Last updated: 09/02/2022 09:50:04
Phase 2a, AMP challenge, dose escalation study to assess the dose response for topical efficacy and systemic activity in asthmatic subjects
EudraCT ID
EU CT Number
Not applicable
Trial status
Study complete
Study complete
Trial overview
Official title: An escalating dose, randomized, placebo-controlled, incomplete-block, 2-period cross-over study to assess the dose response for topical efficacy via airway responsiveness to adenosine-5'-monophosphate (AMP) challenge and the dose response for systemic activity via 24h plasma cortisol suppression and thereby the relative therapeutic index for fluticasone furoate (FF), fluticasone propionate (FP) and budesonide (BUD) in asthmatic subjects
Trial description: This is a randomized, placebo-controlled, 2-period crossover, escalating repeat dose study, aiming to investigate whether higher potency of different inhaled corticosteroid confers an improvement in the topical efficacy to systemic activity ratio in asthmatic subjects. It will compare the dose response for topical efficacy via airway responsiveness (to adenosine-5'-monophosphate [AMP] challenge), and the dose response for systemic activity via 24 hour plasma cortisol suppression, and thereby compare the relative therapeutic index, for the following inhaled corticosteroids: fluticasone furoate (FF), fluticasone propionate (FP) and budesonide (BUD). There will be a screening visit 4 - 42 days before the first dose of study treatment, and AMP challenge Provocative concentration 20 (PC20) of <=80 milligrams per milliliter (mg/mL) at screening visit 2 i.e. at 4 – 14 days before the first dose of study treatment. Subjects will be randomized to one of 5 or 12 treatment sequences, and will have one or two treatment periods, each comprising 5 consecutive 7-day phases of escalating doses of either FF, FP, BUD or placebo. There will be a 25- to 42-day washout period between treatment periods. The study duration for each subject will be approximately 13 or 24 weeks including the follow-up period.
Primary purpose:
Treatment
Trial design:
Crossover Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Allocation:
Randomized
Primary outcomes:
Provocative concentration (PC) of AMP causing a 20% reduction in forced expiratory volume in 1 second (FEV1) (AMP PC20)
Timeframe: At Day 7 (12 hours post dose) of each escalation phase in both treatment periods
24-hour weighted mean plasma cortisol suppression
Timeframe: Day 6 to Day 7 of each escalation phase in both treatment periods
Dose at which 20% cortisol suppression is reached ([ED20] cortisol suppression)
Timeframe: Day 6 to Day 7 of each escalation phase in both treatment periods
Dose at which 80% of the maximum AMP PC20 is reached ([ED80] for AMP PC20)
Timeframe: Day 6 to Day 7 of each escalation phase in both treatment periods
Secondary outcomes:
Number of subjects with any adverse event (AE) and any serious adverse event (SAE) as a measure of safety and tolerability
Timeframe: Approximately 24weeks
Peak expiratory flow rate (PEFR) as a measure of safety and tolerability
Timeframe: On Days 1, 8, 15, 22, and 29 in both treatment periods
Systolic and diastolic blood pressure (BP) as a measure of safety
Timeframe: Days 1 (pre-dose) and 36 in both treatment periods
Pulse rate as a measure of safety
Timeframe: Days 1 (pre-dose) and 36 in both treatment periods
Body temperature as a measure of safety
Timeframe: Days 1 (pre-dose) and 36 in both treatment periods
Respiratory rate as a measure of safety
Timeframe: Days 1 (pre-dose) and 36 in both treatment periods
Physical examinations as a measure of safety
Timeframe: At Screening and Follow-up (at approximately Week 24)
Number of subjects with abnormal Hematology laboratory tests
Timeframe: Approximately 24weeks
Number of subjects with abnormal clinical chemistry laboratory tests
Timeframe: Approximately 24weeks
Number of subjects with abnormal routine urinalysis laboratory tests
Timeframe: Approximately 24weeks
Forced expiratory volume in 1 second (FEV1) as a measure of safety and tolerability
Timeframe: At Day 1 (pre-dose) in both treatment periods and Follow-up (at approximately Week 24)
Forced vital capacity (FVC) as a measure of safety and tolerability
Timeframe: At Day 1 (pre-dose) in both treatment periods and Follow-up (at approximately Week 24)
Interventions:
Enrollment:
56
Primary completion date:
2018-20-12
Observational study model:
Not applicable
Time perspective:
Not applicable
Clinical publications:
Peter Daley-Yates, Noushin Brealey, Sebin Thomas, Daren Austin, Shaila Shabbir, Tim Harrison, Dave Singh, Neil Barnes.Therapeutic index of inhaled corticosteroids in asthma: a dose-response comparison on airway hyperresponsiveness and adrenal axis suppression.Br J Clin Pharmacol.2020;
DOI: 10.1111/bcp.14406
PMID: 32484940
Peter Daley-Yates, Brian Keppler, Noushin Brealey, Shaila Shabbir, Dave Singh and Neil Barnes. Inhaled glucocorticoid-induced metabolome changes in asthma.Eur J Endocrinol.2022;187(3):413-427
DOI: https://doi.org/10.1530/EJE-21-0912
PMID: 35900313
Medical condition
Asthma
Product
budesonide, fluticasone furoate, fluticasone propionate
Collaborators
Not applicable
Study date(s)
February 2017 to December 2018
Type
Interventional
Phase
2
Participation criteria
Sex
Female & Male
Age
18 - 65 years
Accepts healthy volunteers
No
- Inclusion Criteria - Subjects must be 18 to 65 years of age inclusive, at the time of signing the informed Consent. - Documented history of bronchial asthma, first diagnosed at least 6 months prior to the screening visit - Pre-bronchodilator FEV1 >=65% of predicted at screening; 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 - 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 - Current therapy could include short-acting Beta2-agonists (SABA) prescribed SABA for at least 12 weeks prior to screening, if needed; subjects receiving low-dose ICS 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; or 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; or no clinical asthma worsening which in the opinion of the investigator requires additional asthma treatment other than study medication or salbutamol; subjects taking Long-acting beta2-agonist (LABA), long-acting muscarinic antagonist (LAMA), leukotriene receptor antagonist (LTRA) therapy within three 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. - Bodyweight >=50 Kilogram (kg) and BMI within the range 18.0-35.0 kg/meter (m)^2 (inclusive) - 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: • 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. 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. • Reproductive potential and agrees to follow one of the 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. The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception. - Aspartate aminotransferase and Alanine transaminase <2x upper limit of normal (ULN); alkaline phosphatase and bilirubin ≤1.5 x ULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%) - 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. - Having provided written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
- Exclusion Criteria: - A history of life-threatening asthma, defined as an asthma episode that required intubation and/or was associated with hypercapnia, respiratory arrest or hypoxic seizures within the last 5 years. - 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. - 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. - A subject will not be eligible if he/she has clinical visual evidence of oral candidiasis at screening. - 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. - Use of prohibited medications including, anti-depressant drugs, and anti-asthma drugs (other than short acting inhaled beta-agonists supplied as rescue medication, oral contraceptives, non-steroidal anti-inflammatory drugs, stable doses of antihistamines, 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 beta-agonists, for 8 hours prior to spirometry. - Subjects undergoing de-sensitization therapy - 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. - History of regular alcohol consumption exceeding 21 units per week for men and 14 units per 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. - All subjects who are currently or in the last month have worked night-shifts are excluded from the study - 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. - 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.) - 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. - Pregnant females as determined by positive urine HCG test at screening or by positive urine HCG test prior to dosing and lactating females. - Subjects with active or chronic infections including hepatitis B or C, human immunodeficiency virus. A positive serology at screening. - Allergies: History of severe milk protein allergy Drug Allergy defined as 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 defined as history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation. - Significant abnormality in the 12-lead electrocardiogram (ECG) performed at screening. The mean of the three individual ECGs will be taken. Mean QT interval corrected for heart rate (QTc) >450 millisecond (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).
Inclusion and exclusion criteria
Inclusion criteria:
- Inclusion Criteria
- Subjects must be 18 to 65 years of age inclusive, at the time of signing the informed Consent.
- Documented history of bronchial asthma, first diagnosed at least 6 months prior to the screening visit
- Pre-bronchodilator FEV1 >=65% of predicted at screening; 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
- 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
- Current therapy could include short-acting Beta2-agonists (SABA) prescribed SABA for at least 12 weeks prior to screening, if needed; subjects receiving low-dose ICS 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; or 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; or no clinical asthma worsening which in the opinion of the investigator requires additional asthma treatment other than study medication or salbutamol; subjects taking Long-acting beta2-agonist (LABA), long-acting muscarinic antagonist (LAMA), leukotriene receptor antagonist (LTRA) therapy within three 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.
- Bodyweight >=50 Kilogram (kg) and BMI within the range 18.0-35.0 kg/meter (m)^2 (inclusive)
- 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. 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.
- Reproductive potential and agrees to follow one of the 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. The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception.
- Aspartate aminotransferase and Alanine transaminase <2x upper limit of normal (ULN); alkaline phosphatase and bilirubin ≤1.5 x ULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%)
- 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.
- Having provided written informed consent, which includes compliance with the requirements and restrictions listed in the consent form. Exclusion Criteria:
- A history of life-threatening asthma, defined as an asthma episode that required intubation and/or was associated with hypercapnia, respiratory arrest or hypoxic seizures within the last 5 years.
- 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.
- 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.
- A subject will not be eligible if he/she has clinical visual evidence of oral candidiasis at screening.
- 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.
- Use of prohibited medications including, anti-depressant drugs, and anti-asthma drugs (other than short acting inhaled beta-agonists supplied as rescue medication, oral contraceptives, non-steroidal anti-inflammatory drugs, stable doses of antihistamines, 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 beta-agonists, for 8 hours prior to spirometry.
- Subjects undergoing de-sensitization therapy
- 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.
- History of regular alcohol consumption exceeding 21 units per week for men and 14 units per 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.
- All subjects who are currently or in the last month have worked night-shifts are excluded from the study
- 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.
- 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.)
- 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.
- Pregnant females as determined by positive urine HCG test at screening or by positive urine HCG test prior to dosing and lactating females.
- Subjects with active or chronic infections including hepatitis B or C, human immunodeficiency virus. A positive serology at screening.
- Allergies: History of severe milk protein allergy Drug Allergy defined as 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 defined as history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation.
- Significant abnormality in the 12-lead electrocardiogram (ECG) performed at screening. The mean of the three individual ECGs will be taken. Mean QT interval corrected for heart rate (QTc) >450 millisecond (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).
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:
Trial location(s)
Location
GSK Investigational Site
Harrow, Middlesex, United Kingdom, HA1 3UJ
Status
Study Complete
Study documents
Clinical study report
Available language(s): English
Protocol
Available language(s): English
Statistical analysis plan
Available language(s): English
If you wish to request for full study report, please contact - [email protected]
Results overview
Results posted on ClinicalTrials.gov
Recruitment status
Study complete
Actual primary completion date
2018-20-12
Actual study completion date
2018-20-12
Plain language summaries
Plain language summaries of clinical trial results for Phase 2-4 clinical trials that were initiated on or after January 2022 will be posted by GSK within one year following study completion.
Additional information about the trial
Additional information
Not applicable
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