusion criteria.