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

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
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.

Official Title
-----------------
A Single-center, Randomized, Double Blind, Placebo-Controlled, Parallel Group Study to Investigate the Relative Efficacy and Safety of Immunotherapy With SUBLIVAC FIX Phleum Pratense in Grass Pollen-Allergic Subjects With IgE-Mediated Seasonal ARC

Conditions
-----------------
Allergic Rhinitis, Allergic Rhinoconjunctivitis

Intervention / Treatment
-----------------
* Biological: SUBLIVAC FIX Phleum Prat.


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects who signed informed consent. Subjects aged ≥18 and ≤65 years at signing of informed consent. Subjects with at least two-year clinical history of allergic rhinitis/rhinoconjunctivitis to grass pollen, with or without concomitant asthma (asthma must be controlled). Subjects with a forced expiratory volume at one second (FEV1) >70% of the predicted value as measured during screening or documented within 1 year of study start. Subjects with a positive skin prick test (SPT) (mean wheal diameter of at least 3 mm larger than the negative control; negative control should be <2 mm, histamine control should be positive (mean wheal diameter of at least 3 mm larger than the negative control)) for grass pollen assessed during screening or a documented positive response obtained within 1 year before screening. Subjects with a grass pollen specific IgE greater than or equal to 0.7 kiloUnits (kU)/L assessed during screening or a documented positive result obtained within 1 year before screening. Subjects with a TSS of at least 10/24 during baseline EEC challenge (V2) in combination with a staff assessed score of at least 2/3 for two objective TSS symptoms (i.e. running nose, sneezing or red eyes), during the baseline EEC challenge. Exclusion Criteria: Subjects with (expected) clinically relevant symptoms at the timing of the scheduled EEC assessments at Visit 2 and Visit 6 due to concomitant sensitization i.e. positive SPT (mean wheal diameter of at least 3 mm larger than the negative control) and a history of allergic response to the causative allergen, at the discretion of the investigator. Patients with grass pollen induced asthma. Subjects who cannot tolerate the Baseline Challenge in the EEC. Subjects who received immunotherapy (SCIT or SLIT) with grass pollen allergens within the past 5 years. (Ongoing) allergen-specific immunotherapy with any allergen(s) during the study period. Subjects with unsuccessful allergen-specific immunotherapy within the past 5 years (e.g., but not limited to, prematurely stopped immunotherapy due to non-compliance, AEs or lack of therapeutic effect), at the discretion of the investigator. Subjects undergoing anti-IgE therapy within the 6 months prior to inclusion and/or during the study. Subjects suffering from severe immune disorders (including auto-immune diseases) and/or diseases requiring immunosuppressive drugs. Subjects suffering from active malignancies or any malignant disease (except for localized basal cell cancers of the skin as long as they have been adequately treated and no recurrence within 3 months of screening visit) during 5 years prior to screening. Subjects suffering from severe uncontrolled diseases that could increase the risk for participating in the study, including but not limited to: cardiovascular insufficiency, any severe or unstable lung diseases, endocrine diseases, clinically significant renal or hepatic diseases, or haematological disorders at the discretion of the Investigator. Subjects who have active inflammation or infection of the target organs (nose, eyes or lower airways) at Visit 1. Subjects suffering from diseases with a contraindication for the use of adrenaline (e.g. hyperthyroidism, glaucoma). Subjects receiving vaccination within one week before start of therapy or during the up-dosing phase. Subjects receiving treatment with systemic steroids within 4 weeks before visit 1 and/or during the study. Subjects receiving treatment with systemic or local β-blockers anytime during the study. Subjects who participated in a clinical study within the last 3 months (e.g. new investigational drug or biological) or within the last 30 days (e.g. bio-equivalent drug), at the discretion of the Investigator. Female subjects of child-bearing potential who are pregnant, lactating or using inadequate contraceptive measures (adequate contraceptive measures will be: sexual abstinence; oral contraceptives, trans dermal patches or depot injection of a progestogen drug (starting at least 4 weeks prior to investigational medicinal product (IMP) administration); double barrier method: condom or occlusive cap (diaphragm or cervical/vault caps) plus spermicidal agent; intrauterine device (IUD), intrauterine system (IUS), implant, or vaginal ring (placed at least 4 weeks prior to IMP administration); or male partner sterilization (vasectomy with documentation of azoospermia) prior to the female subject's entry into trial and is the sole sexual partner for that female subject. Subjects that have a history of alcohol, drug or medication abuse within the past year before study start. Subjects with any clinically relevant abnormal laboratory parameter at screening. Subjects that lack cooperation or compliance, as judged by the investigator. Subjects suffering from severe psychiatric, psychological, or neurological disorders. Subjects who are employees of the sponsor or contract research organisation and/or 1st grade relatives or partners of the (principal) investigator.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: SUBLIVAC FIX Phleum Prat. 0 AUN/ml<br>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. | Biological: SUBLIVAC FIX Phleum Prat.<br>* sublingual daily administration<br>|
| Experimental: SUBLIVAC FIX Phleum Prat. 10,000 AUN/ml<br>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. | Biological: SUBLIVAC FIX Phleum Prat.<br>* sublingual daily administration<br>|
| Experimental: SUBLIVAC FIX Phleum Prat. 40,000 AUN/ml<br>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. | Biological: SUBLIVAC FIX Phleum Prat.<br>* sublingual daily administration<br>|
| Experimental: SUBLIVAC FIX Phleum Prat. 80,000 AUN/ml<br>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. | Biological: SUBLIVAC FIX Phleum Prat.<br>* sublingual daily administration<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | 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) | 

Secondary Outcome Measures

| Outcome Measure | 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. | 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) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Sublingual immunotherapy, Dose range finding, Grass pollen, Allergic rhinitis/rhinoconjunctivitis, Immunogenicity