Efficacy and Safety of PQ Grass in Subjects With Seasonal Allergic Rhinitis and/or Rhinoconjunctivitis Induced by Grass Pollen

The PQGrass306 (G306) clinical trial is the pivotal Phase III efficacy clinical trial of PQ Grass.

The aim of the G306 pivotal clinical trial is to confirm the efficacy and safety of the optimal effective dose of PQ Grass 27600 SU. This will be determined through the measurements of the effect of PQ Grass on the symptoms of seasonal allergic rhinitis (SAR)/rhinoconjunctivitis and the use of relief medications to control these symptoms during the peak grass pollen season (GPS).

Multi-centre, randomised, parallel group, double-blind, placebo-controlled clinical trial to confirm the efficacy and safety of the optimal effective dose of PQ Grass (27600 SU).

Randomized study subjects, in a randomisation ratio of 1:1, will receive either treatment with 6 injections of active treatment (900, 2700, 6000, 6000, 6000 and 6000 SU sequentially) to achieve a cumulative nominal dose of 27600 SU, or 6 injections of placebo prior to the onset of the grass pollen season (GPS).

The aim of the study is to confirm the efficacy and safety of the optimal effective dose of the PQ Grass 27600 SU dose. Efficacy will be determined through the measurements of the effect of PQ Grass on the symptoms of seasonal allergic rhinitis (SAR)/rhinoconjunctivitis and the use of relief medications to control these symptoms during the peak GPS.

Eligibility Criteria:
Inclusion Criteria:

1. Capable of giving signed informed consent as described in Appendix 1 which includes compliance with the requirements and restrictions listed in the ICF (informed consent form) and in this clinical trial protocol and to attend required clinical trial visits.
2. Subject who has a signed and dated ICF.
3. Subject must be 18 to 65 years of age inclusive, at the time of signing the ICF.
4. Male or female.
5. Female subjects who are not of childbearing potential (defined as at least 12 months natural spontaneous amenorrhoea, or at least 6 weeks following surgical menopause/permanent sterilisation \[hysterectomy, bilateral oophorectomy and bilateral salpingectomy\]) or females of childbearing potential who agree to comply with the contraceptive requirements of the clinical trial protocol.
6. Good general health, as determined by the Investigator, based on a medical evaluation, including medical history, physical examination, mental status assessment and laboratory tests. A subject with a clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included only if the Investigator agrees that the finding is unlikely to introduce additional risk factors and will not interfere with the clinical trial procedures.
7. Positive history of moderate to severe symptoms of SAR/rhinoconjunctivitis ascribed to grass (Pooideae) pollen exposure of at least 2 seasons duration, despite having received allergy pharmacotherapy (e.g., antihistamines, nasal corticosteroids, leukotriene modifiers, etc.) during the last 2 consecutive grass pollen seasons prior to the clinical trial, confirmed by subject records.

   Please note: Subjects with asthma may be included, but the asthma must be well controlled (according to current Global Initiative for Asthma \[GINA\] guidelines \[GINA 2022\]).
8. A positive SPT (skin prick test) to histamine (wheals \[longest diameter\] ≥3 mm) and a negative SPT to the negative control (wheal diameter = 0 mm) at screening.
9. A positive SPT for grass pollen (wheals \[longest diameter\] ≥3 mm).
10. Grass specific IgE (immunoglobulin E) class ≥2 as documented by an ImmunoCAP test at screening.
11. Forced expiratory volume in one second (FEV1) ≥70% of predicted, with a FEV1/forced vital capacity (FVC) ratio \>75% and PEFR (peak expiratory flow rate) ≥70% of predicted at screening.

Exclusion Criteria:

1. Pregnant or lactating subject.
2. Presence of any medical history of moderate to severe allergy symptoms (verified by a positive SPT at screening or positive specific IgE \[≥2\] at screening) to any other seasonal allergen (other than grass) or perennial allergens.

