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

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.

Eligibility Criteria:
Inclusion Criteria:

1. Subjects who signed informed consent.
2. Subjects aged ≥18 and ≤65 years at signing of informed consent.
3. Subjects with at least two-year clinical history of allergic rhinitis/rhinoconjunctivitis to grass pollen, with or without concomitant asthma (asthma must be controlled).
4. 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.
5. 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.
6. 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.
7. 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:

1. 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.
2. Patients with grass pollen induced asthma.
3. Subjects who cannot tolerate the Baseline Challenge in the EEC.
4. Subjects who received immunotherapy (SCIT or SLIT) with grass pollen allergens within the past 5 years.
5. (Ongoing) allergen-specific immunotherapy with any allergen(s) during the study period.
6. 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.
7. Subjects undergoing anti-IgE therapy within the 6 months prior to inclusion and/or during the study.
8. Subjects suffering from severe immune disorders (including auto-immune diseases) and/or diseases requiring immunosuppressive drugs.
9. 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.
10. 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.
11. Subjects who have active inflammation or infection of the target organs (nose, eyes or lower airways) at Visit 1.
12. Subjects suffering from diseases with a contraindication for the use of adrenaline (e.g. hyperthyroidism, glaucoma).
13. Subjects receiving vaccination within one week before start of therapy or during the up-dosing phase.
14. Subjects receiving treatment with systemic steroids within 4 weeks before visit 1 and/or during the study.
15. Subjects receiving treatment with systemic or local β-blockers anytime during the study.
16. 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.
17. 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.
18. Subjects that have a history of alcohol, drug or medication abuse within the past year before study start.
19. Subjects with any clinically relevant abnormal laboratory parameter at screening.
20. Subjects that lack cooperation or compliance, as judged by the investigator.
21. Subjects suffering from severe psychiatric, psychological, or neurological disorders.
22. Subjects who are employees of the sponsor or contract research organisation and/or 1st grade relatives or partners of the (principal) investigator.