| 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 | 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 evaluate the efficacy of repeat intravenous dose administration of GSK679586 in patients with severe asthma |
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| E.2.2 | Secondary objectives of the trial |
1) To evaluate the effect of GSK679586 with respect to ACQ-7 and FEV1 for other designated efficacy windows.
2) To evaluate the safety & tolerability of repeat intravenous dose administration of GSK679586 in patients with severe asthma.
3) To evaluate the plasma pharmacokinetics (PK) of repeat intravenous doses of GSK679586 in patients with severe asthma
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female between 18 and 75 years of age (inclusive).
2. A female subject is eligible to participate if she is of:
• Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea, view protocol for further information.
3. Male subjects with a partner of child-bearing potential must agree to use one of the contraception methods listed in Section 7.1 from administration of the first dose, during the course of the study and 18 weeks after the last dose of study drug. Since stage-dependent evaluation of spermatogenesis has not yet been completed, 18 weeks of male contraception after the last dose of study drug will be enforced for the time being. This requirement may be changed in light of the emerging spermatogenesis data.
4. BMI within the range 19 – 35 kg/m2 (inclusive).
5. Subjects who have been diagnosed with asthma for ≥ 6 months (according to current GINA Guidelines) requiring regular treatment with inhaled corticosteroid (ICS) ≥ 500 μg/day fluticasone or equivalent. Patients also taking long-acting β-agonists are eligible provided they meet the other inclusion criteria.
6. Subjects must have been on a stable dose of ≥ 500 μg/day fluticasone or equivalent for ≥ 4 weeks before screening. This requires that there have been no changes to the asthma medication in the 4 weeks prior to Visit 1 and in the period between Visit 1 & Visit 1a (if performed) and Visit 1a and Visit 1b (if performed). Subjects will be permitted to remain on all other concomitant asthma medication (with the exception of omalizumab) throughout the study.
7. Subjects on regular OCS as maintenance treatment for their asthma, whose usual long term daily maintenance dose is a maximum of 25 mg prednisolone can be included in the study. Subjects may have their maintenance dose varied up to a maximum daily dose of 30 mg prednisolone or equivalent, and down to a minimum daily dose of 5 mg prednisolone or equivalent during the 4 weeks prior to screening and throughout the study, providing these variations do not result in their usual long term daily maintenance dose being higher that 25mg prednisolone per day.
8. Baseline (pre-bronchodilator) FEV1 35-80% predicted at screening.
9. Subjects must demonstrate reversible airways disease as indicated by an increase of FEV1 ≥12% from baseline within 30 minutes (±5 minutes) of inhaled salbutamol or albuterol via a metered dose inhaler with or without spacer or 30 minutes after nebulised salbutamol or albuterol. Subjects must have abstained from using all bronchodilator therapy prior to assessment of their pulmonary function (i.e. withdrawal from long-acting betaagonist treatment for ≥ 12 hours, short-acting β-agonist treatment for ≥ 6 hours and long-acting anti-cholinergic treatment for ≥ 72 hours prior to Visit 1, 1a or 1b). A second test of β-agonist reversibility will be permitted at Visit 1a if the subject does not meet this entry criterion at Visit 1. A third test of β-agonist reversibility will be permitted at Visit 1b if the subject does
not meet this entry criterion at Visit 1a.
10. Subjects must be symptomatic at screening (as measured by an Asthma Control Questionnaire (ACQ-7) composite score ≥ 1.5).
11. Chest x-ray is negative for any finding associated with an acute or chronic lung infection at screening. A chest X-ray taken within 6 months prior to Screening (Visit 1) may be used. Only if clinically warranted should the x-ray be repeated at screening. For sites in Germany, if a chest X-ray (or CT scan) is not available in the 6 months preceding the Screening (Visit 1), the subject will not be eligible for the study.
12. Subjects must be a non-smoker or ex-smoker with ≤ 12 pack-years (eg, 1 pack per day for 12 years) who stopped ≥ 6 months ago. [(number of pack years = (number of cigarettes per day / 20) x number of years smoked].
13. Subjects must be able to give written informed consent prior to participation in the study, which will include the ability to comply with the requirements and restrictions listed in the consent form.
