| 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 | 20.0 |
| 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 assess the dose response and relative potency for increasing doses of Fluticasone Furoate (FF), Fluticasone Propionate (FP) and Budesonide (BUD) in the adenosine monophosphate (AMP) challenge model at 12 hours after the last dose on Day 7.
- To assess the dose response and relative potency for FF, FP and BUD on 24 hour plasma cortisol suppression on treatment from pre-dose PM dose on Day 6 to pre-dose PM dose Day 7.
- To assess the therapeutic index for FF, FP and BUD. |
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| E.2.2 | Secondary objectives of the trial |
| - To assess the safety and tolerability of all treatments. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Age of subject: 18 to 65 years of age inclusive, at the time of signing the informed consent.
2. Asthma: Documented history of bronchial asthma, first diagnosed at least 6 months prior to the screening visit.
3. Severity of disease:
a) Pre-bronchodilator FEV1 ≥ 65% of predicted at screening.
b) The pre-dose baseline FEV1 should not have changed significantly in the opinion of the investigator from the screening baseline value and should be ≥ 65% predicted for the subject to continue.
c) Documented sensitivity to AMP with a provocative concentration of AMP resulting in a fall of ≥20% FEV1 with a PC20 AMP ≤80 mg/mL at the screening visit.
4. Current Therapy:
• Short-Acting Beta2-Agonists (SABA): prescribed SABA for at least 12 weeks prior to screening, if needed.
• Subjects receiving low-dose ICS as defined in Appendix 5 may take part after a 4 week ICS washout prior to AMP challenge. The subject’s asthma symptoms must remain stable during this 4-week period as assessed at screening visit 2. Stable asthma is defined as:
• No more than 2 consecutive days where ≥12 inhalations/day of salbutamol were used.
• No severe asthma exacerbations requiring use of systemic corticosteroids (tablets, suspension, or injection) or an in-patient hospitalization or emergency department visit due to asthma that required systemic corticosteroids.
• No clinical asthma worsening which in the opinion of the investigator requires additional asthma treatment other than study medication or salbutamol.
• Subjects taking LABA, LAMA, leukotriene receptor antagonist (LTRA) therapy within 3 months prior to the start of the study are not eligible.
• Subjects taking biological therapies within 6 months prior to start of the study are not eligible.
5. Bodyweight and Body Mass Index (BMI): Bodyweight ≥ 50 kg and BMI within the range 18.0-35.0 kg/m2 (inclusive).
6. Gender: Male and female.
Females:
A 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 prior to randomization:
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 in the Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential from 30 days prior to the first dose of study medication and until at least five terminal half-lives after the last dose of study medication (Appendix 4).
The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception.
7. Liver criteria: Aspartate aminotransferase (AST) and Alanine transaminase (ALT) < 2x upper limit of normal (ULN); alkaline phosphatase and bilirubin 1.5x ULN (isolated bilirubin >1.5x ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
8. Light smokers, who smoke ≤ 20 cigarettes per week or equivalent unit dose of other tobacco products or e-cigarettes, are eligible for the study. Smokers who intend to stop, reduce or increase their smoking habit during the study period are not eligible.
9. Having provided written informed consent, which includes compliance with the requirements and restrictions listed in the consent form. |
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| E.4 | Principal exclusion criteria |
1. A history of life-threatening asthma. NOTE: Life-threatening asthma is defined as an asthma episode that required intubation and/or was associated with hypercapnia, respiratory arrest or hypoxic seizures within the last 5 years.
2. Other significant pulmonary diseases to include (but not limited to): severe pneumonia within 6 months of the screening visit, pneumothorax, atelectasis, pulmonary fibrotic disease, bronchopulmonary dysplasia, chronic bronchitis, emphysema, chronic obstructive pulmonary disease, tuberculosis or other respiratory abnormalities other than asthma.
3. Respiratory Infection: Culture-documented or suspected bacterial or viral infection of the upper or lower respiratory tract, sinus or middle ear within 4 weeks of screening that:
• 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. Oropharyngeal examination: A subject will not be eligible if he/she has clinical visual evidence of oral candidiasis at screening.
5. Asthma Exacerbation: Any asthma exacerbation requiring oral corticosteroids within 12 weeks of screening or that resulted in overnight hospitalization requiring additional treatment for asthma within 6 months prior to randomization.
6. Use of prohibited medications:
Any other medications including, anti-depressant drugs, and anti-asthma drugs (other than short acting inhaled β-agonists supplied as rescue medication, oral contraceptives not listed in Appendix 4, non-steroidal anti-inflammatory drugs, stable doses of anti-histamines, and paracetamol) for 1 week prior to screening and throughout the course of the study. Anti-histamines should be withheld 4 days prior to AMP challenge.
• Subjects must also be able to abstain from short acting inhaled β-agonists, for 8 hours prior to spirometry.
7. Subjects undergoing de-sensitization therapy.
8. Tobacco Use: Current smokers who smoke > 20 cigarettes per week or the equivalent unit dose of other tobacco products or e-cigarettes, or smokers with a smoking history of ≥10 pack years.
9. History of regular alcohol consumption exceeding 21 units/week for men and 14 units/week for females (1 unit= 5 ounces (150 mL) of wine or 12 ounces (360 mL) of beer or 1.5 ounces (45 mL) of spirits) within 6 months of screening.
10. All subjects who are currently or in the last month have worked night-shifts are excluded from the study.
11. Previous Participation: Exposure to more than four new chemical entities within 12 months prior to the first dosing day or received an investigational product within 30 days of study start, or 5 half-lives of study drug if that is longer.
12. Other concurrent Diseases/Abnormalities: A subject has any clinically significant, uncontrolled condition or disease state that, in the opinion of the investigator, would put the safety of the subject at risk through study participation or would confound the interpretation of the study results if the condition/disease exacerbated during the study. (e.g. stroke or myocardial infarction within 3 months, uncontrolled hypertension, congestive heart failure, uncontrolled diabetes mellitus.)
13. Evidence of cancer or history of cancer in the past 5 years other than adequately treated basal or squamous cell carcinoma of the skin or adequately treated in situ carcinoma of the cervix.
14. Pregnancy and Lactating Females:
• Pregnant females as determined by positive urine HCG test at screening or by positive urine HCG test prior to dosing.
• Lactating females.
15. Subjects with active or chronic infections including hepatitis B or C, human immunodeficiency virus (HIV). A positive serology at screening.
16. Allergies:
• Milk Protein Allergy: History of severe milk protein allergy.
• Drug Allergy: Any adverse reaction including immediate or delayed hypersensitivity to intranasal, inhaled, or systemic corticosteroid therapy. Known or suspected sensitivity to the constituents of FF, FP or BUD (i.e., lactose or magnesium stearate, etc).
• Historical Allergy: History of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation.
17. 12-Lead electrocardiogram (ECG) abnormality: Significant abnormality in the 12-lead ECG performed at screening. The mean of the three individual ECGs will be taken.
Mean QT interval corrected for heart rate (QTc) >450 msec for males or QTc >470 msec for female subjects and > 480 in subjects with bundle branch block.
The QTc is the QT interval corrected for heart rate according to Fridericia’s formula (QTcF). |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
- Provocative concentration of AMP causing a 20% fall in forced expiratory volume in 1 second (FEV1) (AMP PC20).
- Suppression of 24hour weighted mean plasma cortisol compared to placebo.
- (ED20) cortisol suppression: Dose at which 20% cortisol suppression is reached /ED80 for AMP PC20: Dose at which 80% of the maximum AMP PC20 is reached. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
- AMP measurements taken at screening, then days 8, 15, 22, 29 & 36 of the treatment period (s).
- Plasma Cortisol samples taken pre-dose on days 1, 6, 7, 13, 14, 20, 21, 27, 28, 34 & 35 of the treatment period(s). |
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| E.5.2 | Secondary end point(s) |
| - Safety and tolerability. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| - Safety and tolerability of all treatments will be evaluated at each visit to the unit; assessed by adverse events (AEs), peak expiratory flow rate (PEFR), vital signs, physical examinations, laboratory assessments, and spirometry. |
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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 | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Partial blind & Partial Cross-over |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 4 |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 8 |
| 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 | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 8 |
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