Trial Outcomes & Findings for Efficacy and Safety of SUBLIVAC Phleum for Immunotherapy of Grass Pollen-Allergy (NCT NCT02556801)

Last Updated: 2019-09-13

Results Overview

The primary endpoint was the TSS after 10 months of treatment (at visit 6). The mean TSS at visit 6 was calculated as an average of all non-missing TSS scores between 1 and 6 hours after start of Environmental Exposure Chamber (EEC) challenge at visit 6. TSS was computed as the sum of individual scores for eight nasal and non-nasal symptoms (rhinorrhea, congestion, sneezing, itchiness, itchy/gritty eyes, tearing/watery eyes, red/burning eyes, and ear/palate itching). Each of eight symptoms was rated on a scale of 0-3 as follows: 0, none; 1, mild; 2, moderate; 3, severe. The range of TSS is from 0 to 24 units on a scale. The highest the score, the more severe symptoms a subject experiences. Negative change of TSS between baseline and visit 6 was expected (reduced symptoms), more negative change at visit 6 versus baseline represents better outcome of the study.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

168 participants

Primary outcome timeframe

10 months after treatment start (baseline - Visit 2)

Results posted on

2019-09-13

Participant Flow

The total recruitment period of the study was from September until November 2015. As soon as approx. 160 subjects had been randomized, recruitment was stopped and the investigator was informed to end recruitment of patients. Already screened patients were randomized, if eligible. See summary in the table below.

Participant milestones

Participant milestones
Measure	Placebo Subjects received placebo (containing no allergen extract) sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.	SP 10,000 AUN/ml Subjects received SUBLIVAC FIX Phleum Pratense 10,000 AUN/ml) sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.	SP 40,000 AUN/ml Subjects received SUBLIVAC FIX Phleum Pratense 40,000 AUN/ml sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.	SP 80,000 AUN/ml Subjects received SUBLIVAC FIX Phleum Pratense 80,000 AUN/ml sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.
Overall Study STARTED	42	42	42	42
Overall Study COMPLETED	40	35	38	37
Overall Study NOT COMPLETED	2	7	4	5

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Subjects received placebo (containing no allergen extract) sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.	SP 10,000 AUN/ml Subjects received SUBLIVAC FIX Phleum Pratense 10,000 AUN/ml) sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.	SP 40,000 AUN/ml Subjects received SUBLIVAC FIX Phleum Pratense 40,000 AUN/ml sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.	SP 80,000 AUN/ml Subjects received SUBLIVAC FIX Phleum Pratense 80,000 AUN/ml sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.
Overall Study Lost to Follow-up	1	0	2	0
Overall Study Withdrawal by Subject	1	1	1	0
Overall Study Protocol Violation	0	3	1	1
Overall Study Adverse Event	0	2	0	3
Overall Study Pregnancy	0	1	0	0
Overall Study Personal reasons patient	0	0	0	1

Baseline Characteristics

Efficacy and Safety of SUBLIVAC Phleum for Immunotherapy of Grass Pollen-Allergy

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=42 Participants Patients received placebo (containing no allergen extract) sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.	SP 10,000 AUN/ml n=42 Participants Patients received SUBLIVAC FIX Phleum Pratense 10,000 AUN/ml) sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.	SP 40,000 AUN/ml n=42 Participants Patients received SUBLIVAC FIX Phleum Pratense 40,000 AUN/ml sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.	SP 80,000 AUN/ml n=42 Participants Patients received SUBLIVAC FIX Phleum Pratense 80,000 AUN/ml sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.	Total n=168 Participants Total of all reporting groups
Age, Categorical <=18 years	1 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	1 Participants n=21 Participants
Age, Categorical Between 18 and 65 years	41 Participants n=5 Participants	42 Participants n=7 Participants	42 Participants n=5 Participants	42 Participants n=4 Participants	167 Participants n=21 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Age, Continuous	39.5 years STANDARD_DEVIATION 12.1 • n=5 Participants	42.4 years STANDARD_DEVIATION 11.6 • n=7 Participants	39.2 years STANDARD_DEVIATION 10.6 • n=5 Participants	40.9 years STANDARD_DEVIATION 10.4 • n=4 Participants	40.5 years STANDARD_DEVIATION 11.2 • n=21 Participants
Sex: Female, Male Female	27 Participants n=5 Participants	23 Participants n=7 Participants	22 Participants n=5 Participants	28 Participants n=4 Participants	100 Participants n=21 Participants
Sex: Female, Male Male	15 Participants n=5 Participants	19 Participants n=7 Participants	20 Participants n=5 Participants	14 Participants n=4 Participants	68 Participants n=21 Participants
Region of Enrollment Canada	42 participants n=5 Participants	42 participants n=7 Participants	42 participants n=5 Participants	42 participants n=4 Participants	168 participants n=21 Participants

PRIMARY outcome

Timeframe: 10 months after treatment start (baseline - Visit 2)

Population: The Intention-to-Treat population (ITT) includes all randomized subjects who received at least one dose of the study drug and for whom at least one post-baseline measurement for the primary efficacy endpoint was available.

Outcome measures

Outcome measures
Measure	Placebo n=40 Participants Subjects received placebo (containing no allergen extract) sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.	SP 10,000 AUN/ml n=35 Participants Subjects received SUBLIVAC FIX Phleum Pratense 10,000 AUN/ml) sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.	SP 40,000 AUN/ml n=38 Participants Subjects received SUBLIVAC FIX Phleum Pratense 40,000 AUN/ml sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.	SP 80,000 AUN/ml n=37 Participants Subjects received SUBLIVAC FIX Phleum Pratense 80,000 AUN/ml sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.
Mean Total Symptom Score (TSS) After 10 Months of Treatment (Visit 6) Compared to Placebo	10.01 Score on a scale Standard Error 0.80	8.06 Score on a scale Standard Error 0.85	8.19 Score on a scale Standard Error 0.82	7.69 Score on a scale Standard Error 0.83

SECONDARY outcome

Timeframe: 10 months after treatment start compared to first day of treatment (TSS at baseline measured at Visit 2, before IMP administration)

Population: The Intention-to-Treat population (ITT) consists of all randomized subjects who received at least one dose of the study drug and for whom at least one post-baseline measurement for the primary efficacy endpoint was available.

The change from baseline of the mean TSS at visit 6. The baseline will be calculated as an average of all non-missing TSS scores between 1 and 6 hours after start of Environmental Exposure Chamber (EEC) challenge at visit 2. The range of TSS is from 0 to 24 units on a scale. The highest the score, the more severe symptoms a subject experiences. Negative change of TSS between baseline and visit 6 was expected (reduced symptoms), more negative change at visit 6 versus baseline represents better outcome of the study.

Outcome measures

Outcome measures
Measure	Placebo n=40 Participants Subjects received placebo (containing no allergen extract) sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.	SP 10,000 AUN/ml n=35 Participants Subjects received SUBLIVAC FIX Phleum Pratense 10,000 AUN/ml) sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.	SP 40,000 AUN/ml n=38 Participants Subjects received SUBLIVAC FIX Phleum Pratense 40,000 AUN/ml sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.	SP 80,000 AUN/ml n=37 Participants Subjects received SUBLIVAC FIX Phleum Pratense 80,000 AUN/ml sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.
Change From Baseline in Mean Total Symptom Score (TSS) After 10 Months of Treatment (Visit 6)	-3.45 mean Total Symptom Score Standard Error 0.80	-5.37 mean Total Symptom Score Standard Error 0.85	-5.24 mean Total Symptom Score Standard Error 0.81	-5.74 mean Total Symptom Score Standard Error 0.83

SECONDARY outcome

Timeframe: 5 months after treatment start compared to first day of treatment (TSS at baseline measured at Visit 2, before IMP administration)

The change from baseline of the mean TSS at visit 4. The mean TSS at visit 4 will be calculated as an average of all non-missing TSS between 1 and 6 hours after start of Environmental Exposure Chamber (EEC) challenge at visit 4. The baseline will be calculated as an average of all non-missing TSS between 1 and 6 hours after start of EEC challenge at visit 2. The range of TSS is from 0 to 24 units on a scale. The highest the score, the more severe symptoms a subject experiences. Negative change of TSS between baseline and visit 4 was expected (reduced symptoms), more negative change at visit 4 versus baseline represents better outcome of the study.The highest the score, the more severe symptoms a subject experiences.

