| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Mild to moderate persistent asthma |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10003553 |
| E.1.2 | Term | 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 establish the efficacy of three oral dose schedules of OC000459 (leading to > or = 8% improvement in clinic FEV1 over placebo) over a treatment period of 12 weeks |
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| E.2.2 | Secondary objectives of the trial |
• To assess the effects of three oral dose schedules of OC000459 in comparison to placebo on the Asthma Control Questionnaire1,2 (ACQ) and the Standardised Asthma Quality of Life Questionnaire3 (AQLQ(S)).
• To investigate the effects of three oral dose schedules of OC000459 in comparison to placebo on clinic PEF and FEV1 and Vitalograph® 2110 spirometer/e-diary information on PEF, asthma symptoms and salbutamol MDI usage in this population.
• To assess the safety and tolerability of three oral dose schedules of OC000459
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion criteria at screening (visit 1)
1. Male or female asthmatics, any racial group. Females of childbearing potential (i.e. having had a menstrual period within two years prior to the date of screening) must practise two forms of contraception (i.e. two of the following at the same time – oral contraception, barrier contraception, intrauterine device) and must have a negative pregnancy test (blood or urine) at screening.
2. Aged 18-55 years inclusive.
3. Non smokers for at least the past 12 months with a pack history < or = 10 pack years (Pack years = (No of cigarettes smoked/day/20) x No of years smoked).
4. Meeting the following asthma criteria:
a. Mild to moderate persistent asthma according to GINA4 guidelines for at least 12 months (Appendix 1)
b. Typical symptoms including but not limited to cough, wheezing and shortness of breath with periodic intervals requiring treatment with bronchodilators.
5. Subjects must be free from significant cardiac, pulmonary (other than mild to moderate persistent asthma), gastrointestinal, hepatic, renal, haematological and neurological disease as determined by history, physical examination and screening investigations in the opinion of the Investigator.
6. Subjects with a 12-lead electrocardiogram (ECG) with no clinically significant abnormalities in the opinion of the Investigator, determined at screening.
7. Subjects with normal haematology and clinical chemistry parameters determined at screening (any out of range values must not be clinically significant in the opinion of the Investigator).
8. Capable of giving informed consent which includes compliance with the requirements and restrictions listed in the consent form.
9. Subjects with a chest X-ray with no clinically significant abnormalities in the opinion of the Investigator within the six months prior to the start of screening (must be documented in the subject’s hospital case notes or must be undertaken as part of the screening procedure).
Randomisation criteria (weeks 3 and 4, visits 4 and 5)
1. At weeks 3 and 4 (visits 4 and 5), valid clinic FEV1 readings while not taking salbutamol for at least 6 hours must have been stable (i.e. the difference in percent of predicted must be within 15% of each other) and the average of these readings must lie within the limits of 60-85% of predicted. Predicted normal values will be calculated according to ECCS criteria7 . Patients whose weeks 3 and 4 (visits 4 and 5) readings do not conform to these criteria and are randomised will be withdrawn from the study.
2. An increase in FEV1 of at least 12% and/or absolute increase of at least 200 ml documented between 20 and 30 minutes after inhaled salbutamol 400 μg both at weeks 3 and 4 (visits 4 and 5).
3. The subjects’ use of salbutamol MDI must be an average of >1 actuation/day over the last 7 days of the placebo run-in period; where day 7 is the day before randomisation (data to be collected by the Vitalograph® 2110 spirometer/e-diary and must have been entered on at least 4 of the 7 days).
4. Ability to give an adequate (see Study Reference Manual) home PEF test and to record salbutamol MDI usage correctly (data to be collected by the Vitalograph® 2110 diary) on at least 4 days out of 7 in each of the two weeks prior to randomisation.
5. Able to perform technically satisfactory respiratory function tests reliably both in clinic and with the Vitalograph 2110 spirometer/e-diary.
