Dupilumab As An Adjunct For Subcutaneous Grass Immunotherapy

Phase 2

Completed

Conditions: Allergic Rhinitis

Interventions: Drug: Timothy Grass SCIT
Drug: Dupilumab
Drug: Placebo matching dupilumab
Drug: Placebo matching SCIT

Registration Number: NCT03558997

Lead Sponsor: Regeneron Pharmaceuticals

Brief Summary: The primary objective is to assess whether 16 weeks of treatment with dupilumab as an adjunct to Timothy Grass Subcutaneous Immunotherapy (SCIT) improves upon the efficacy of Timothy Grass SCIT to reduce provoked allergic rhinitis symptoms, as measured by Total Nasal Symptom Score (TNSS) after nasal allergen challenge (NAC) with Timothy Grass extract at week 17.

The secondary objectives of the study are:

* To assess whether 16 weeks of treatment with dupilumab as compared to placebo reduces provoked allergic rhinitis symptoms, as measured by TNSS after nasal allergen challenge (NAC) with Timothy Grass extract

* To assess whether 16 weeks of treatment with dupilumab as compared to dupilumab + SCIT reduces provoked allergic rhinitis symptoms, as measured by TNSS after nasal allergen challenge (NAC) with Timothy Grass extract

* To assess changes in serum Timothy-grass-specific immunoglobulin G4 (IgG4), serum Timothy grass-specific immunoglobulin E (IgE), and ratio of serum Timothy Grass-specific IgG4 to IgE over 16 weeks of treatment with dupilumab + SCIT as compared to SCIT monotherapy

* To evaluate the safety and tolerability of 16 weeks of treatment with dupilumab as an adjunct to Timothy Grass SCIT

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 103

Inclusion Criteria

Male and female participants aged 18 to 55
History of grass pollen-induced seasonal allergic rhinitis
Grass pollen allergy confirmed by both:
1. Positive skin prick test (SPT) with Timothy Grass extract (mean wheal diameter at least ≥5 mm greater than a negative control)
2. Positive serum Timothy Grass-specific IgE (≥0.35KU/L)

Key

Exclusion Criteria

Significant rhinitis, sinusitis, outside of the grass pollen season
Any contraindications to SCIT (i.e, severe cardiovascular disease, malignancies, autoimmune disease, use of beta blocker, asthma severe enough to require chronic medication, acute infection)
Use of systemic corticosteroids within 4 weeks of screening visits or any NAC visits
Abnormal lung function as judged by the investigator
A clinical history of asthma requiring chronic medication such as regular inhaled corticosteroids for >4 weeks per year
History of significant recurrent sinusitis, defined as 3 episodes per year for the last 2 years, all of which required antibiotic treatment
History of chronic sinusitis (with or without nasal polyps)
Tobacco smoking (ANY) within the last year

Note: Other protocol defined inclusion/ exclusion criteria apply

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
SCIT	Timothy Grass SCIT	Participants received SCIT titrated up to a 4000 bioequivalent allergy unit (BAU) for 8 weeks followed by maintenance dose of 4000 BAU for following 8 weeks and SC injections of placebo matched to Dupilumab Q2W for 16 weeks. Both SCIT and placebo matched to Dupilumab doses were administered with a gap of 1 or 7 days.
Dupilumab + SCIT	Timothy Grass SCIT	Participants received SC injections of Dupilumab at a loading dose of 600 mg on Day 1, followed by 300 mg Q2W for 16 weeks and SCIT titrated up to 4000 BAU for 8 weeks followed by maintenance dose of 4000 BAU for following 8 weeks. Both SCIT and Dupilumab doses were administered with a gap of 1 or 7 days.
Dupilumab	Dupilumab	Participants received placebo matched to SCIT and subcutaneous (SC) injections of Dupilumab at a loading dose of 600 milligrams (mg) on Day 1, followed by a 300 mg for Q2W for 16 weeks. Both placebo matched to SCIT and Dupilumab doses were administered with a gap of 1 or 7 days.
Placebo	Placebo matching dupilumab	Participants received placebo matched to Dupilumab and placebo matched to Timothy grass subcutaneous immunotherapy (SCIT) every 2 weeks (Q2W) for 16 weeks. Both placebo doses were administered with a gap of 1 or 7 days.
Placebo	Placebo matching SCIT	Participants received placebo matched to Dupilumab and placebo matched to Timothy grass subcutaneous immunotherapy (SCIT) every 2 weeks (Q2W) for 16 weeks. Both placebo doses were administered with a gap of 1 or 7 days.
Dupilumab	Placebo matching SCIT	Participants received placebo matched to SCIT and subcutaneous (SC) injections of Dupilumab at a loading dose of 600 milligrams (mg) on Day 1, followed by a 300 mg for Q2W for 16 weeks. Both placebo matched to SCIT and Dupilumab doses were administered with a gap of 1 or 7 days.
SCIT	Placebo matching dupilumab	Participants received SCIT titrated up to a 4000 bioequivalent allergy unit (BAU) for 8 weeks followed by maintenance dose of 4000 BAU for following 8 weeks and SC injections of placebo matched to Dupilumab Q2W for 16 weeks. Both SCIT and placebo matched to Dupilumab doses were administered with a gap of 1 or 7 days.
Dupilumab + SCIT	Dupilumab	Participants received SC injections of Dupilumab at a loading dose of 600 mg on Day 1, followed by 300 mg Q2W for 16 weeks and SCIT titrated up to 4000 BAU for 8 weeks followed by maintenance dose of 4000 BAU for following 8 weeks. Both SCIT and Dupilumab doses were administered with a gap of 1 or 7 days.