Outcome measures

Outcome measures
Measure	Placebo n=40 Participants Subjects received placebo (containing no allergen extract) sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.	SP 10,000 AUN/ml n=35 Participants Subjects received SUBLIVAC FIX Phleum Pratense 10,000 AUN/ml) sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.	SP 40,000 AUN/ml n=38 Participants Subjects received SUBLIVAC FIX Phleum Pratense 40,000 AUN/ml sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.	SP 80,000 AUN/ml n=37 Participants Subjects received SUBLIVAC FIX Phleum Pratense 80,000 AUN/ml sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.
Change From Baseline in Mean Total Symptom Score (TSS) After 5 Months of Treatment (Visit 4)	-2.40 mean Total Symptom Score Standard Error 0.74	-3.00 mean Total Symptom Score Standard Error 0.79	-4.24 mean Total Symptom Score Standard Error 0.76	-4.18 mean Total Symptom Score Standard Error 0.78

SECONDARY outcome

Timeframe: 10 months after treatment start compared to first day of treatment (TSS at baseline measured at Visit 2, before IMP injection)

The change from baseline of the mean TNSS at visit 6. The mean TNSS at visit 6 will be calculated as an average of all non-missing TNSS between 1 and 6 hours after start of EEC challenge at visit 6. The baseline will be calculated as an average of all non-missing TNSS between 1 and 6 hours after start of Environmental Exposure Chamber (EEC) challenge at visit 2. TNSS will be computed as the sum of individual scores for four nasal symptoms (running nose, congestion, itchy nose, and sneezing). Each of the four symptoms will be rated on a scale of 0-3 as follows: 0, none; 1, mild; 2, moderate; and 3, severe. The range of TNSS is from 0 to 12 units on a scale. The highest the score, the more severe symptoms a subject experiences.Negative change of TNSS between baseline and visit 6 was expected (reduced symptoms), more negative change at visit 6 versus baseline represents better outcome of the study.

Outcome measures

Outcome measures
Measure	Placebo n=40 Participants Subjects received placebo (containing no allergen extract) sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.	SP 10,000 AUN/ml n=35 Participants Subjects received SUBLIVAC FIX Phleum Pratense 10,000 AUN/ml) sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.	SP 40,000 AUN/ml n=38 Participants Subjects received SUBLIVAC FIX Phleum Pratense 40,000 AUN/ml sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.	SP 80,000 AUN/ml n=37 Participants Subjects received SUBLIVAC FIX Phleum Pratense 80,000 AUN/ml sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.
Change From Baseline in Mean Total Nasal Symptom Score (TNSS) After 10 Months of Treatment (Visit 6)	-1.87 mean Total Nasal Symptom Score Standard Error 0.43	-2.76 mean Total Nasal Symptom Score Standard Error 0.46	-2.75 mean Total Nasal Symptom Score Standard Error 0.44	-2.98 mean Total Nasal Symptom Score Standard Error 0.44

SECONDARY outcome

Timeframe: 5 months after treatment start compared to first day of treatment (TSS at baseline measured at Visit 2, before IMP injection)

The change from baseline of the mean TNSS at visit 4. The mean TNSS at visit 4 will be calculated as an average of all non-missing TNSS between 1 and 6 hours after start of Environmental Exposure Chamber (EEC) challenge at visit 4. The baseline will be calculated as an average of all non-missing TNSS between 1 and 6 hours after start of during EEC challenge at visit 2. TNSS will be computed as the sum of individual scores for four nasal symptoms (running nose, congestion, itchy nose, and sneezing). Each of the four symptoms will be rated on a scale of 0-3 as follows: 0, none; 1, mild; 2, moderate; and 3, severe. The range of TNSS is from 0 to 12 units on a scale. The highest the score, the more severe symptoms a subject experiences. Negative change of TSS between baseline and visit 6 was expected (reduced symptoms), more negative change at visit 4 versus baseline represents better outcome of the study.

Outcome measures

Outcome measures
Measure	Placebo n=40 Participants Subjects received placebo (containing no allergen extract) sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.	SP 10,000 AUN/ml n=35 Participants Subjects received SUBLIVAC FIX Phleum Pratense 10,000 AUN/ml) sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.	SP 40,000 AUN/ml n=38 Participants Subjects received SUBLIVAC FIX Phleum Pratense 40,000 AUN/ml sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.	SP 80,000 AUN/ml n=37 Participants Subjects received SUBLIVAC FIX Phleum Pratense 80,000 AUN/ml sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.
Change From Baseline in Mean Total Nasal Symptom Score (TNSS) After 5 Months of Treatment (Visit 4)	-1.52 mean Total Nasal Symptom Score Standard Error 0.39	-1.59 mean Total Nasal Symptom Score Standard Error 0.42	-2.14 mean Total Nasal Symptom Score Standard Error 0.40	-2.02 mean Total Nasal Symptom Score Standard Error 0.42

