| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Respiratory conditions such as mild asthma. |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 15.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10003553 |
| E.1.2 | Term | Asthma |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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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 |
• Part 1 (SAD) - to evaluate the safety and tolerability of single ascending inhaled doses of GRC 17536 in healthy male subjects.
• Part 2 (MAD) - to evaluate the safety and tolerability of twice daily multiple ascending inhaled doses of GRC 17536 at three dose levels (highest safe once daily doses identified in SAD) in subjects with mild asthma.
• Part 3 (Allergen Challenge) - to evaluate the allergen-induced early and late phase asthmatic response (LAR) as measured by maximal percent decrease in the forced expiratory volume in 1 second (FEV1) and area under the effect curve (AUEC) from the baseline (pre-allergen challenge) to the period beginning 3 hours and ending 8 hours after allergen challenge at the two highest identified doses of GRC 17536 and placebo.
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| E.2.2 | Secondary objectives of the trial |
• Part 1 (SAD)-Evaluate the PK parameters of single ascending inhaled doses of GRC 17536 in healthy male subjects
• Part 2 (MAD)-Evaluate the multiple dose PK parameters of inhaled GRC 17536 at three twice daily dose levels in subjects with mild asthma
• Part 3 (Allergen Challenge)
– Absolute count, percentage differential and percentage change in sputum eosinophils,neutrophils at approximately 8 hrs and 24 hrs after allergen challenge comparing GRC 17536 to placebo
- Safety and tolerability of GRC 17536
–To evaluate allergen-induced early phase asthmatic response (EAR) as measured by maximal percent decrease in the forced expiratory volume in 1 second (FEV1) and area under the effect curve (AUEC) from the baseline (pre-allergen) to the first 3 hrs after allergen challenge (0-3 h) between the two highest identified dose of GRC 17536 and placebo
– FeNO change from baseline Day 1 to Day 14 (pre-challenge) and Day 14 (pre-challenge) to 3,8 and 24 hrs after allergen challenge.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Part 1 (SAD): Healthy subjects
1. Subjects who are able and willing to give written informed consent;
2. Male subjects aged 18 to 50 years inclusive;
3. Weight ≥50 kg;
4. Body mass index (BMI) between 18.0 and 30.0 kg/m2 inclusive;
5. Healthy as determined by pre-study medical history, physical examination, and 12-lead ECG;
6. Non-smokers or ex-smokers for at least 12 months with less than a 10-pack per year history;
7. Clinical laboratory tests within the reference ranges or clinically acceptable to the Investigator;
8. Negative screens for drugs of abuse and alcohol (urine) at screening and admission. Subjects must test negative for the following: amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, ethanol, opiates and cotinine;
9. Medical history must be verified by either a personal physician or medical practitioner as appropriate
10. Male subjects should agree not to not donate sperm for 3 months post last dose; and
11. Female partners (of child bearing potential) of male subjects should use 2 methods of highly effective contraception for 3 months post last dose.
Parts 2 (MAD) and 3 (Allergen challenge):
1. Subjects who are able and willing to give written informed consent
2. Male and non-childbearing female subjects aged 18 to 65 years inclusive;
3. Weight ≥50 kg;
4. Body mass index (BMI) between 18.0 and 32.0 kg/m2 inclusive
5. Female subjects should be of non-child bearing potential, either surgically sterile or post menopausal for 2 years prior to screening, as confirmed by follicle stimulating hormone (FSH) and luteinizing hormone (LH);
6. Male subjects should agree to not donate sperm from first dose until 3 months post last dose
7. Two methods of highly effective contraception should be used if the female partner of a male subject is of child bearing potential (Section 9.4.1)
8. Steroid-naïve subjects with mild asthma for at least 6 months that satisfy the Global Initiative for Asthma (GINA) (6) definition of asthma, but otherwise healthy;
9. Non-smokers or ex-smokers for at least 12 months with less than a 10 pack year history;
10. Not taking any concomitant anti-asthma (except short-acting inhaled β2-agonists or anti-allergy medication (except antihistamines) for at least 6 weeks prior to screening visit and willing to continue throughout the study period;
11. Pre-bronchodilator FEV1 of >70% of the predicted normal value for age, height and sex at screening and prior to first dose administration;
12. Positive methacholine with a provocative concentration of methacholine resulting in a 20% fall in FEV1 (PC20 methacholine) of equal to or less than 8 mg/mL at screening (Part 3 only);
13. Documented allergy to at least one common allergen (house dust mite, pollen allergens or cat dander) as confirmed by a skin prick test wheal ≥3 mm in diameter). Historical data (up to 1 year) may be used (Part 3 only);
14. Early asthmatic response (EAR) (FEV1 fall of ≥ 20%, 0 to 60 minutes after allergen challenge) and LAR (FEV1 fall of ≥15% 3 to 8 hours after challenge) (Part 3 only); and.
15. Able to provide an acceptable a sputum sample which is suitable for analysis (Part 3 only).
To be randomised on Day 1 in Part 3, subjects must have:
Compliance with withholding of disallowed concomitant medication.
