E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 12.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10001705 |
E.1.2 | Term | Allergic asthma |
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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 evaluate the efficacy of AZD8848 on the Late Asthmatic Response (LAR) compared with placebo after 8 doses of once weekly intranasal administration in mild to moderate asthma patients challenged with inhaled allergen (Main Part only). |
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E.2.2 | Secondary objectives of the trial |
• To evaluate the efficacy of AZD8848 compared with placebo after 8 doses of once weekly intranasal administration in mild to moderate asthma patients challenged with inhaled allergen as measured by the Early Asthmatic Response (EAR), Bronchial Hyperreactivity (BHR) and Sputum Biomarkers (Main Part only). • To investigate tolerability and safety of AZD8848 after 8 doses of once weekly intranasal administration in asthma patients (Pilot and Main Parts). • To investigate plasma concentrations of the acid metabolite around Cmax after the first and last dose of AZD8848 administered intranasally (concentrations represent the sum of AZD8848 and acid metabolite) (Main Part only). • To investigate the influence of butyrylcholinesterase genotype on pharmacokinetic and pharmacodynamic responses (Main Part only). |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
The sub study taking the form of samples for DNA analysis of pharmacogenetic (PGt) analysis.
The participation in the genetic research activity is an optional part of the study. Patients must give separate informed consent before a blood sample is taken. Pharmacogenetic data will be reported separately from the CSR. |
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E.3 | Principal inclusion criteria |
1. Provision of informed consent prior to any study specific procedures
2. Male or female patients aged 18 to 55 years (inclusive). Females must be of non-childbearing potential or must have been stable on a highly effective contraceptive method for at least 3 months prior to Visit 1 and be willing to continue on the chosen contraceptive method, with additional use of a condom, until Visit 19. Women must be non-lactating and must have a date of menstruation consistent with non-pregnancy (see section 4.1.2 for more details)
3. A minimum of 6 months documented history of asthma defined according to the GINA guidelines (Global Initiative for Asthma 2008) prior to Visit 1
4. The presence of allergic sensitivity (grass, house dust mite, cat) verified by a positive skin prick test documented within the previous 24 months or at Visit 1
5. FEV1 (forced expiratory volume in 1 second) >70% of predicted normal value, prebronchodilator
6. The presence of an Early Asthmatic Response corresponding to ≥ 20% FEV1 decrease within 2 hours post-allergen challenge as verified and documented within the previous 12 months or at screening. The inhaled allergen will be one of those giving a positive response in the skin prick test (see section 6.2.1).
7. Methacholine PC20 (the provocative concentration of methacholine causing a 20% fall in FEV1) <16 mg/mL as verified and documented within the previous 12 months or at screening (Visit 1)
8. Body mass index between 19 and 33 kg/m2
9. Non- or ex-smokers who are expected to not smoke for the duration of the trial up to Visit 12 (an ex-smoker being defined as someone who <10 pack-year history and who has completely stopped smoking for at least 6 months before Visit 1)
10. Ability to metabolise AZD8848 (an in vitro screening assay will determine esterase metabolic activity in a blood sample taken at Visit 1 using a pre-defined limit)
For inclusion in the main part, note the additional criteria for LAR:
6. Early Asthmatic Response corresponding to ≥20% FEV1 decrease within 2 hours and Late Asthmatic Response corresponding to ≥15 % FEV1 decrease between 4-10 hours post-allergen challenge on two consecutive occasions. The inhaled allergen will be the one of those giving a positive response in the skin prick test (see section 6.2.1).
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E.4 | Principal exclusion criteria |
1. Any clinically relevant disease and/or abnormality (past or present), which, in the opinion of the Investigator, may either put the patient at risk because of participation in the study, or influence the results of the study, or the patient’s ability to participate in the study. Includes pregnant or lactating females.