   Exception: Period 1, Period 2 and Period 3 of the entire clinical trial will be conducted outside of the pollen season(s) of concern or perennial allergies are irrelevant due to avoidance measures (e.g., cats and dog allergy). Subjects with mild allergy symptoms (only) to any other allergen apart from grass may be included at the discretion of the Investigator. In countries in Europe where Bermuda grass is present, any medical history of moderate to severe allergy symptoms to Bermuda grass (verified by a positive SPT or positive specific IgE \[Class ≥2\]), will also represent a reason for exclusion as it will not be possible to conduct Period 1, Period 2 and Period 3 of the entire clinical trial outside of Bermuda grass pollen season. Albeit Bermuda grass being commonly defined as a grass, it belongs to the Poaceae family, while the sentence (other than grass) in Exclusion criterion #2 refers to grass of Pooideae subfamily (as defined in Inclusion criterion #7).
3. Subjects at US clinical trial sites in regions where southern grasses (Bahia grass, Bermuda grass or Johnson grass) are the dominant grasses and the main cause of grass allergy symptoms with a positive SPT to any of the 3 grasses (irrespective of the severity of symptoms).
4. Moderate to severe symptoms during the 3 years prior to Visit 1 to any other seasonal or perennial allergen not tested in the SPT done at screening that cannot be avoided during the Period 1 to Period 3 of the clinical trial and the symptoms of which may interfere with administration of treatment and/or impact the data collected.
5. Presence of any medical condition that may reduce the ability to survive a serious allergic reaction.
6. Presence of active systemic autoimmune disorder, systemic autoimmune disorders in remission or active organ specific autoimmune disorder.
7. Presence of active malignant neoplasia, severe cardiovascular disease (e.g., coronary artery disease, cardiac insufficiency, etc.), pulmonary insufficiency, severe psychiatric disorders or primary and secondary immunodeficiencies.
8. History of any other immunological disorder or other diseases (including, but not limited cardiovascular \[including uncontrolled or inadequately controlled hypertension\], gastro-intestinal, hepatic, renal, haematological, neurological, endocrine or pulmonary disease) that in the opinion of the Investigator may pose a safety risk or compromise the interpretation of efficacy of the clinical trial treatment.
9. Presence of severe or poorly controlled or uncontrolled asthma as defined by at least 1 of the following criteria:

   1. Severe asthma (as per the current GINA guidelines \[GINA, 2022\]).
   2. Uncontrolled or poorly controlled asthma as per the current GINA guidelines (GINA, 2022).
   3. Asthma that requires more than a daily dose above 800 μg of inhaled budesonide (or clinically comparable inhaled corticosteroid) as per the current GINA guidelines (GINA, 2022).
   4. History of 2 or more systemic corticosteroid courses within 6 months of screening or Visit 2 or 1 course of systemic corticosteroids within 3 months of screening or Visit 2 to treat asthma.
   5. Prior intubation/mechanical ventilation for asthma.
   6. Emergency room visit or hospitalisation for asthma in the 12 months prior to screening or Visit 2.
   7. Any history of a life-threatening asthma attack.
   8. FEV1 \<70% of predicted or FEV1/FVC ≤75% or PEFR \<70% of predicted with or without controller medications at screening or Visit 2.
10. Presence non-atopic rhinitis and/or rhino-sinusitis (with or without polyps).
11. Presence of nasal polyps and/or chronic sinusitis.
12. Presence of any acute or chronic ocular disorder, other than allergic conjunctivitis.
13. Eye surgery within the past 6 months.
14. Presence of any skin conditions (e.g., skin abnormalities, tattoos etc.), which might interfere with the interpretation of the SPT results.
15. Clinical history of Type I diabetes or poorly controlled Type II diabetes.
16. Moderate to severe upper or lower respiratory infections requiring medication within 14 days before screening (Visit 1) or Visit 2.
17. Presence of acute or chronic infection, fever or inflammation at screening or Visit 2.
18. Clinical history of severe systemic reaction or serious systemic reaction in response to AIT (allergen immunotherapy) in the past.
19. Clinical history of severe or life-threatening anaphylactic reactions to foods, insect venom, exercise, drugs or idiopathic anaphylaxis.
20. Clinical history of allergy, hypersensitivity or intolerance to the excipients of the investigational drug/placebo.
21. Clinical history of allergy, hypersensitivity or intolerance to the relief medications (for relief of allergy symptoms during Period 3) provided for use in this clinical trial.
22. Clinical history of hereditary angioedema.
23. Unable to receive epinephrine therapy (i.e., use of epinephrine is contraindicated such as in subjects with hyperthyroidism, uncontrolled hypertension, cardiac arrhythmias, closed angle glaucoma or subjects taking other sympathomimetics).
24. Tyrosine metabolism disorders, especially tyrosinemia and alkaptonuria.
25. Clinical history of drug or alcohol abuse, which, in the Investigator's opinion, could interfere with the subject's ability to participate in the clinical trial.
26. Subjects who have suspicion or symptoms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (as assessed by the Investigator) or who have had unprotected contact with a confirmed case of COVID-19 (coronavirus disease 2019) in the 2 weeks prior to screening or Visit 2 (based on the Investigator's discretion).
27. Subjects who were hospitalised for COVID-19 within 6 months prior to screening or Visit 2.
28. Any history of AIT for grass pollen allergy in the past or history of AIT for any other type of allergy (excluding food allergy) in the past 5 years.
29. Inability to adhere to the washout periods listed in the protocol, with respect to screening and to refrain from using the medications indicated until after Visit 11.
30. Treatment with a preparation containing MPL (monophosphoryl lipid-A) (e.g., Cervarix, Shingrix, Fendrix) within 2 years prior to Visit 1 and until after completion of Visit 11 (with the exception of the investigational drug).
31. Previous history of epinephrine auto-injector use.
32. β-blocker medication (local or systemic, including eye drops) for any indication.
33. Monoamine oxidase inhibitors and tricyclic antidepressants. Please note: Tricyclic antidepressants should be avoided at least 2 weeks prior to screening.
34. Any previous therapy (within the previous 5 years) or current therapy with anti IgE (e.g., omalizumab \[Xolair\]) or anti-interleukins (e.g., mepolizumab).
35. Current or past therapy (within the previous 5 years) with any other immunomodulatory biologics.
36. Unable to refrain from any vaccination (including influenza vaccine and COVID-19 vaccine) during the clinical trial (unless administered \>30 days prior to randomisation).

    Please note: Emergency vaccinations (e.g., tetanus due to injury) can be administered at any time. Booster vaccinations (only) for COVID-19 can be administered during the clinical trial apart from during the treatment period. There should be at least 14 days interval from the last administration of the investigational drug/placebo prior to administration of a COVID-19 booster injection.
37. Participation in a clinical research trial with any investigational drug within 4 weeks of Visit 1 or concomitantly with this clinical trial.

    Please note: The period of exclusion begins at the time of the last visit of the prior clinical research trial. Subjects consented and screened, but not dosed in the prior clinical research trial are not excluded.
38. Personal, financial or other dependent relationship (e.g., employee or immediate relative) with the clinical trial site, Sponsor, Sponsor's representative, or another individual who has access to the clinical trial protocol.
39. Vulnerable subjects or those in judicial or governmental detention, detainment or imprisonment in a public institution.
40. Subjects likely to have prolonged periods of absence (e.g., business or personal travel) during the GPS defined as:

    * Absence of a total of 22 days or more in similar geographical regions (as determined by the Investigator), with no single trip in a similar geographical region exceeding 14 days.
    * Absence of a total of 15 days or more in non-similar geographic regions (as determined by the Investigator), with no single trip in a non-similar geographical region exceeding 7 days.
41. Have changed residence to a different geographical region(s) since the last GPS.

Exception: The old and new residences are in the same or similar geographical region as determined by the Investigator.