6. Able to use a salbutamol MDI reliably with the correct inhaler technique.
7. Females of childbearing potential must have a negative pregnancy test (urine or blood) at the time of randomisation.
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| E.4 | Principal exclusion criteria |
1. Positive salivary or urinary cotinine or Smokerlyzer test at screening.
2. Presence of any clinically significant respiratory disease other than a history of mild to moderate persistent asthma (e.g. chronic bronchitis, chronic obstructive pulmonary disease, emphysema, cystic fibrosis).
3. Exacerbation of asthma in the three months preceding the screening period requiring emergency treatment, intubation or oral or intravenous steroids.
4. History of desensitisation therapy or anti-IgE therapy in the past year.
5. Use of inhaled or systemic corticosteroids in the period from 28 days prior to screening until the final follow up visit of the trial.
6. Any infirmity, disability, or geographic location which, in the opinion of the principal investigator, would limit compliance with the protocol.
7. Clinical evidence of lower respiratory tract infection requiring a course of antibiotics in the month (28 days) prior to screening or during screening.
8. The subject has participated in a study with a new molecular entity during the previous four months or any other trial during the previous three months.
9. The subject regularly, or on average, drinks more than four units of alcohol per day and/or uses drugs of abuse.
10. The subject has a history of testing positive for hepatitis C antibody or hepatitis B surface antigen or for HIV.
11. The subject has a history of gastrointestinal disorder likely to influence drug absorption.
12. A history of hypersensitivity and/or idiosyncrasy to any of the test compounds including formulation components employed in this study.
13. Any previous clinical trial involving the administration of OC000459.
14. Any diagnosis of cancer within five years of accrual to the study.
15. Any psychiatric disorder that would impair the subject’s ability to give written informed consent or to comply with the requirements of the study.
16. Receipt of prescribed or over the counter medication within 14 days prior to the first study day (first day of the placebo run in period) and for the duration of the trial (until the final follow up visit), including vitamins with the exception of salbutamol MDI (salbutamol MDI will be supplied by the Sponsor for use during the trial) and up to 2 g of paracetamol daily as well as short acting antihistamines for the treatment of allergic rhinitis (with the prior agreement of the investigator). Hormone replacement therapy such as insulin for insulin dependent diabetes mellitus, hormone replacement therapy for women going through the menopause and thyroxine for hypothyroidism is also allowed. The oral contraceptive pill is also allowed for women of child bearing potential. In particular, ketoconazole, all non-steroidal anti-inflammatory drugs (e.g. ibuprofen) or asthma medications such as theophylline, disodium cromoglycate, leukotriene antagonists, steroids, anticholergics or long acting beta-2 agonists are prohibited during the trial period.
17. Active tuberculosis present in any organ, according to medical history.
18. Churg-Strauss syndrome.
19. Pregnancy or lactation.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary objective of the study is to assess the effects of three dosing regimens of OC000459 in comparison to placebo on respiratory function (FEV1) in asthmatics with an FEV1 of 60-85% of predicated at baseline. The primary analysis will be based on the clinic assessments taken before the morning dose, planned to be at least 6 hours since the last use of salbutamol MDI. The average change from baseline over the double-blind treatment will be analysed using ANOVA with treatment, centre and sex as factors; and baseline FEV1 (average of visits 4 and 5) and age as covariates. The primary analysis, based on the full analysis set of subjects, will include all subjects who have a baseline FEV1 and at least one FEV1 assessment during the double blind treatment phase. The primary comparisons of interest will be of each of the active treatment groups against placebo. Tests will use a 1.67% level of significance, using a Bonferroni adjustment to protect for multiple comparisons.
In addition, the change and percentage change in FEV1 will be summarised at each visit during the double blind treatment period and at the end of the washout, together with an LOCF to the end of the double-blind treatment period summary. These summaries will include comparisons between each active treatment group and placebo, incorporating confidence intervals for the difference in means.
Additionally, the above analyses will be repeated for the per-protocol set of subjects.
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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 | No |
| E.6.7 | Pharmacodynamic | No |
| 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 | 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
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 39 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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