SECONDARY outcome

Timeframe: during the grass pollen season: estimated between 6 and 10 months after start of treatment at Visit 2

The mean CSMS will be calculated as an average of all non-missing daily CSMS during the grass pollen season. Subjects that did not complete at least 75% of their diary data, and subjects who have been on holidays outside the region for more than 7 days during the actual grass pollen season will be excluded from the analysis. The daily CSMS will be computed according to the definition given by the EAACI Position Paper. The actual grass pollen season would start on the first of 3 consecutive days that have a grass pollen count ≥ 10 ppm3 per 24 hours and the season would end on the first of 3 consecutive days that have a grass pollen count \< 10 ppm3 per 24 hours. The defined pollen season could consist of several separate periods that comply with this definition. The CSMS has a range from 0 to 6 and the higher the score, the more severe symptoms a subject is experiencing.

Outcome measures

Outcome measures
Measure	Placebo n=40 Participants Subjects received placebo (containing no allergen extract) sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.	SP 10,000 AUN/ml n=35 Participants Subjects received SUBLIVAC FIX Phleum Pratense 10,000 AUN/ml) sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.	SP 40,000 AUN/ml n=38 Participants Subjects received SUBLIVAC FIX Phleum Pratense 40,000 AUN/ml sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.	SP 80,000 AUN/ml n=37 Participants Subjects received SUBLIVAC FIX Phleum Pratense 80,000 AUN/ml sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.
Mean Combined Symptom and Medication Scores (CSMS) During the Grass Pollen Season.	1.032 mean Combined Symptom Medication Score Standard Error 0.135	0.678 mean Combined Symptom Medication Score Standard Error 0.124	0.638 mean Combined Symptom Medication Score Standard Error 0.128	0.752 mean Combined Symptom Medication Score Standard Error 0.122

SECONDARY outcome

Timeframe: 5 and 10 months after treatment start compared to first day of treatment (IgE at baseline measured at Visit 2, before IMP administration)

Changes from baseline in serum specific immunoglobulin levels (IgE) after after 5 months of treatment (Visit 4) and after 10 months of treatment (Visit 6). Measurements at visit 1 will be used as baseline.

Outcome measures

Outcome measures
Measure	Placebo n=40 Participants Subjects received placebo (containing no allergen extract) sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.	SP 10,000 AUN/ml n=35 Participants Subjects received SUBLIVAC FIX Phleum Pratense 10,000 AUN/ml) sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.	SP 40,000 AUN/ml n=38 Participants Subjects received SUBLIVAC FIX Phleum Pratense 40,000 AUN/ml sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.	SP 80,000 AUN/ml n=37 Participants Subjects received SUBLIVAC FIX Phleum Pratense 80,000 AUN/ml sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.
Change From Baseline in Serum Specific Immunoglobulin (IgE) Levels After 5 Months (Visit 4) and 10 Months (Visit 6) of Treatment After 5 months (Visit 4)	1.48 Geometric Mean fold change Interval 1.15 to 1.89	2.83 Geometric Mean fold change Interval 2.17 to 3.69	3.59 Geometric Mean fold change Interval 2.78 to 4.62	3.45 Geometric Mean fold change Interval 2.67 to 4.46
Change From Baseline in Serum Specific Immunoglobulin (IgE) Levels After 5 Months (Visit 4) and 10 Months (Visit 6) of Treatment After 10 months (Visit 6)	1.73 Geometric Mean fold change Interval 1.35 to 2.22	2.47 Geometric Mean fold change Interval 1.89 to 3.22	2.90 Geometric Mean fold change Interval 2.25 to 3.73	2.37 Geometric Mean fold change Interval 1.84 to 3.07

SECONDARY outcome

Timeframe: 5 and 10 months after treatment start compared to first day of treatment (IgG at baseline measured at Visit 2, before IMP injection)

Changes from baseline in serum specific immunoglobulin levels (IgG ATG, IgG AP1 and IgG AP5) after after 5 months of treatment (Visit 4) and after 10 months of treatment (Visit 6). Measurements at visit 1 will be used as baseline.