14. Subjects must be able to read, comprehend, and write at a level sufficient to complete study related materials.
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| E.4 | Principal exclusion criteria |
1. History of regular alcohol consumption within 6 months of the study defined as:
• For European and South African sites: an average weekly intake of greater than 21 units or an average daily intake of greater than 3 units (males), or defined as an average weekly intake of greater than 14 units or an average daily intake of greater than 2 units (females). One unit is equivalent to a half-pint (220mL) of beer or 1 (25ml) measure of spirits or 1 glass (125ml) of wine.
• For US sites: an average weekly intake of >14 drinks/week for men or >7 drinks/week for women. One drink is equivalent to (12 g alcohol) = 5 ounces (150 ml) of wine or 12 ounces (360 ml) of beer or 1.5 ounces (45 ml) of 80 proof distilled spirits.
2. Acute asthma exacerbation requiring hospitalization for >48 hours within 3 months prior to screening.
3. Discharge from hospital following endotracheal intubation for asthma-related exacerbation within the past 6 months.
4. Respiratory illness within 4 weeks of screening.
5. Current or recent lower respiratory tract infection (resolved less than 6 weeks from screening).
6. History of recurrent lower respiratory tract infection (more than 3 in the three months prior to screening) requiring antibiotics
7. Presence of other respiratory disease or chronic pulmonary condition other than asthma that is uncontrolled with standard treatment and in the opinion of the Investigator and/or the Medical Monitor participation could present a risk to the patient.
8. A mean QTc(B) or QTc(F) value at screening >450msec for males or >480 msec for females taken from assessments in triplicate, or an ECG that is not suitable for QT measurements (e.g. Left bundle branch block or poorly defined termination of the T wave).
9. The subject has taken methotrexate, troleandomycin, oral gold, cyclosporin, or any other experimental anti-inflammatory therapies within 3 months of screening
10. The subject has used omalizumab within 4 months of treatment (Visit 4)
11. Treatment with an investigational drug within 30 days or five half-lives or twice the duration of the biological effect of the investigational product (whichever is longer), prior to the screening visit (Visit 1) (this includes investigational formulations of marketed products).
12. Exposure to more than four new chemical entities within 12 months prior to the first dosing day.
13. A usual daily maintenance dose of prednisolone (or equivalent) of >25 mg/day within 4 weeks before the screening visit (Visit 1).
14. Live/attenuated vaccinations within 4 weeks of screening (Visit 1) or during the study
15. The subject has clinically significant cardiovascular, neurological, renal, endocrine, gastrointestinal, hepatic, or haematologic abnormalities that are uncontrolled with standard treatment and in the opinion of the Investigator and/or the Medical Monitor their participation could present a risk to the patient.
16. The subject has abnormal laboratory values considered by the Investigator to be clinically significant that could present a risk to the patient, specifically patients with alanine aminotransferase or aspartate transaminase values greater than 1.5 x the upper limit of normal.
17. The subject has a recent (≤1 year from screening) history (or suspected recent history) of alcohol misuse or substance abuse.
18. The subject has a known immunodeficiency disorder.
19. The subject is unable to follow study instructions such as dosing directions, study diary completion, use of the peak flow meter or use of a metered dose inhaler.
20. The subject has a gastrointestinal or respiratory parasitic infestation within the 6 months prior to screening (Visit 1).
21. The subject is unable to refrain from travelling to countries with a high prevalence of infectious (especially parasitic) disease from when the first dose is administered until 18 weeks after the last dose of study drug.
22. A positive pre-study Hepatitis B surface antigen, positive Hepatitis C antibody, or HIV antibody testing result.
23. History of sensitivity to heparin or heparin-induced thrombocytopenia.
24. Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products within 6 months prior to screening.
25. History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation.
26. Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
27. Pregnant females as determined by positive serum hCG test at screening or prior to dosing.
28. Lactating females.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from baseline in Asthma Control Questionnaire (ACQ7) over 12 weeks. |
|
| 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
| 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 | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 26 |
| 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
| |
| 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 | 7 |
| 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 | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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