Primary Outcome Measures

Name	Time	Method
Percent Change From Baseline in Total Nasal Symptom Score (TNSS) Area Under Curve (AUC) (0-1 Hour (hr) Post Peak TNSS) in Response to Post Nasal Allergen Challenge (NAC) at Week 17	Baseline, Week 17	TNSS was participant-reported composite symptom assessment of 4 symptoms (rhinorrhea, nasal congestion, nasal itching \& sneezing), each scored on a scale from 0 to 3 where 0 = none, 3 = severe. TNSS total score was calculated as the sum of the response for all 4 individual nasal symptom scores and ranged from 0 to 12, where higher score indicated more severe symptoms. AUC of TNSS/component from time of the first observation to time of the last observation (AUC \[0-1 hr\]) was calculated by using the trapezoid rule. Data was reported for Dupilumab + SCIT and placebo matched to Dupilumab + SCIT monotherapy group in this outcome measure.

Secondary Outcome Measures

Name	Time	Method
Percent Change From Baseline in Total Nasal Symptom Score (TNSS) Area Under Curve (AUC) Post Nasal Allergen Challenge (NAC) Over the First Hour of the Challenge (0-1 Hour (hr) Post Peak TNSS) at Week 17	Baseline, Week 17	TNSS was participant-reported composite symptom assessment of 4 symptoms (rhinorrhea, nasal congestion, nasal itching \& sneezing) each scored on a scale from 0 to 3 where 0 = none, 3 = severe. TNSS total score was calculated as the sum of the response for all 4 individual nasal symptom scores and ranged from 0 to 12, where higher score indicated more severe symptoms. AUC of TNSS/component from time of the first observation to time of the last observation (AUC \[0-1 hr\]) was calculated by using the trapezoid rule. Data was reported for Dupilumab + placebo matched to SCIT and placebo matched to dupilumab + placebo matched to SCIT.
Change From Baseline in Log-Transformed Value of Serum Timothy Grass Specific Immunoglobulin G4 (sIgG4) to Serum Timothy Grass Specific Immunoglobulin E (sIgE) Ratio to Week 17	Baseline, Week 17	Biomarkers measured in serum or plasma to determine effects on biomarkers of relevant physiological and pathogenic processes. Data was reported for Dupilumab + SCIT and placebo matched to Dupilumab + SCIT monotherapy group in this outcome measure. Missing value was imputed by LOCF method for visits between post-baseline to Week 17.
Change From Baseline in Serum Timothy Grass Specific Immunoglobulin E (sIgE) to Week 17	Baseline, Week 17	Measurement of Timothy Grass specific sIgE was performed in serum or plasma to determine effects on biomarkers of relevant physiological and pathogenic processes. Data was reported for Dupilumab + SCIT and placebo matched to Dupilumab + SCIT monotherapy group in this outcome measure. Missing value was imputed by LOCF method for visits between post-baseline to Week 17.
Percent Change From Baseline in Serum Timothy Grass Specific Immunoglobulin E (sIgE) to Week 17	Baseline, Week 17	Measurement of Timothy Grass specific sIgE was performed in serum or plasma to determine effects on biomarkers of relevant physiological and pathogenic processes. Data was reported for Dupilumab + SCIT and placebo matched to Dupilumab + SCIT monotherapy group in this outcome measure. Missing value was imputed by LOCF method for visits between post-baseline to Week 17.
Change From Baseline in Total Nasal Symptom Score (TNSS) Area Under Curve (AUC) Post Nasal Allergen Challenge (NAC) Over the First Hour After the Challenge (0-1 Hour (hr) Post Peak TNSS) at Week 17 in SCIT vs. Dupilumab + SCIT	Baseline, Week 17	TNSS was participant-reported composite symptom assessment of 4 symptoms (rhinorrhea, nasal congestion, nasal itching \& sneezing) each scored on a scale from 0 to 3 where 0 = none, 3 = severe. TNSS total score was calculated as the sum of the response for all 4 individual nasal symptom scores and ranged from 0 to 12, where higher score indicated more severe symptoms. AUC of TNSS/component from time of the first observation to time of the last observation (AUC \[0-1 hr\]) was calculated by using the trapezoid rule. Data was reported for Dupilumab + SCIT and placebo matched to Dupilumab + SCIT monotherapy group in this outcome measure.
Change From Baseline in Total Nasal Symptom Score (TNSS) Area Under Curve (AUC) Post Nasal Allergen Challenge (NAC) Over the First Hour After the Challenge (0-1 Hour (hr) Post Peak TNSS) at Week 17 in Placebo vs. Dupilumab	Baseline, Week 17	TNSS was participant-reported composite symptom assessment of 4 symptoms (rhinorrhea, nasal congestion, nasal itching \& sneezing) each scored on a scale from 0 to 3 where 0 = none, 3 = severe. TNSS total score was calculated as the sum of the response for all 4 individual nasal symptom scores and ranged from 0 to 12, where higher score indicated more severe symptoms. AUC of TNSS/component from time of the first observation to time of the last observation (AUC \[0-1 hr\]) was calculated by using the trapezoid rule. Data was reported for Dupilumab + placebo matched to SCIT and placebo matched to dupilumab + placebo matched to SCIT group in this outcome measure.
Change From Baseline in TNSS Area Under Curve (AUC) Post Nasal Allergen Challenge (NAC) Over the First Hour of the Challenge (0-1 Hour (hr) Post Peak TNSS) at Week 17	Baseline, Week 17	TNSS was participant-reported composite symptom assessment of 4 symptoms (rhinorrhea, nasal congestion, nasal itching \& sneezing) each scored on a scale from 0 to 3 where 0 = none, 3 = severe. TNSS total score was calculated as the sum of responses for all 4 individual nasal symptom scores and ranged from 0 to 12, where higher score indicated more severe symptoms. AUC of TNSS/component from time of the first observation to time of the last observation (AUC \[0-1 hr\]) was calculated by using the trapezoid rule. Data was reported for Dupilumab + SCIT and Dupilumab + placebo matched to SCIT group in this outcome measure.
Percent Change From Baseline in TNSS Area Under Curve (AUC) Post Nasal Allergen Challenge (NAC) Over the First Hour of the Challenge (0-1 Hour (hr) Post Peak TNSS) at Week 17	Baseline, Week 17	TNSS was participant-reported composite symptom assessment of 4 symptoms (rhinorrhea, nasal congestion, nasal itching \& sneezing) each scored on a scale from 0 to 3 where 0 = none, 3 = severe. TNSS total score was calculated as the sum of the response for all 4 individual nasal symptom scores and ranged from 0 to 12, where higher score indicated more severe symptoms. AUC of TNSS/component from time of the first observation to time of the last observation (AUC \[0-1 hr\]) was calculated by using the trapezoid rule. Data was reported for Dupilumab + SCIT and Dupilumab + placebo matched to SCIT group in this outcome measure.
Change From Baseline in Serum Timothy Grass Specific Immunoglobulin G4 (sIgG4) to Week 17	Baseline, Week 17	Measurement of Timothy Grass specific IgG4 was performed in serum or plasma to determine effects on biomarkers of relevant physiological and pathogenic processes. Data was reported for Dupilumab + SCIT and placebo matched to Dupilumab + SCIT monotherapy group in this outcome measure. Missing values were imputed by Last Observation Carried Forward (LOCF) method for visits between post-baseline to Week 17.
Percent Change From Baseline in Serum Timothy Grass Specific Immunoglobulin G4 (sIgG4) to Week 17	Baseline, Week 17	Measurement of Timothy Grass specific IgG4 was performed in serum or plasma to determine effects on biomarkers of relevant physiological and pathogenic processes. Data was for Dupilumab + SCIT and placebo matched to Dupilumab + SCIT monotherapy group in this outcome measure. Missing value was imputed by LOCF method for visits between post-baseline to Week 17.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs	Baseline through Week 24	Treatment-emergent adverse events (TEAEs) were defined as adverse events (AEs) that developed or worsened or became serious during on-treatment period (time from the first dose of study drug up to the end of study \[Week 24\]). A serious adverse event (SAE) was defined as any untoward medical occurrence that resulted in any of the following outcomes: death, life-threatening, required initial or prolonged in-participant hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. Any TEAE included participants with both serious and non-serious AEs.