Outcome measures

Outcome measures
Measure	Placebo n=40 Participants Subjects received placebo (containing no allergen extract) sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.	SP 10,000 AUN/ml n=35 Participants Subjects received SUBLIVAC FIX Phleum Pratense 10,000 AUN/ml) sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.	SP 40,000 AUN/ml n=38 Participants Subjects received SUBLIVAC FIX Phleum Pratense 40,000 AUN/ml sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.	SP 80,000 AUN/ml n=37 Participants Subjects received SUBLIVAC FIX Phleum Pratense 80,000 AUN/ml sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.
Change From Baseline in Serum Specific Immunoglobulin (IgG) Levels After 5 Months (Visit 4) and 10 Months (Visit 6) of Treatment IgG ATG after 5 months (Visit 4)	0.99 Geometric Mean fold change Interval 0.91 to 1.08	1.10 Geometric Mean fold change Interval 1.0 to 1.2	1.28 Geometric Mean fold change Interval 1.18 to 1.4	1.23 Geometric Mean fold change Interval 1.13 to 1.34
Change From Baseline in Serum Specific Immunoglobulin (IgG) Levels After 5 Months (Visit 4) and 10 Months (Visit 6) of Treatment IgG ATG after 10 months (Visit 6)	0.98 Geometric Mean fold change Interval 0.86 to 1.11	1.21 Geometric Mean fold change Interval 1.05 to 1.39	1.57 Geometric Mean fold change Interval 1.37 to 1.79	1.36 Geometric Mean fold change Interval 1.19 to 1.55
Change From Baseline in Serum Specific Immunoglobulin (IgG) Levels After 5 Months (Visit 4) and 10 Months (Visit 6) of Treatment IgG AP1 after 5 months (Visit 4)	0.98 Geometric Mean fold change Interval 0.94 to 1.03	0.97 Geometric Mean fold change Interval 0.92 to 1.02	1.08 Geometric Mean fold change Interval 1.03 to 1.13	1.00 Geometric Mean fold change Interval 0.96 to 1.05
Change From Baseline in Serum Specific Immunoglobulin (IgG) Levels After 5 Months (Visit 4) and 10 Months (Visit 6) of Treatment IgG AP1 after 10 months (Visit 6)	0.99 Geometric Mean fold change Interval 0.93 to 1.05	1.01 Geometric Mean fold change Interval 0.94 to 1.07	1.20 Geometric Mean fold change Interval 1.13 to 1.28	1.10 Geometric Mean fold change Interval 1.03 to 1.17
Change From Baseline in Serum Specific Immunoglobulin (IgG) Levels After 5 Months (Visit 4) and 10 Months (Visit 6) of Treatment IgG AP5 after 5 months (Visit 4)	0.99 Geometric Mean fold change Interval 0.92 to 1.06	1.03 Geometric Mean fold change Interval 0.96 to 1.11	1.15 Geometric Mean fold change Interval 1.07 to 1.24	1.14 Geometric Mean fold change Interval 1.06 to 1.22
Change From Baseline in Serum Specific Immunoglobulin (IgG) Levels After 5 Months (Visit 4) and 10 Months (Visit 6) of Treatment IgG AP5 after 10 months (Visit 6)	0.98 Geometric Mean fold change Interval 0.88 to 1.09	1.07 Geometric Mean fold change Interval 0.96 to 1.2	1.25 Geometric Mean fold change Interval 1.12 to 1.39	1.23 Geometric Mean fold change Interval 1.11 to 1.37

SECONDARY outcome

Timeframe: 5 and 10 months after treatment start compared to first day of treatment (IgG4 at baseline measured at Visit 2, before IMP injection)

Changes from baseline in serum specific immunoglobulin levels (IgG4 ATG, IgG4 AP1 and IgG4 AP5) after 5 months of treatment (Visit 4) and after 10 months of treatment (Visit 6). Measurements at visit 1 will be used as baseline.

