| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Body processes [G] - Immune system processes [G12] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10001723 |
| E.1.2 | Term | Allergic rhinitis |
| E.1.2 | System Organ Class | 100000004855 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
• To investigate the effect of repeat oral doses of ONO-4053 versus placebo on nasal symptoms (Total Nasal Symptom Score) elicited by allergen chamber challenge in subjects with allergic rhinitis.
• To investigate the safety and tolerability of repeat oral doses of ONO-4053 versus placebo in subjects with allergic rhinitis.
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| E.2.2 | Secondary objectives of the trial |
• To investigate the effect of repeat oral doses of ONO-4053 versus Cetirizine on nasal symptoms (Total Nasal Symptom Score) elicited by allergen chamber challenge in subjects with allergic rhinitis.
• To investigate the effect of repeat oral doses of ONO-4053 versus placebo and Cetirizine on nasal, eye and other symptoms, nasal obstruction (active anterior rhinomanometry) and nasal secretion weight elicited by allergen chamber challenge in subjects with allergic rhinitis.
• To investigate pharmacokinetics of ONO-4053 following repeat oral doses in subjects with allergic rhinitis.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. The subject has provided written informed consent, which signifies an agreement to enter the study and comply with the restrictions and requirements listed in the informed consent form.
2. The subject is aged between 18 and 65 years inclusive.
3. The subject has a body mass index of 19.0–30.0 kg/m2 inclusive and weighs ≥45.0 kg (female) and ≥50.0 kg (male) and no more than 100.0 kg at Screening (Visit 1).
4. The subject has a documented history of allergic rhinitis as determined by the presence of rhinitis symptoms that last for several months of the year, for at least two years, and are not attributed to infections or nasal abnormalities.
5. The subject has a positive skin prick test (wheal size ≥ 3 mm) for grass pollen at Screening (Visit 1) or within the 12 months preceding Screening (Visit 1).
6. The subject has a serum specific IgE of at least 0.7kU/L (Radioallergosorbent test (RAST) ≥ class 2) for grass pollen at Screening (Visit 1) or within the 12 months preceding Screening (Visit 1).
7. The subject exhibits a moderate to severe response to approximately 1500 grass pollen grains/m3 within the first 2 hours in the allergen challenge chamber at Screening (Visit 2). A moderate to severe response is defined as a total nasal symptom score of at least 6 (Total nasal symptom score is the sum of nasal obstruction, rhinorrhoea, itchy nose and sneezing, each of which has been scored on a scale from 0 to 3) and a nasal obstruction subscore of at least 2 (scored on a scale from 0 to 3).
8. The subject demonstrates a forced expiratory volume in one second (FEV1) ≥ 80% of predicted (Standardized Lung Function Test per European Coal and Steel Community) at Screening (Visit 1 or 2).
9. Male subjects should be willing to use barrier contraception i.e., condoms with spermicide from the time of the first dose until 3 months after the last dose and agree to refrain from sperm donation for a period until 3 months after the last dose of study medication. Additionally, male subjects will be advised that their female partners of child-bearing potential should use an additional effective method of contraception for the same period.
10. Female subjects fulfil one of the following three criteria:
a) Post-menopausal, defined as amenorrhoea for at least 24 months together with an appropriate clinical profile (i.e., no alternative medical cause) and confirmed at Screening (Visit 1) by FSH levels above the lower limit of the laboratory range for post-menopausal women.
b) Not of child-bearing potential with a documented history of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.
c) Of child-bearing potential with negative pregnancy test at Screening and on admission to the clinical unit (Visit 3), and must have a history of consistent use of a highly effective method of birth control for the previous 3 months of Screening (Visit 1) and be prepared to continue to use a highly effective method of contraception from Screening (Visit 1) until the Follow-up visit.
11. The subject is available to complete all study measurements.
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| E.4 | Principal exclusion criteria |
1. The subject has a clinically relevant medical history, presence of any clinically significant disease or disorder, clinically significant laboratory, physical examination or ECG abnormalities at Screening (Visit 1 or 2) which in the opinion of the Investigator would place the subject at undue risk, influence the results or ability of the subject to participate in the study.
2. Pregnant or breast-feeding females.
3. The subject on examination is found to have nasal structural abnormalities or nasal polyps; nasal surgery ≤ 56 days (8 weeks) prior to Screening (Visit 1).
4. The subject has a history of frequent nosebleeds, nasal biopsy, nasal trauma or nasal surgery.
5. The subject has a respiratory infection within 7 days, or a respiratory infection requiring antibiotic therapy within 14 days of Screening (Visits 1 and 2).
6. The subject has a respiratory disease, other than mild asthma not requiring treatment and associated with normal lung function.
7. The subject is concurrently participating, or has participated in a study with an investigational medicinal product during the previous 3 months or in any clinical study in the month prior to Screening (Visit 1).
8. The subject has used any medications within the time windows, which are stated in the table of section 8.1. Prohibited medication.
9. The subject regularly, or on average, drinks more than 3 units of alcohol per day - where 1 unit = ½ pint of beer (284mL), or 1 glass of wine (125mL), or 1 measure of spirit (25mL).
10. The subject is infected with Hepatitis B, Hepatitis C, or Human Immunodeficiency Virus (HIV) virus at Screening (Visit 1).
11. The subject has a current or chronic history of liver disease, or known hepatic (e.g. Gilbert’s syndrome) or biliary abnormalities.
12. The subject has an impaired hepatic function at Screening (Visit 1) defined as raised alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2 x Upper limit of normal (ULN), alkaline phosphatase (ALP), total bilirubin or gamma glutamyl transpeptidase (GGT) >1.5 x ULN.
13. The subject has a history of an allergic drug or food reaction that, in the opinion of the responsible physician, contraindicates their participation (e.g. aspirin allergy, antibiotics allergy).
14. The subject has other clinically significant diseases or conditions which could interfere with the objectives of the study.
15. The subject has donated a unit of blood (≥450mL) and/or received any blood or blood products within the previous 3 months of Screening (Visit 1) or intends to donate within 12 weeks of completing the study.
16. The subject has a positive test for drugs of abuse or alcohol at Screening (Visit 1).
17. The subject has a suspected hypersensitivity or intolerance to the study drugs or any ingredients of the study medication as detailed in the IB.
18. The subject has any conditions or factors which would make the subject unlikely to be able to stay in the chamber for 6 hours.
19. The subject is at risk of non-compliance with the study procedures/restrictions.
20. The subject has any other reason that the Investigator considers makes the subject unsuitable to participate.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
• Area under the PD effect time curves (AUE0-2h, 2-6h and 0-6h) of Total Nasal Symptom Score (TNSS) on Day 8 (nasal obstruction, rhinorrhoea, nasal itching and sneezing will be scored on a categorical scale from 0 to 3. Individual scores will be summed to produce the TNSS).
• AEs, physical examination, vital signs, 12-lead ECG, lung function test and safety laboratory evaluations.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
• AUE (0-2h, 2-6h and 0-6h) of individual nasal symptom scores of TNSS: nasal obstruction, rhinorrhoea, nasal itching and sneezing (will be scored on a categorical scale of 0 to 3).
• AUE (0-2h, 2-6h and 0-6h) of Total Ocular Symptom Score (TOSS): Watery eyes, itchy eyes and red eyes will be scored on a categorical scale of 0 to 3. Individual scores will be summed to produce the TOSS.
• AUE (0-2h, 2-6h and 0-6h) of Miscellaneous Allergy Symptom Score (MASS): Cough, itchy throat and itchy ears will be scored on a categorical scale of 0 to 3. Individual scores will be summed to produce the MASS.
•AUE (0-2h, 2-6h and 0-6h) of Global symptom score (sum of TNSS, TOSS and MASS).
• AUE (0-2h, 2-6h and 0-6h) of Active anterior rhinomanometry (the sum of left and right nostril for evaluation).
• AUE (0-2h, 2-6h and 0-6h) of Nasal secretion weight.
• AUE(0-2h, 2-6h and 0-6h) of sum of three nasal symptom scores on Day 8 (nasal obstruction, rhinorrhoea and sneezing will be scored on a categorical scale from 0 to 3. Individual scores will be summed to produce the sum score).
• Pharmacokinetics of plasma ONO-4053: concentration prior to dosing on Day 1 (treatment periods 2, 3 and 4 only) and trough concentration prior to dosing on Day 8; Day 8 post allergen challenge (6 h post dose).
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Daily during the study unless specified otherwise. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | |
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