2. Symptomatic allergic rhinitis (those with a history of allergic rhinitis may participate if asymptomatic at screening and if, in the opinion of the Investigator, it is unlikely that disease exacerbation will occur during the course of the study)
3. Any clinical relevant abnormal findings in physical examination, clinical chemistry, haematology, urinalysis, vital signs, or ECG at baseline which, in the opinion of the investigator, may put the patient at risk because of participation in the study
4. QTcF >450ms, confirmed with repeated measurements at Visit 1
5. Rhythm, conduction (eg intermittent or constant Bundle branch block; Intraventricular conduction disturbance with repolarisation changes: intermittent or constant AV block (including 1st degree AV block with PR interval >220msec, 2nd or 3rd degree AV block)); or morphologic changes affecting repolirization (eg, flat, biphasic or inverted T waves in primary lead V2), that may limit ability to measure QTc and assess changes in QTc intervals or QTc morphology
6. History of additional risk factors for Torsade de pointes (eg heart failure, hypokaelamia, family history of Long QT syndrome, or sudden death)
7. Medical history suggesting or confirming abnormal immune function, except for asthma
8. Family history (parent or sibling) of autoimmune disease including but not limited to Wegener’s granulomatosis, system lupus erythematosus, rheumatoid arthritis, Sjögren’s syndrome, multiple sclerosis, autoimmune thrombocytopenia, primary biliary cirrhosis or any other autoimmune disease considered clinically relevant by the investigator
9. Any detection of anti-PR3 autoantibodies in the blood
10. History of or ongoing immunotherapy
11. Topical or inhaled glucocorticosteroid +/- Long-Acting β-Agonists (LABAs) treatment within 4 weeks prior to Visit 1
12. Systemic glucocorticosteroid therapy for any reason within 6 weeks prior to Visit 1
13. Antihistamine treatment within 1 week prior to Visit 1. This period should be extended for antihistamines with a long half-life (see exclusion criteria 14)
14. Use of any medication (including vaccinations, over the counter drugs and herbal medicines such as St John's Wort) or therapy within 2 weeks prior to Visit 1 which may potentially expose the patient to any significant systemic exposure that may interfere with the objectives of the study or the safety of the patients as judged by the investigator, except for inhaled short-acting β2 agonists for treatment of asthma symptoms and occasional intake of paracetamol
15. An exacerbation of asthma (use of oral or parenteral antibiotics and/or glucocorticosteriods and/or hospitalisation related to asthma) within 4 weeks prior to Visit 1, or during the screening period
16. Positive results on screening tests for pregnancy, hepatitis B, C and/or HIV
17. Any respiratory tract infection (bacterial, viral or fungal infections of the airways) or any other clinically significant illness within 2 weeks prior to Visit 1 being symptomatic enough to affect study conduct or the well-being of the patient as judged by the investigator
18. Structural abnormalities of the nose or nasal disorder symptomatic enough to cause significant nasal obstruction as judged by the Investigator
19. Known or suspected hypersensitivity to Investigational drug or any excipients
20. Definite or suspected personal history of significant adverse drug reactions/anaphylactic reaction
21. History of or current alcohol and/or drug abuse, as judged by the Investigator, or positive drugs of abuse test
22. Planned surgery, dental procedure, or hospitalisation during the study, and/or major surgery or significant trauma within 3 months of Visit 1
23. Participation in another clinical study with an Investigational Product within 3 months before the start of the present study
24. Have significant blood loss (>500 mL) or donated blood in the 30 days before Visit 1 or donation of > 1350 mL within 12 months prior to Visit 1
25. Patients who, in the opinion of the Investigator, should not participate in the study
26. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
27. Previous randomisation of treatment in the present study |
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E.5 End points |
E.5.1 | Primary end point(s) |
• Efficacy − FEV1 (Late Asthmatic Response) - Primary Variable − FEV1 (Early Asthmatic Response) − PC20 (Methacholine challenge) − Sputum Cellularity and Cytokines
• Safety and Tolerability − Vital signs, ECG, clinical chemistry, haematology, urinalysis, physical examination, clinical inspection of the nose, spirometry (FEV1), autoantibodies, adverse events
• Pharmacokinetics and Pharmacogenetics − Concentration of acid metabolite in plasma (representing the sum of the concentration of AZD8848 and acid metabolite) − Butyrylcholinesterase gene |
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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 | Yes |
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 | Yes |
E.8.1.6 | Cross over | No |
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.8.3 |
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 | Information not present in EudraCT |
E.8.7 | Trial has a data monitoring committee | Yes |
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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The end of the study is defined as LSLV, the last telephone contact performed for the Main Part of the study. |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |