| 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 | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.1 |
| 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 |
| To investigate the efficacy of inhaled GSK2269557 administered once daily for 28 days in subjects with persistent uncontrolled asthma, compared with placebo. |
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| E.2.2 | Secondary objectives of the trial |
Efficacy
To characterise the clinical response of inhaled GSK2269557 administered once daily for 28 days in subjects with persistent uncontrolled asthma, compared with placebo.
Safety
To assess the safety and tolerability of inhaled GSK2269557 administered once daily for 28 days in subjects with persistent uncontrolled asthma, compared with placebo.
Pharmacokinetics
To evaluate the plasma pharmacokinetics of inhaled GSK2269557 administered once daily for 28 days in subjects with persistent uncontrolled asthma.
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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 |
Title:
Genetic Research
Objectives:
The objectives of the genetic research are to investigate the relationship between genetic variants and:
• Response to medicine, including any treatment regimens under investigation in this study or any concomitant medicines;
• Asthma susceptibility, severity, and progression and related conditions
Title:
Sputum Sub-study (Exploratory)
Objectives:
To explore the pharmacodynamic effects of inhaled GSK2269557 administered once daily for 14 days in subjects with persistent
uncontrolled asthma, compared with placebo.
Pharmacodynamic / biomarkers endpoints may include, but are not limited to:
- mRNA analysis in induced sputum and blood, prior to and after 14-days exposure to GSK2269557. |
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| E.3 | Principal inclusion criteria |
1. Between 18 and 70 years of age inclusive, at the time of signing the informed consent.
2. Documented history of bronchial asthma, first diagnosed at least 6 months prior to the screening visit and currently being treated only with an intermittent SABA or other non-corticosteroid controllers.
Non corticosteroid controllers (e.g. leukotriene receptor antagonists; LTRAs) must be discontinued from Screening until the end of Treatment Period 2.
3. Able to replace current SABA treatment with salbutamol Metered Dose Inhaler (MDI) at Screening for use as needed for the duration of the study. Judged capable of withholding salbutamol for at least 4 hours prior to FEV1 assessments.
4. No use of an ICS or LABA for at least 12 weeks prior to first dose of study medication.
5. A best pre-bronchodilator FEV1 ≥ 60% of the predicted normal value at Screening. Predicted values will be based upon [Quanjer, 2012].
6. FEV1 increase by ≥12% and ≥ 200 mL over baseline value within 10−40 minutes of inhalation of 400 mcg salbutamol MDI (a spacer device may be used if required).
7. Positive skin prick test to common aero-allergen(s) at screening (not historical).
8. Sputum sub-study only: Able to produce > 100 mg of sputum at Screening or during the Run-in Period.
9. Body weight ≥45 kg and body mass index (BMI) within the range 18–32 kg/m2 (inclusive)
10. Male subject. Male subjects with female partners of child bearing potential must comply with the following contraception requirements from the first dose of study medication until completion of the follow-up visit.
a. Vasectomy with documentation of azoospermia.
b. Male condom plus partner use of one of the contraceptive options below.
• Contraceptive subdermal implant with a <1% rate of failure per year, as stated in the product label
• Intrauterine device or intrauterine system with a <1% rate of failure per year, as stated in the product label
• Oral contraceptive, either combined or progestogen alone
• Injectable progestogen
• Contraceptive vaginal ring
• Percutaneous contraceptive patches
11. Female subject: is eligible to participate if she is not pregnant (as confirmed by a negative urine human chorionic gonadotrophin (hCG) test), not lactating, and at least one of the following conditions applies:
a. Non-reproductive potential defined as:
• Pre-menopausal females with one of the following:
• Documented tubal ligation
•Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion
• Hysterectomy
• Documented Bilateral Oophorectomy
• Postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) and estradiol levels consistent with menopause (refer to laboratory reference ranges for confirmatory levels)]. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment.
b. Reproductive potential and agrees to follow one of the options listed below in the GSK Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) requirements from 30 days prior to the first dose of study medication and until completion of the follow-up visit.
• Contraceptive subdermal implant that meets the effectiveness criteria including a <1% rate of failure per year, as stated in the product label
• Intrauterine device or intrauterine system that meets the effectiveness criteria including a <1% rate of failure per year, as stated in the product label
• Oral contraceptive, either combined or progestogen alone
• Injectable progestogen
• Contraceptive vaginal ring
• Percutaneous contraceptive patches
• Male partner sterilization with documentation of azoospermia prior to the female subject’s entry into the study, and this male is the sole partner for that subject.
• Male condom combined with a vaginal spermicide (foam, gel, film, cream, or suppository)
This list does not apply to FRP with same sex partners, when this is their preferred and usual lifestyle or for subjects who are and will continue to be abstinent from penile-vaginal intercourse on a long term and persistent basis.
12. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and in this protocol. The informed consent must be signed prior to any study related procedure, including change in asthma medication. |
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| E.4 | Principal exclusion criteria |
1. History of life-threatening asthma, defined as an asthma episode that required intubation and/or was associated with hypercapnoea, respiratory arrest and/or hypoxic seizures.
