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The purpose of this study is to assess safety, tolerability and demonstrate a dose response signal using Total Symptom Score (TSS), based on challenges with grass pollen in an Environmental Exposure Chamber (EEC), followed by estimation of the minimum effective dose of SUBLIVAC FIX Phleum (SP) after 10 months of treatment compared to placebo.
The study has 4 treatment groups: 3 different doses of SP and placebo will be tested.
The current dose range finding study with SP has been designed to test three different concentrations of SUBLIVAC FIX Phleum (SP) that includes 3 doses (10,000 AUN/mL; 40,000 AUN/mL; 80,000 AUN/mL) and placebo to demonstrate a dose response signal and to estimate the minimal effective dose of SP. The study will be conducted in the target population of seasonal allergic subjects in a fully validated Environmental Exposure Chamber (EEC) system. The EEC system is a facility that has temporal uniformity of airborne allergen (pollen) exposure to subjects. Use of the EEC ensures exposure to relatively consistent levels of allergen. This facility has been used in a number of immunotherapy trials and is an improved challenge model of AR compared to the previously used nasal provocation test. Treatment duration of this study is extended to 10 months.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| SUBLIVAC FIX Phleum Prat. 0 AUN/ml | Placebo Comparator | 42 subjects received placebo (SUBLIVAC FIX Phleum Pratense 0 AUN/ml) sublingually. Subjects will start with one drop and add one drop each consecutive day until the maintenance dose of 5 drops per day is reached. Next treatment at maintenance dose is continued during 10 months. |
|
| SUBLIVAC FIX Phleum Prat. 10,000 AUN/ml | Experimental | 42 subjects received SUBLIVAC FIX Phleum Pratense 10,000 AUN/ml) sublingually. Subjects will start with one drop and add one drop each consecutive day until the maintenance dose of 5 drops per day is reached. Next treatment at maintenance dose is continued during 10 months. |
|
| SUBLIVAC FIX Phleum Prat. 40,000 AUN/ml | Experimental | 40 subjects received SUBLIVAC FIX Phleum Pratense 40,000 AUN/ml sublingually. Subjects will start with one drop and add one drop each consecutive day until the maintenance dose of 5 drops per day is reached. Next treatment at maintenance dose is continued during 10 months. |
|
| SUBLIVAC FIX Phleum Prat. 80,000 AUN/ml | Experimental | 40 subjects received SUBLIVAC FIX Phleum Pratense 80,000 AUN/ml sublingually. Subjects will start with one drop and add one drop each consecutive day until the maintenance dose of 5 drops per day is reached. Next treatment at maintenance dose is continued during 10 months. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| SUBLIVAC FIX Phleum Prat. | Biological | sublingual daily administration |
|
| Measure | Description | Time Frame |
|---|---|---|
| Mean Total Symptom Score (TSS) After 10 Months of Treatment (Visit 6) Compared to Placebo | 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. | 10 months after treatment start (baseline - Visit 2) |
| Measure | Description | Time Frame |
|---|---|---|
| Change From Baseline in Mean Total Symptom Score (TSS) After 10 Months of Treatment (Visit 6) | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Number and Severity of Local Reactions | 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. |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Peter Couroux, MD | Inflamax | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Inflamax Research Inc. | Mississauga | ON L4W 1A4 | Canada |
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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.