Outcome measures

Outcome measures
Measure	Placebo n=40 Participants Subjects received placebo (containing no allergen extract) sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.	SP 10,000 AUN/ml n=35 Participants Subjects received SUBLIVAC FIX Phleum Pratense 10,000 AUN/ml) sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.	SP 40,000 AUN/ml n=38 Participants Subjects received SUBLIVAC FIX Phleum Pratense 40,000 AUN/ml sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.	SP 80,000 AUN/ml n=37 Participants Subjects received SUBLIVAC FIX Phleum Pratense 80,000 AUN/ml sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.
Change From Baseline in Serum Specific Immunoglobulin (IgG4) Levels After 5 Months (Visit 4) and 10 Months (Visit 6) of Treatment IgG4 ATG after 5 months (Visit 4)	1.01 Geometric Mean fold change Interval 0.83 to 1.24	1.34 Geometric Mean fold change Interval 1.08 to 1.67	2.18 Geometric Mean fold change Interval 1.77 to 2.68	2.05 Geometric Mean fold change Interval 1.67 to 2.54
Change From Baseline in Serum Specific Immunoglobulin (IgG4) Levels After 5 Months (Visit 4) and 10 Months (Visit 6) of Treatment IgG4 ATG after 10 months (Visit 6)	1.11 Geometric Mean fold change Interval 0.85 to 1.46	1.65 Geometric Mean fold change Interval 1.24 to 2.2	3.21 Geometric Mean fold change Interval 2.44 to 4.23	2.36 Geometric Mean fold change Interval 1.79 to 3.12
Change From Baseline in Serum Specific Immunoglobulin (IgG4) Levels After 5 Months (Visit 4) and 10 Months (Visit 6) of Treatment IgG4 AP1 after 5 months (Visit 4)	1.04 Geometric Mean fold change Interval 0.87 to 1.24	1.22 Geometric Mean fold change Interval 1.02 to 1.48	2.06 Geometric Mean fold change Interval 1.72 to 2.47	1.63 Geometric Mean fold change Interval 1.36 to 1.95
Change From Baseline in Serum Specific Immunoglobulin (IgG4) Levels After 5 Months (Visit 4) and 10 Months (Visit 6) of Treatment IgG4 AP1 after 10 months (Visit 6)	1.12 Geometric Mean fold change Interval 0.9 to 1.39	1.56 Geometric Mean fold change Interval 1.24 to 1.96	2.66 Geometric Mean fold change Interval 2.14 to 3.32	1.90 Geometric Mean fold change Interval 1.52 to 2.37
Change From Baseline in Serum Specific Immunoglobulin (IgG4) Levels After 5 Months (Visit 4) and 10 Months (Visit 6) of Treatment IgG4 AP5 after 5 months (Visit 4)	1.03 Geometric Mean fold change Interval 0.73 to 1.44	1.57 Geometric Mean fold change Interval 1.09 to 2.25	2.42 Geometric Mean fold change Interval 1.71 to 3.42	2.91 Geometric Mean fold change Interval 2.05 to 4.13
Change From Baseline in Serum Specific Immunoglobulin (IgG4) Levels After 5 Months (Visit 4) and 10 Months (Visit 6) of Treatment IgG5 AP5 after 10 months (Visit 6)	1.16 Geometric Mean fold change Interval 0.79 to 1.72	1.94 Geometric Mean fold change Interval 1.28 to 2.94	3.12 Geometric Mean fold change Interval 2.09 to 4.66	3.35 Geometric Mean fold change Interval 2.23 to 5.03

OTHER_PRE_SPECIFIED outcome

Timeframe: Ongoing during 10 months treatment period

Population: The Safety population consists of all randomized subjects who received at least one dose of the study drug. The subjects were included in the treatment group corresponding to the study drug they actually received.

The total number and severity (mild, moderate or severe) of local reactions (reported as TEAE) in the active treatment groups and placebo treatment group. Intensity grading: Mild: Awareness of symptoms but easily tolerated, no disruption of normal activities. Moderate: Discomfort enough to cause interference with usual activity. Severe: Incapacitating with inability to work or do usual activity.

Outcome measures

Outcome measures
Measure	Placebo n=42 Participants Subjects received placebo (containing no allergen extract) sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.	SP 10,000 AUN/ml n=42 Participants Subjects received SUBLIVAC FIX Phleum Pratense 10,000 AUN/ml) sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.	SP 40,000 AUN/ml n=42 Participants Subjects received SUBLIVAC FIX Phleum Pratense 40,000 AUN/ml sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.	SP 80,000 AUN/ml n=42 Participants Subjects received SUBLIVAC FIX Phleum Pratense 80,000 AUN/ml sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.
Number and Severity of Local Reactions Total local reactions	26 reactions	55 reactions	91 reactions	147 reactions
Number and Severity of Local Reactions Mild local reactions	26 reactions	52 reactions	82 reactions	140 reactions
Number and Severity of Local Reactions Moderate local reactions	0 reactions	3 reactions	8 reactions	7 reactions
Number and Severity of Local Reactions Severe local reactions	0 reactions	0 reactions	1 reactions	0 reactions

OTHER_PRE_SPECIFIED outcome

Timeframe: Ongoing during 10 months treatment period

The total number and severity (Grade I, Grade II or Grade III) of systemic reactions in the active treatment groups and placebo treatment group. The grading was done according to the World Allergy Organization grading system: Grade 0: No symptoms or non-immunotherapy-related symptoms Grade I: Mild systemic reactions, symptoms: localized urticaria, rhinitis or mild asthma (PF \< 20% decrease from baseline) Grade II: Moderate systemic reactions, symptoms: Slow onset (\>15 min) of generalized urticaria and/or moderate asthma (PF \< 40% decrease from baseline) Grade III: Severe (non-life-threatening) systemic reactions, symptoms: Rapid onset (\<15 min) of generalized urticaria, angioedema or severe asthma (PF \> 40% decrease from baseline) Grade IV: Anaphylactic shock, symptoms: Immediate evoked reaction of itching, flushing, erythema, generalized urticaria, stridor (angioedema), immediate asthma, hypotension, etc.

Outcome measures

Outcome measures
Measure	Placebo n=42 Participants Subjects received placebo (containing no allergen extract) sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.	SP 10,000 AUN/ml n=42 Participants Subjects received SUBLIVAC FIX Phleum Pratense 10,000 AUN/ml) sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.	SP 40,000 AUN/ml n=42 Participants Subjects received SUBLIVAC FIX Phleum Pratense 40,000 AUN/ml sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.	SP 80,000 AUN/ml n=42 Participants Subjects received SUBLIVAC FIX Phleum Pratense 80,000 AUN/ml sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.
Number and Severity of Systemic Reactions Total Systemic reacions	69 reactions	6 reactions	14 reactions	27 reactions
Number and Severity of Systemic Reactions Systemic reactions Grade I	69 reactions	6 reactions	14 reactions	27 reactions
Number and Severity of Systemic Reactions Systemic reactions Grade II	0 reactions	0 reactions	0 reactions	0 reactions
Number and Severity of Systemic Reactions Systemic reactions Grade III	0 reactions	0 reactions	0 reactions	0 reactions

Adverse Events

Placebo

Serious events: 0 serious events

Other events: 26 other events

Deaths: 0 deaths

SP 10,000 AUN/ml

Serious events: 1 serious events

Other events: 36 other events

Deaths: 0 deaths

SP 40,000 AUN/ml

Serious events: 0 serious events

Other events: 33 other events

Deaths: 0 deaths

SP 80,000 AUN/ml

Serious events: 1 serious events

Other events: 36 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Placebo n=42 participants at risk Patients received placebo (containing no allergen extract) sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.	SP 10,000 AUN/ml n=42 participants at risk Patients received SUBLIVAC FIX Phleum Pratense 10,000 AUN/ml) sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.	SP 40,000 AUN/ml n=42 participants at risk Patients received SUBLIVAC FIX Phleum Pratense 40,000 AUN/ml sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.	SP 80,000 AUN/ml n=42 participants at risk Patients received SUBLIVAC FIX Phleum Pratense 80,000 AUN/ml sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.
Hepatobiliary disorders Cholecystitis	0.00% 0/42 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	0.00% 0/42 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	0.00% 0/42 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	2.4% 1/42 • Number of events 1 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.
Pregnancy, puerperium and perinatal conditions Spontaneous abortion	0.00% 0/42 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	2.4% 1/42 • Number of events 1 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	0.00% 0/42 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	0.00% 0/42 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.