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| E.4 | Principal exclusion criteria |
Part 1 (SAD): Healthy subjects
1. Subjects with evidence or history of clinically significant haematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease;
2. Subjects with a supine systolic blood pressure (SBP) ≥160 mmHg and/or a supine diastolic blood pressure (DBP) ≥100 mmHg;
3. History of alcohol abuse or drug addiction as seen on positive screen on drugs of abuse or positive alcohol test;
4. Positive screen on hepatitis B surface antigen (HBsAg), antibodies to the hepatitis C virus (HCV) or antibodies to the human immunodeficiency virus (HIV) 1/2;
5. 12-lead ECG demonstrating QTcF >450 ms at screening;
6. Abnormal liver function tests;
7. Current diagnosis of active epilepsy or any active seizure disorder;
8. Subjects who have a significant infection or known inflammatory process on screening or admission;
9. Subjects who have acute gastrointestinal symptoms at the time of screening or admission;
10. Subjects who have an acute infection such as influenza at the time of screening or admission;
11. Subjects who have received any investigational drug (including GRC 17536) in any clinical trial within 3 months, or who are on extended follow-up;
12. Subjects who do not agree to use medically acceptable methods of contraception;
13. Strong or moderate inhibitors or inducers of CYP3A4;
14. Herbal medication/supplements, St John’s Wort and grapefruit juice for 14 days prior to screening;
Parts 2 (MAD) and 3 (Allergen challenge):
1. Subjects with evidence or history of clinically significant haematological, renal, endocrine, pulmonary (excluding mild asthma), gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease.
2. Worsening of asthma in the 4 weeks preceding the screening visit (requiring daily use of nebulised β2-agonists or any use of long acting β agonists (LABA), or requiring in-patient hospitalisation for asthma control, or requiring emergency room treatment, or requiring systemic corticosteroids for asthma control) or respiratory infection in the 4 weeks preceding the screening visit or during the admission period 1;
3. Use of any immunotherapy within 3 months prior to screening;
4. Use of nasal or inhaled corticosteroids, intraophthalmic corticosteroids, nasal, inhaled, or intraophthalmic cromolyn sodium or nedocromil, leukotriene receptor antagonists and 5-lipoxygenase inhibitors within 6 weeks prior to screening;
5. Patient on LABA and long-acting anti cholinergics;
6. History of life-threatening asthma,
7. Symptomatic with allergic rhinitis (eg, hay fever), requiring treatment, at screening or predicted to have symptomatic allergic rhinitis (eg, hay fever) during the time of study, requiring treatment;
8. History of serious adverse reaction, severe hypersensitivity or allergy to any drug or in any other circumstance (e.g. anaphylaxis);
9. Clinically significant abnormalities in physical examination and/or in laboratory test results (including haematology and chemistry panels, urinalysis) as assessed by the Investigator;
10. Subjects who have received any investigational drug (including GRC 17536) in any clinical trial within 3 months, or who are on extended follow-up;
11. Current diagnosis of active epilepsy or any active seizure disorder requiring chronic therapy with anti-epileptic drug(s);
12. Strong or moderate inhibitors or inducers of CYP3A4
13. Herbal medication/supplements, St John’s Wort and grapefruit juice for 14 days prior to screening;
14. Abnormal liver function tests;
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| E.5 End points |
| E.5.1 | Primary end point(s) |
• Part 1: adverse events (AEs), clinical laboratory tests, vital signs, FEV1, physical examination and 12 lead ECG after a single dose
• Part 2: AEs, clinical laboratory tests, vital signs, FEV1, physical examination and 12 lead ECG after multiple doses
• Part 3: Maximal percentage decrease from pre-allergen challenge value in FEV1 during 3 hours to 8 hours post-allergenchallenge
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part 1 and part 2: Safety evaluation throughout the study
Part 3: FEV1 during 3 hours to 8 hours post-allergenchallenge
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| E.5.2 | Secondary end point(s) |
Part 1, 2, and 3 pharmacokinetic variables
Part 3:
• The area under the effect curve (AUEC) between 0 hours and 3 hours and 3 hours and 8 hours post-allergenchallenge;
• Absolute and % differential count of eosinophils and neutrophils at 8 and 24 hours post-allergenchallenge;
• Change from baseline (Day 1) in FeNO on Day 14 at the pre-challenge and at 3, 8 and 24 hours post-allergenchallenge.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Part 1, part 2 and Part 3: PK evaluation at various timepoints.
Part3: 0 hours and 3 hours and 3 hours and 8 hours post-allergenchallenge;
• Absolute and % differential count of eosinophils and neutrophils at 8 and 24 hours post-allergenchallenge;
• FeNO on Day 1, and on Day 14 at the pre-challenge 3, 8 and 24 hours post-allergenchallenge.
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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 | No |
| E.6.4 | Safety | Yes |
| 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 | No |
| 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) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| First administration to humans through Inhalation route, GRC 17536 administered orally |
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| 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| 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 | 0 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
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