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| FG001 | 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. |
| FG002 | 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. |
| FG003 | 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | Placebo | 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. |
| BG001 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Mean Total Symptom Score (TSS) After 10 Months of Treatment (Visit 6) Compared to Placebo | 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. | 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. | Posted | Least Squares Mean | Standard Error | Score on a scale | 10 months after treatment start (baseline - Visit 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.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Placebo | 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Cholecystitis | Hepatobiliary disorders | MedDRA (19.0) | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Ear pruritus | Ear and labyrinth disorders | MedDRA (19.0) | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Andrey Larionov, MD, Head of Clinical Development | HAL Allergy | +31881959189 | alarionov@hal-allergy.com |
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| ID | Term |
|---|---|
| D065631 | Rhinitis, Allergic |
| ID | Term |
|---|---|
| D012220 | Rhinitis |
| D009668 | Nose Diseases |
| D012140 | Respiratory Tract Diseases |
| D012130 | Respiratory Hypersensitivity |
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Double-blind study
|
| 10 months after treatment start compared to first day of treatment (TSS at baseline measured at Visit 2, before IMP administration) |
| Change From Baseline in Mean Total Symptom Score (TSS) After 5 Months of Treatment (Visit 4) | 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. | 5 months after treatment start compared to first day of treatment (TSS at baseline measured at Visit 2, before IMP administration) |
| Change From Baseline in Mean Total Nasal Symptom Score (TNSS) After 10 Months of Treatment (Visit 6) | 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. | 10 months after treatment start compared to first day of treatment (TSS at baseline measured at Visit 2, before IMP injection) |
| Change From Baseline in Mean Total Nasal Symptom Score (TNSS) After 5 Months of Treatment (Visit 4) | 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. | 5 months after treatment start compared to first day of treatment (TSS at baseline measured at Visit 2, before IMP injection) |
| Mean Combined Symptom and Medication Scores (CSMS) During the Grass Pollen Season. | 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. | during the grass pollen season: estimated between 6 and 10 months after start of treatment at Visit 2 |
| Change From Baseline in Serum Specific Immunoglobulin (IgE) Levels After 5 Months (Visit 4) and 10 Months (Visit 6) of Treatment | 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. | 5 and 10 months after treatment start compared to first day of treatment (IgE at baseline measured at Visit 2, before IMP administration) |
| Change From Baseline in Serum Specific Immunoglobulin (IgG) Levels After 5 Months (Visit 4) and 10 Months (Visit 6) of Treatment | 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. | 5 and 10 months after treatment start compared to first day of treatment (IgG at baseline measured at Visit 2, before IMP injection) |
| Change From Baseline in Serum Specific Immunoglobulin (IgG4) Levels After 5 Months (Visit 4) and 10 Months (Visit 6) of Treatment | 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. | 5 and 10 months after treatment start compared to first day of treatment (IgG4 at baseline measured at Visit 2, before IMP injection) |
| Ongoing during 10 months treatment period |
| Number and Severity of Systemic Reactions | 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. | Ongoing during 10 months treatment period |
| Withdrawal by Subject |
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| Protocol Violation |
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| Adverse Event |
|
| Pregnancy |
|
| Personal reasons patient |
|
| SP 10,000 AUN/ml |
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. |
| BG002 | SP 40,000 AUN/ml | 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. |
| BG003 | SP 80,000 AUN/ml | 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. |
| BG004 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| ID | Title | Description |