Other adverse events

Additional Information

Andrey Larionov, MD, Head of Clinical Development

HAL Allergy

Phone: +31881959189

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Placebo n=42 participants at risk Patients received placebo (containing no allergen extract) sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.	SP 10,000 AUN/ml n=42 participants at risk Patients received SUBLIVAC FIX Phleum Pratense 10,000 AUN/ml) sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.	SP 40,000 AUN/ml n=42 participants at risk Patients received SUBLIVAC FIX Phleum Pratense 40,000 AUN/ml sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.	SP 80,000 AUN/ml n=42 participants at risk Patients received SUBLIVAC FIX Phleum Pratense 80,000 AUN/ml sublingually. Subjects started with one drop and one drop was added each consecutive day until the maintenance dose of 5 drops per day was reached. Next treatment at maintenance dose was continued during 10 months.
Ear and labyrinth disorders Ear pruritus	0.00% 0/42 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	7.1% 3/42 • Number of events 4 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	9.5% 4/42 • Number of events 4 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	21.4% 9/42 • Number of events 11 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.
Eye disorders Eye pruritus	4.8% 2/42 • Number of events 2 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	2.4% 1/42 • Number of events 1 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	7.1% 3/42 • Number of events 3 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	21.4% 9/42 • Number of events 11 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.
Gastrointestinal disorders Abdominal pain	7.1% 3/42 • Number of events 3 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	4.8% 2/42 • Number of events 2 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	4.8% 2/42 • Number of events 2 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	4.8% 2/42 • Number of events 2 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.
Gastrointestinal disorders Dyspepsia	2.4% 1/42 • Number of events 1 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	0.00% 0/42 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	2.4% 1/42 • Number of events 1 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	7.1% 3/42 • Number of events 4 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.
Gastrointestinal disorders Hypoaesthesia oral	4.8% 2/42 • Number of events 2 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	2.4% 1/42 • Number of events 1 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	9.5% 4/42 • Number of events 6 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	9.5% 4/42 • Number of events 5 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.
Gastrointestinal disorders Lip pruritus	0.00% 0/42 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	2.4% 1/42 • Number of events 3 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	7.1% 3/42 • Number of events 4 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	16.7% 7/42 • Number of events 7 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.
Gastrointestinal disorders Lip swelling	0.00% 0/42 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	9.5% 4/42 • Number of events 6 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	4.8% 2/42 • Number of events 2 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	21.4% 9/42 • Number of events 13 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.
Gastrointestinal disorders Mouth swelling	0.00% 0/42 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	7.1% 3/42 • Number of events 3 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	4.8% 2/42 • Number of events 4 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	16.7% 7/42 • Number of events 10 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.
Gastrointestinal disorders Nausea	0.00% 0/42 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	7.1% 3/42 • Number of events 4 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	4.8% 2/42 • Number of events 6 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	9.5% 4/42 • Number of events 5 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.
Gastrointestinal disorders Oral discomfort	0.00% 0/42 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	2.4% 1/42 • Number of events 1 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	2.4% 1/42 • Number of events 1 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	14.3% 6/42 • Number of events 8 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.
Gastrointestinal disorders Oral Pruritus	7.1% 3/42 • Number of events 7 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	11.9% 5/42 • Number of events 7 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	19.0% 8/42 • Number of events 11 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	26.2% 11/42 • Number of events 14 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.
Gastrointestinal disorders Paraesthesia oral	7.1% 3/42 • Number of events 5 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	16.7% 7/42 • Number of events 11 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	26.2% 11/42 • Number of events 16 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	26.2% 11/42 • Number of events 17 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.
Gastrointestinal disorders Tongue pruritus	2.4% 1/42 • Number of events 1 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	7.1% 3/42 • Number of events 3 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	19.0% 8/42 • Number of events 12 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	11.9% 5/42 • Number of events 5 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.
Gastrointestinal disorders Vomiting	0.00% 0/42 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	2.4% 1/42 • Number of events 1 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	2.4% 1/42 • Number of events 1 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	7.1% 3/42 • Number of events 3 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.
General disorders Influenza like illness	2.4% 1/42 • Number of events 1 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	0.00% 0/42 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	2.4% 1/42 • Number of events 1 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	7.1% 3/42 • Number of events 3 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.
Infections and infestations Upper respiratory tract infection	31.0% 13/42 • Number of events 18 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	26.2% 11/42 • Number of events 17 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	31.0% 13/42 • Number of events 17 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	23.8% 10/42 • Number of events 14 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.
Nervous system disorders Headache	26.2% 11/42 • Number of events 17 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	14.3% 6/42 • Number of events 9 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	16.7% 7/42 • Number of events 9 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	26.2% 11/42 • Number of events 14 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.
Respiratory, thoracic and mediastinal disorders Cough	4.8% 2/42 • Number of events 2 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	2.4% 1/42 • Number of events 1 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	2.4% 1/42 • Number of events 1 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	7.1% 3/42 • Number of events 4 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.
Respiratory, thoracic and mediastinal disorders Rhinorrhoea	4.8% 2/42 • Number of events 29 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	2.4% 1/42 • Number of events 1 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	4.8% 2/42 • Number of events 2 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	7.1% 3/42 • Number of events 4 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.
Respiratory, thoracic and mediastinal disorders Throat irritation	4.8% 2/42 • Number of events 2 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	14.3% 6/42 • Number of events 6 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	21.4% 9/42 • Number of events 12 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	31.0% 13/42 • Number of events 16 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.
Skin and subcutaneous tissue disorders Pruritus	0.00% 0/42 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	2.4% 1/42 • Number of events 1 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	0.00% 0/42 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.	11.9% 5/42 • Number of events 6 • Adverse event monitoring was performed throughout the conduct of the trial, from subject screening to the end of subject's participation, approximately one year.