2. Any severe asthma exacerbation, defined as deterioration of asthma requiring the use of systemic corticosteroids (oral, parenteral or depot) within 12 weeks of Screening, or an inpatient hospitalisation or emergency department visit due to asthma that required systemic corticosteroids within 6 months of Screening.
3. Respiratory Infection: culture-documented or suspected bacterial or viral infection of the upper or lower respiratory tract, sinus or middle ear that has not resolved within 4 weeks of Screening and led to a change in asthma management or, in the opinion of the investigator, is expected to affect the subject’s asthma status or the subject’s ability to participate in the study.
4. Concurrent Respiratory Disease: current evidence of pneumonia, pneumothorax, atelectasis, pulmonary fibrotic disease, bronchopulmonary dysplasia, chronic bronchitis, emphysema, chronic obstructive pulmonary disease, lung cancer, or other respiratory abnormalities other than asthma.
5. ALT >2xULN and bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
6. Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
7. QTc > 450 msec or QTc > 480 msec in subjects with Bundle Branch Block.
NOTES:
Based on the averaged QTc values of triplicate ECGs obtained over a brief recording period (e.g. 5–10 minutes)
The QTc is the QT interval corrected for heart rate according to Bazett’s formula (QTcB), Fridericia’s formula (QTcF), and/or another method, machine-read or manually over-read.
The specific formula that will be used to determine eligibility and discontinuation for an individual subject should be determined prior to initiation of the study. Several different formulae cannot be used to calculate the QTc for an individual subject and then the lowest QTc value used to include or discontinue the subject from the trial.
For purposes of data analysis, QTcB, QTcF, another QT correction formula, or a composite of available values of QTc will be used, as specified in the Reporting and Analysis Plan (RAP).
8. Other Laboratory Abnormalities or Concurrent Diseases/Clinical: clinically significant laboratory abnormality, uncontrolled condition or disease state that, in the opinion of the investigator (in consultation with the GSK Medical Monitor, if required), would put the safety of the subject at risk through study participation or would confound the interpretation of the efficacy results if the condition/disease exacerbated during the study.
9. Use of any of the prohibited medications listed in Table 4 (Section 6.12.2).
10. Current smokers or subjects with a history of smoking within 6 months of Screening, or with a total pack year history of >5 pack years or those subjects using a nicotine replacement or containing product within 5 half-lives of the first dose of study medication in the current study.
11. History of regular alcohol consumption within 6 months of the study defined as an average weekly intake of >21 units for males or >14 units for females. One unit is equivalent to 8 g of alcohol: a half-pint (~240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.
12. History of sensitivity to any of the study medications, or components thereof (including lactose) or a history of drug or other allergy (including a milk protein allergy) that, in the opinion of the investigator or Medical Monitor, contraindicates their participation.
13. Sputum sub-study only: History of sensitivity to the induced sputum procedure.
14. Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result at Screening or within 3 months prior to first dose of study medication.
15. Where participation in the study would result in donation of blood or blood products in excess of 500 mL within 56 days.
16. The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dose of study medication in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
17. Exposure to more than 4 investigational medicinal products within 12 months prior to the first dose of study medication.
18. Affiliation with investigator site: subject is an investigator; sub-investigator; study co-ordinator; employee of a participating investigator or study site; or, an immediate family member of the aforementioned, that is involved in this study.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from baseline in trough FEV1 at Day 28 |
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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) |
1.Weighted mean (0-4 hours) FEV1 at Day 28
2.Change from baseline in trough FEV1 at Day 7 and Day 14
3. Change from baseline in FVC at Day 7, Day 14 and Day 28
4. Change from baseline in FEV1/FVC at Day 7, Day 14 and Day 28
5.Change from baseline in Asthma Control Test (ACT) score at Day 28
6.Change from baseline in daily FEV1 (AM) and PEF (AM and PM) averaged over the treatment period
7.Change from baseline in trough FeNO at Day 7, Day 14 and Day 28
8.Mean number of inhalations per day of rescue medication (salbutamol) and percentage of rescue free days over the treatment period
9.Adverse Events
10.Haematology and Clinical Chemistry
11.Vital signs
12.12-lead ECG
13.Trough plasma concentration after 7 days, 14 days and 28 days of treatment
14.Day 28 plasma exposure up to 3.5 hours post dose
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.0–4 h on Day 28
2.pre-dose Day 7 and pre-dose Day 14
3.Pre-dose Day 28
4.daily morning FEV1 (Day 1 to Day 28) and daily morning and evening PEF (Day 1 to Day 28)
5.pre-dose Day 7, Day 14 and Day 28
6.Day 1 to Day 28
7.Day 1, Treatment Period 1 to Follow-up
8.Screening to Day 28, Treatment Period 2
9.Screening to Follow-up
10.Screening to Day 28, Treatment Period 2
11.pre-dose Day 7, Day 14 and Day 28
12.Day 28 pre-dose, and Day 28 5 to 10 minutes post-dose and 2.5 to 3.5 hours post-dose
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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 | 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 | 2 |
| 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 | 10 |
| 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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| The end of the study is defined as the last subject’s last visit/contact. |
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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 | 12 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 12 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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