|---|---|---|
| OG000 | 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. |
| OG001 | 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. |
| OG002 | 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. |
| OG003 | 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. |
|
|
|
| Secondary | Change From Baseline in Mean Total Symptom Score (TSS) After 10 Months of Treatment (Visit 6) | 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. | 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. | Posted | Least Squares Mean | Standard Error | mean Total Symptom Score | 10 months after treatment start compared to first day of treatment (TSS at baseline measured at Visit 2, before IMP administration) |
|
|
|
|
| Secondary | Change From Baseline in Mean Total Symptom Score (TSS) After 5 Months of Treatment (Visit 4) | 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. | 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. | Posted | Least Squares Mean | Standard Error | mean Total Symptom Score | 5 months after treatment start compared to first day of treatment (TSS at baseline measured at Visit 2, before IMP administration) |
|
|
|
|
| Secondary | Change From Baseline in Mean Total Nasal Symptom Score (TNSS) After 10 Months of Treatment (Visit 6) | 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. | Posted | Least Squares Mean | Standard Error | mean Total Nasal Symptom Score | 10 months after treatment start compared to first day of treatment (TSS at baseline measured at Visit 2, before IMP injection) |
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|
|
| Secondary | Change From Baseline in Mean Total Nasal Symptom Score (TNSS) After 5 Months of Treatment (Visit 4) | 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. | Posted | Least Squares Mean | Standard Error | mean Total Nasal Symptom Score | 5 months after treatment start compared to first day of treatment (TSS at baseline measured at Visit 2, before IMP injection) |
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| Secondary | Mean Combined Symptom and Medication Scores (CSMS) During the Grass Pollen Season. | 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. | 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. | Posted | Least Squares Mean | Standard Error | mean Combined Symptom Medication Score | during the grass pollen season: estimated between 6 and 10 months after start of treatment at Visit 2 |
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| Secondary | Change From Baseline in Serum Specific Immunoglobulin (IgE) Levels After 5 Months (Visit 4) and 10 Months (Visit 6) of Treatment | 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. | 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. | Posted | Geometric Mean | 95% Confidence Interval | Geometric Mean fold change | 5 and 10 months after treatment start compared to first day of treatment (IgE at baseline measured at Visit 2, before IMP administration) |
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| Secondary | Change From Baseline in Serum Specific Immunoglobulin (IgG) Levels After 5 Months (Visit 4) and 10 Months (Visit 6) of Treatment | 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. | 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. | Posted | Geometric Mean | 95% Confidence Interval | Geometric Mean fold change | 5 and 10 months after treatment start compared to first day of treatment (IgG at baseline measured at Visit 2, before IMP injection) |
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| Secondary | Change From Baseline in Serum Specific Immunoglobulin (IgG4) Levels After 5 Months (Visit 4) and 10 Months (Visit 6) of Treatment | 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. | 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. | Posted | Geometric Mean | 95% Confidence Interval | Geometric Mean fold change | 5 and 10 months after treatment start compared to first day of treatment (IgG4 at baseline measured at Visit 2, before IMP injection) |
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| Other Pre-specified | Number and Severity of Local Reactions | 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. | 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. | Posted | Number | reactions | Ongoing during 10 months treatment period |
|
|
|
| Other Pre-specified | Number and Severity of Systemic Reactions | 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. | 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. | Posted | Number | reactions | Ongoing during 10 months treatment period |
|
|
|
| 0 |
| 42 |
| 0 |
| 42 |
| 26 |
| 42 |
| EG001 | SP 10,000 AUN/ml | 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. | 0 | 42 | 1 | 42 | 36 | 42 |
| EG002 | SP 40,000 AUN/ml | 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. | 0 | 42 | 0 | 42 | 33 | 42 |
| EG003 | SP 80,000 AUN/ml | 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. | 0 | 42 | 1 | 42 | 36 | 42 |
| Spontaneous abortion | Pregnancy, puerperium and perinatal conditions | MedDRA (19.0) | Systematic Assessment |
|
| Eye pruritus | Eye disorders | MedDRA (19.0) | Systematic Assessment |
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| Abdominal pain | Gastrointestinal disorders | MedDRA (19.0) | Systematic Assessment |
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| Dyspepsia | Gastrointestinal disorders | MedDRA (19.0) | Systematic Assessment |
|
| Hypoaesthesia oral | Gastrointestinal disorders | MedDRA (19.0) | Systematic Assessment |
|
| Lip pruritus | Gastrointestinal disorders | MedDRA (19.0) | Systematic Assessment |
|
| Lip swelling | Gastrointestinal disorders | MedDRA (19.0) | Systematic Assessment |
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| Mouth swelling | Gastrointestinal disorders | MedDRA (19.0) | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA (19.0) | Systematic Assessment |
|
| Oral discomfort | Gastrointestinal disorders | MedDRA (19.0) | Systematic Assessment |
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| Oral Pruritus | Gastrointestinal disorders | MedDRA (19.0) | Systematic Assessment |
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| Paraesthesia oral | Gastrointestinal disorders | MedDRA (19.0) | Systematic Assessment |
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| Tongue pruritus | Gastrointestinal disorders | MedDRA (19.0) | Systematic Assessment |
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| Vomiting | Gastrointestinal disorders | MedDRA (19.0) | Systematic Assessment |
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| Influenza like illness | General disorders | MedDRA (19.0) | Systematic Assessment |
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| Upper respiratory tract infection | Infections and infestations | MedDRA (19.0) | Systematic Assessment |
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| Headache | Nervous system disorders | MedDRA (19.0) | Systematic Assessment |
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| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA (19.0) | Systematic Assessment |
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| Rhinorrhoea | Respiratory, thoracic and mediastinal disorders | MedDRA (19.0) | Systematic Assessment |
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| Throat irritation | Respiratory, thoracic and mediastinal disorders | MedDRA (19.0) | Systematic Assessment |
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| Pruritus | Skin and subcutaneous tissue disorders | MedDRA (19.0) | Systematic Assessment |
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Not provided
Not provided
| D010038 |
| Otorhinolaryngologic Diseases |
| D006969 | Hypersensitivity, Immediate |
| D006967 | Hypersensitivity |
| D007154 | Immune System Diseases |
| Treatment effect |
| -1.79 |
| Standard Error of the Mean |
| 1.14 |
| 2-Sided |
| 90 |
| -3.68 |
| 0.10 |
| Superiority |
| Mixed Models Analysis | 0.024 | Treatment effect | -2.30 | Standard Error of the Mean | 1.15 | 2-Sided | 90 | -4.20 | -0.40 | Superiority |
| Treatment effect |
| -1.84 |
| Standard Error of the Mean |
| 1.06 |
| 2-Sided |
| 90 |
| -3.60 |
| -0.09 |
| Superiority |
| Mixed Models Analysis | 0.050 | Treatment effect | -1.78 | Standard Error of the Mean | 1.08 | 2-Sided | 90 | -3.56 | 0.00 | Superiority |
| Treatment effect |
| -0.88 |
| Standard Error of the Mean |
| 0.61 |
| 2-Sided |
| 90 |
| -1.89 |
| 0.13 |
| Superiority |
| Mixed Models Analysis | =0.038 | Treatment effect | -1.11 | Standard Error of the Mean | 0.62 | 2-Sided | 0.62 | -2.13 | -0.08 | Superiority |
| Treatment effect |
| -0.62 |
| Standard Error of the Mean |
| 0.56 |
| 2-Sided |
| 90 |
| -1.55 |
| 0.32 |
| Superiority |
| Mixed Models Analysis | =0.195 | Treatment effect | -0.500 | Standard Error of the Mean | 0.57 | 2-Sided | 90 | -1.45 | 0.46 | Superiority |
| Treatment effect |
| -0.394 |
| Standard Error of the Mean |
| 0.186 |
| 2-Sided |
| 90 |
| -0.702 |
| -0.086 |
| Superiority |
| ANOVA | =0.063 | Treatment effect | -0.280 | Standard Error of the Mean | 0.182 | 2-Sided | 90 | -0.581 | 0.021 | Superiority |
| After 10 months (Visit 6) |
|
| Mixed Models Analysis |
| <0.001 |
| Treatment effect |
| 2.43 |
| 2-Sided |
| 90 |
| 1.80 |
| 3.27 |
| Superiority |
| Analysis of change from baseline of serum specific IgE levels after 5 months (Visit 4) | Mixed Models Analysis | <0.001 | Treatment effect | 2.34 | 2-Sided | 90 | 1.73 | 3.15 | Superiority |
| Analysis of change from baseline of serum specific IgE levels after 10 months (Visit 6) | Mixed Models Analysis | 0.029 | Treatment effect | 1.42 | 2-Sided | 90 | 1.05 | 1.93 | Superiority |
| Analysis of change from baseline of serum specific IgE levels after 10 months (Visit 6) | Mixed Models Analysis | 0.003 | Treatment effect | 1.67 | 2-Sided | 90 | 1.24 | 2.25 | Superiority |
| Analysis of change from baseline of serum specific IgE levels after 10 months (Visit 6) | Mixed Models Analysis | 0.042 | Treatment effect | 1.37 | 2-Sided | 90 | 1.01 | 1.85 | Superiority |
| IgG ATG after 10 months (Visit 6) |
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| IgG AP1 after 5 months (Visit 4) |
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| IgG AP1 after 10 months (Visit 6) |
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| IgG AP5 after 5 months (Visit 4) |
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| IgG AP5 after 10 months (Visit 6) |
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| Mixed Models Analysis |
| <0.001 |
| Treatment effect |
| 1.29 |
| 2-Sided |
| 90 |
| 1.17 |
| 1.43 |
| Superiority |
| Analysis of change from baseline of serum specific IgG ATG levels after 5 months (Visit 4) | Mixed Models Analysis | <0.001 | Treatment effect | 1.24 | 2-Sided | 90 | 1.12 | 1.37 | Superiority |
| Analysis of change from baseline of serum specific IgG ATG levels after 10 months (Visit 6) | Mixed Models Analysis | 0.015 | Treatment effect | 1.23 | 2-Sided | 90 | 1.05 | 1.45 | Superiority |
| Analysis of change from baseline of serum specific IgG ATG levels after 10 months (Visit 6) | Mixed Models Analysis | <0.001 | Treatment effect | 1.60 | 2-Sided | 90 | 1.37 | 1.87 | Superiority |
| Analysis of change from baseline of serum specific IgG ATG levels after 10 months (Visit 6) | Mixed Models Analysis | <0.001 | Treatment effect | 1.39 | 2-Sided | 90 | 1.19 | 1.62 | Superiority |
| Analysis of change from baseline of serum specific IgG AP1 levels after 5 months (Visit 4) | Mixed Models Analysis | 0.341 | Treatment effect | 0.99 | 2-Sided | 90 | 0.93 | 1.04 | Superiority |
| Analysis of change from baseline of serum specific IgG AP1 levels after 5 months (Visit 4) | Mixed Models Analysis | 0.003 | Treatment effect | 1.10 | 2-Sided | 90 | 1.04 | 1.16 | Superiority |
| Analysis of change from baseline of serum specific IgG AP1 levels after 5 months (Visit 4) | Mixed Models Analysis | 0.269 | Treatment effect | 1.02 | 2-Sided | 90 | 0.97 | 1.08 | Superiority |
| Analysis of change from baseline of serum specific IgG AP1 levels after 10 months (Visit 6) | Mixed Models Analysis | 0.312 | Treatment effect | 1.02 | 2-Sided | 90 | 0.95 | 1.10 | Superiority |
| Analysis of change from baseline of serum specific IgG AP1 levels after 10 months (Visit 6) | Mixed Models Analysis | <0.001 | Treatment effect | 1.22 | 2-Sided | 90 | 1.13 | 1.31 | Superiority |
| Analysis of change from baseline of serum specific IgG AP1 levels after 10 months (Visit 6) | Mixed Models Analysis | 0.008 | Treatment effect | 1.11 | 2-Sided | 90 | 1.03 | 1.20 | Superiority |
| Analysis of change from baseline of serum specific IgG AP5 levels after 5 months (Visit 4) | Mixed Models Analysis | 0.212 | Treatment effect | 1.04 | 2-Sided | 90 | 0.96 | 1.14 | Superiority |
| Analysis of change from baseline of serum specific IgG AP5 levels after 5 months (Visit 4) | Mixed Models Analysis | 0.002 | Treatment effect | 1.16 | 2-Sided | 90 | 1.07 | 1.27 | Superiority |
| Analysis of change from baseline of serum specific IgG AP5 levels after 5 months (Visit 4) | Mixed Models Analysis | 0.004 | Treatment effect | 1.15 | 2-Sided | 90 | 1.06 | 1.25 | Superiority |
| Analysis of change from baseline of serum specific IgG AP5 levels after 10 months (Visit 6) | Mixed Models Analysis | 0.126 | Treatment effect | 1.09 | 2-Sided | 90 | 0.96 | 1.24 | Superiority |
| Analysis of change from baseline of serum specific IgG AP5 levels after 10 months (Visit 6) | Mixed Models Analysis | <0.001 | Treatment effect | 1.28 | 2-Sided | 90 | 1.13 | 1.45 | Superiority |
| Analysis of change from baseline of serum specific IgG AP5 levels after 10 months (Visit 6) | Mixed Models Analysis | 0.002 | Treatment effect | 1.26 | 2-Sided | 90 | 1.11 | 1.43 | Superiority |
| IgG4 ATG after 10 months (Visit 6) |
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| IgG4 AP1 after 5 months (Visit 4) |
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| IgG4 AP1 after 10 months (Visit 6) |
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| IgG4 AP5 after 5 months (Visit 4) |
|
| IgG5 AP5 after 10 months (Visit 6) |
|
| Mixed Models Analysis |
| <0.001 |
| Treatment effect |
| 2.15 |
| 2-Sided |
| 90 |
| 1.68 |
| 2.74 |
| Superiority |
| Analysis of change from baseline of serum specific IgG4 ATG levels after 5 months (Visit 4) | Mixed Models Analysis | <0.001 | Treatment effect | 2.03 | 2-Sided | 90 | 1.59 | 2.59 | Superiority |
| Analysis of change from baseline of serum specific IgG4 ATG levels after 10 months (Visit 6) | Mixed Models Analysis | 0.024 | Treatment effect | 1.48 | 2-Sided | 90 | 1.07 | 2.06 | Superiority |
| Analysis of change from baseline of serum specific IgG4 ATG levels after 10 months (Visit 6) | Mixed Models Analysis | <0.001 | Treatment effect | 2.88 | 2-Sided | 90 | 2.09 | 3.98 | Superiority |
| Analysis of change from baseline of serum specific IgG4 ATG levels after 10 months (Visit 6) | Mixed Models Analysis | <0.001 | Treatment effect | 2.12 | 2-Sided | 90 | 1.54 | 2.93 | Superiority |
| Analysis of change from baseline of serum specific IgG4 AP1 levels after 5 months (Visit 4) | Mixed Models Analysis | 0.102 | Treatment effect | 1.18 | 2-Sided | 90 | 0.95 | 1.47 | Superiority |
| Analysis of change from baseline of serum specific IgG4 AP1 levels after 5 months (Visit 4) | Mixed Models Analysis | <0.001 | Treatment effect | 1.99 | 2-Sided | 90 | 1.61 | 2.46 | Superiority |
| Analysis of change from baseline of serum specific IgG4 AP1 levels after 5 months (Visit 4) | Mixed Models Analysis | <0.001 | Treatment effect | 1.57 | 2-Sided | 90 | 1.27 | 1.94 | Superiority |
| Analysis of change from baseline of serum specific IgG4 AP1 levels after 10 months (Visit 6) | Mixed Models Analysis | 0.019 | Treatment effect | 1.39 | 2-Sided | 90 | 1.07 | 1.81 | Superiority |
| Analysis of change from baseline of serum specific IgG4 AP1 levels after 10 months (Visit 6) | Mixed Models Analysis | <0.001 | Treatment effect | 2.38 | 2-Sided | 90 | 1.84 | 3.08 | Superiority |
| Analysis of change from baseline of serum specific IgG4 AP1 levels after 10 months (Visit 6) | Mixed Models Analysis | <0.001 | Treatment effect | 1.70 | 2-Sided | 90 | 1.31 | 2.19 | Superiority |
| Analysis of change from baseline of serum specific IgG4 AP5 levels after 5 months (Visit 4) | Mixed Models Analysis | 0.048 | Treatment effect | 1.52 | 2-Sided | 90 | 1.01 | 2.31 | Superiority |
| Analysis of change from baseline of serum specific IgG4 AP5 levels after 5 months (Visit 4) | Mixed Models Analysis | <0.001 | Treatment effect | 2.35 | 2-Sided | 90 | 1.56 | 3.53 | Superiority |
| Analysis of change from baseline of serum specific IgG4 AP5 levels after 5 months (Visit 4) | Mixed Models Analysis | <0.001 | Treatment effect | 2.83 | 2-Sided | 90 | 1.88 | 4.24 | Superiority |
| Analysis of change from baseline of serum specific IgG4 AP5 levels after 10 months (Visit 6) | Mixed Models Analysis | 0.040 | Treatment effect | 1.67 | 2-Sided | 90 | 1.03 | 2.69 | Superiority |
| Analysis of change from baseline of serum specific IgG4 AP5 levels after 10 months (Visit 6) | Mixed Models Analysis | <0.001 | Treatment effect | 2.68 | 2-Sided | 90 | 1.67 | 4.30 | Superiority |
| Analysis of change from baseline of serum specific IgG4 AP5 levels after 10 months (Visit 6) | Mixed Models Analysis | <0.001 | Treatment effect | 2.88 | 2-Sided | 90 | 1.80 | 4.62 | Superiority |
| Mild local reactions |
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| Moderate local reactions |
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| Severe local reactions |
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| Systemic reactions Grade I |
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| Systemic reactions Grade II |
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| Systemic reactions Grade III |
|