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The purpose of this study is to test the body's response to several doses of two different inhalation products in healthy volunteers.
Healthy subjects will be enrolled and will receive 2, 6, and 12 inhalations from both the test and reference pMDI products according to a six-period cross-over design. Electrocardiograms (ECGs) and plasma potassium and glucose levels will be measured pre-dose and over 6 hours post-dose.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| test product A | Experimental | salmeterol and fluticasone propionate, 2 puffs |
|
| reference product D | Active Comparator | salmeterol and fluticasone propionate, 2 puffs |
|
| test product B | Experimental | salmeterol and fluticasone propionate, 6 puffs |
|
| reference product E | Active Comparator | salmeterol and fluticasone propionate, 6 puffs |
|
| test product C | Experimental | salmeterol and fluticasone propionate, 12 puffs |
|
| reference product F | Active Comparator |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Salmeterol | Drug | A, D 2 puffs; B, E 6 puffs; C, F 12 puffs |
|
| Measure | Description | Time Frame |
|---|---|---|
| Relative Potency Max Heart Rate | Selection of steepest part of dose response curve for Relative Potency: 6 and 12 inhalation dose pairs. Slope of B and C line compared with slope of E and F to obtain relative potency value. Two inhalation dose not utilized as not on steepest part of curve. | Baseline, up to 6 hrs |
| Relative Potency QTcB Interval | Selection of steepest part of dose response curve for Relative Potency: 2 and 6 inhalation dose pairs. Slope of A and B line compared with slope of D and E to obtain relative potency value. Twelve inhalation dose not utilized as not on steepest part of curve. | Baseline up to 6 hrs |
| Measure | Description | Time Frame |
|---|---|---|
| Max Heart Rate | max heart rate at the 2, 6, or 12 inhalations dose, assessed at multiple times over 6 hours | Baseline through 6 hours |
| Plasma Potassium Level | maximum plasma levels of potassium at 2, 6 or 12 inhalations dose inhalations dose, assessed a multiple times over 6 hours. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Pui Leung, MD | Quotient Clinical Ltd | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Quotient Clinical Ltd | Ruddington | Nottingham | NG11 6JS | United Kingdom |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 28626983 | Result | Harrison LI, Sessions V, Wiggenhorn CJ, Chalmers D, Leung P, Efthimiou J. Comparison of systemic pharmacodynamic effects of two combination pressurized metered dose inhalers that deliver salmeterol and fluticasone propionate. Br J Clin Pharmacol. 2017 Nov;83(11):2377-2385. doi: 10.1111/bcp.13349. Epub 2017 Aug 1. |
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Recruitment began 07 July 2014
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| ID | Title | Description |
|---|---|---|
| FG000 | Sequence 1 (A, F, B, E, C, D) | salmeterol and fluticasone propionate per inhalation A = 2 inhalations (test product), B = 6 inhalations (test product), C = 12 inhalations (test product), D = 2 inhalations (reference product), E = 6 inhalations (reference product) and F = 12 inhalations (reference product) |
| FG001 | Sequence 2 (B, A, C, F, D, E) | salmeterol and fluticasone propionate per inhalation A = 2 inhalations (test product), B = 6 inhalations (test product), C = 12 inhalations (test product), D = 2 inhalations (reference product), E = 6 inhalations (reference product) and F = 12 inhalations (reference product) |
| FG002 | Sequence 3 (C, B, D, A, E, F) | salmeterol and fluticasone propionate per inhalation A = 2 inhalations (test product), B = 6 inhalations (test product), C = 12 inhalations (test product), D = 2 inhalations (reference product), E = 6 inhalations (reference product) and F = 12 inhalations (reference product) |
| FG003 | Sequence 4 (D, C, E, B, F, A) | salmeterol and fluticasone propionate per inhalation A = 2 inhalations (test product), B = 6 inhalations (test product), C = 12 inhalations (test product), D = 2 inhalations (reference product), E = 6 inhalations (reference product) and F = 12 inhalations (reference product) |
| FG004 | Sequence 5 (E, D, F, C, A, B) | salmeterol and fluticasone propionate per inhalation A = 2 inhalations (test product), B = 6 inhalations (test product), C = 12 inhalations (test product), D = 2 inhalations (reference product), E = 6 inhalations (reference product) and F = 12 inhalations (reference product) |
| FG005 | Sequence 6 (F, E, A, D, B, C ) | salmeterol and fluticasone propionate per inhalation A = 2 inhalations (test product), B = 6 inhalations (test product), C = 12 inhalations (test product), D = 2 inhalations (reference product), E = 6 inhalations (reference product) and F = 12 inhalations (reference product) |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
all subjects who received at least one test and one reference product for same dose
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| ID | Title | Description |
|---|---|---|
| BG000 | All Subjects | salmeterol and fluticasone propionate |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | age range of 18 to 55 years inclusive |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Relative Potency Max Heart Rate | Selection of steepest part of dose response curve for Relative Potency: 6 and 12 inhalation dose pairs. Slope of B and C line compared with slope of E and F to obtain relative potency value. Two inhalation dose not utilized as not on steepest part of curve. | relative potency calculated for dose pairs B (6 inhalations) and C (12 inhalations), compared with E (6 inhalations) and F (12 inhalations) | Posted | Number | 90% Confidence Interval | unitless | Baseline, up to 6 hrs |
|
Adverse events were collected for up to 2 months for each subject. The duration of the clinical phase of the study was 4 months.
All subjects who received a dose of at least one product
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Test Product A | salmeterol and fluticasone propionate salmeterol (as salmeterol xinafoate): 2 inhalations fluticasone propionate: 2 inhalations |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| headache | Nervous system disorders | MedDRA (Unspecified) | Non-systematic Assessment |
There are no limitations or caveats.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Pui Leung | Quotient Clinical Ltd | 44(0)115 974 9000 | Pui Leung <Pui.Leung@quotientclinical.com> |
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| ID | Term |
|---|---|
| D000068299 | Salmeterol Xinafoate |
| D000068298 | Fluticasone |
| ID | Term |
|---|---|
| D000420 | Albuterol |
| D004983 | Ethanolamines |
| D000605 | Amino Alcohols |
| D000438 | Alcohols |
| D009930 |
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salmeterol and fluticasone propionate, 12 puffs
|
|
| fluticasone propionate | Drug | A, D 2 puffs; B, E 6 puffs; C, F 12 puffs |
|
|
| baseline through 6 hours |
| Max Plasma Glucose Level | maximum levels of glucose at the 2, 6 or 12 inhalations dose, assessed at multiple times over 6 hours. | baseline through 6 hours |
| Max QTcB | For each dose, the 95% CIs for the mean difference for the test product versus the reference product were calculated. | Baseline through 6 hours |
| poor inhalation technique |
|
| protocol stop criteria |
|
| Adverse Event |
|
| Mean |
| Standard Deviation |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| BMI | Mean | Standard Deviation | kg/m2 |
|
| forced expiratory volume at one second | forced expiratory volume at one second > 85% predicted | Mean | Standard Deviation | % predicted normal |
|
| Units | Counts |
|---|
| Participants |
|
|
|
| Primary | Relative Potency QTcB Interval | Selection of steepest part of dose response curve for Relative Potency: 2 and 6 inhalation dose pairs. Slope of A and B line compared with slope of D and E to obtain relative potency value. Twelve inhalation dose not utilized as not on steepest part of curve. | relative potency calculated for dose pairs A (2 inhalations) and B (6 inhalations), compared with D (2 inhalations) and E (6 inhalations) | Posted | Number | 90% Confidence Interval | unitless | Baseline up to 6 hrs |
|
|
|
|
| Secondary | Max Heart Rate | max heart rate at the 2, 6, or 12 inhalations dose, assessed at multiple times over 6 hours | subjects who received the test and the reference product at the 2, 6, or 12 inhalations dose | Posted | Mean | Standard Deviation | bpm | Baseline through 6 hours |
|
|
|
|
| Secondary | Plasma Potassium Level | maximum plasma levels of potassium at 2, 6 or 12 inhalations dose inhalations dose, assessed a multiple times over 6 hours. | subjects who received both the test and reference products at the 2, 6, or 12 inhalations dose | Posted | Mean | Standard Deviation | mmol/L | baseline through 6 hours |
|
|
|
|
| Secondary | Max Plasma Glucose Level | maximum levels of glucose at the 2, 6 or 12 inhalations dose, assessed at multiple times over 6 hours. | subjects who received both the test and reference products at the two inhalations dose | Posted | Mean | Standard Deviation | mmol/L | baseline through 6 hours |
|
|
|
|
| Secondary | Max QTcB | For each dose, the 95% CIs for the mean difference for the test product versus the reference product were calculated. | all subjects who received the test and the reference product at the two inhalations dose | Posted | Mean | Standard Deviation | ms | Baseline through 6 hours |
|
|
|
|
| 4 |
| 49 |
| 0 |
| 49 |
| 4 |
| 49 |
| EG001 | Test Product B | salmeterol and fluticasone propionate salmeterol (as salmeterol xinafoate): 6 inhalations fluticasone propionate: 6 inhalations | 5 | 48 | 0 | 48 | 5 | 48 |
| EG002 | Test Product C | salmeterol and fluticasone propionate salmeterol (as salmeterol xinafoate): 12 inhalations fluticasone propionate: 12 inhalations | 11 | 47 | 0 | 47 | 11 | 47 |
| EG003 | Reference Product D | salmeterol and fluticasone propionate salmeterol (as salmeterol xinafoate): 6 inhalations fluticasone propionate: 6 inhalations | 5 | 47 | 0 | 47 | 5 | 47 |
| EG004 | Reference Product E | salmeterol and fluticasone propionate salmeterol (as salmeterol xinafoate): 12 inhalations fluticasone propionate: 12 inhalations | 4 | 48 | 0 | 48 | 4 | 48 |
| EG005 | Referencet Product F | salmeterol and fluticasone propionate | 8 | 50 | 0 | 50 | 8 | 50 |
| Asthenia | General disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Fatigue | General disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Mouth Ulceration | Gastrointestinal disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Feeling Hot | General disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Feeling Cold | General disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| ECG QT prolonged | Investigations | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Prolongation | Investigations | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Heart Rate increased | Investigations | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Palpitations | Cardiac disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Sinus Tachycardia | Cardiac disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| tremor | Nervous system disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Dizziness | Nervous system disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Nervousness | Psychiatric disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Oropharyngeal Pain | Respiratory, thoracic and mediastinal disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Rhinorrtoea | Respiratory, thoracic and mediastinal disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Back Pain | Musculoskeletal and connective tissue disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Flushing | Vascular disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| URTI | Infections and infestations | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Paraesthesia Oral | Nervous system disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
| Presyncope | Nervous system disorders | MedDRA (Unspecified) | Non-systematic Assessment |
|
The sponsor reserves the right to the first publication of the results. Following the first publication, or if the sponsor confirms in writing no interest in publishing the results, Quotient Clinical Ltd or the Principal Investigator may proceed to publish results from the study, giving the sponsor 60 days to review the manuscript.
| Organic Chemicals |
| D000588 | Amines |
| D010627 | Phenethylamines |
| D005021 | Ethylamines |
| D000730 | Androstadienes |
| D000736 | Androstenes |
| D000731 | Androstanes |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
The potency of the test and reference product was considered equivalent if the 90% CI for the estimate of relative potency was completely contained within the limits of 0.67 to 1.50 |
| For each dose, the 95% CIs for the mean differences for the test product versus the reference product were calculated. | ANOVA | 0.53 | Comparability demonstrated for p>0.05 | Mean Difference (Final Values) | 1.0 | 2-Sided | 95 | -2.5 | 1.3 | Comparability confirmed if confidence interval includes zero. | Equivalence | Comparability confirmed if confidence interval includes zero. |
| For each dose, the 95% CIs for the mean differences for the test product versus the reference product were calculated. | ANOVA | 0.011 | Comparability demonstrated for p>0.05 | Mean Difference (Final Values) | 1.00 | 2-Sided | 95 | -2.5 | 1.3 | Comparability confirmed if confidence interval includes zero. | Equivalence | Comparability confirmed if confidence interval includes zero. |
| For each dose, the 95% CIs for the mean differences for the test product versus the reference product were calculated. | ANOVA | 0.93 | Comparability demonstrated for p>0.05 | Mean Difference (Final Values) | 0 | 2-Sided | 95 | -0.06 | 0.06 | Comparability confirmed if confidence interval includes zero. | Equivalence | Comparability confirmed if confidence interval includes zero. |
| For each dose, the 95% CIs for the mean differences for the test product versus the reference product were calculated. | ANOVA | 0.48 | Comparability demonstrated for p>0.05 | Mean Difference (Final Values) | 0 | 2-Sided | 95 | -0.04 | 0.08 | Comparability confirmed if confidence interval includes zero. | Equivalence | Comparability confirmed if confidence interval includes zero. |
| For each dose, the 95% CIs for the mean differences for the test product versus the reference product were calculated. | ANOVA | 0.42 | Comparability demonstrated for p>0.05 | Mean Difference (Final Values) | 0 | 2-Sided | 95 | -0.224 | 0.093 | Comparability confirmed if confidence interval includes zero. | Equivalence | Comparability confirmed if confidence interval includes zero. |
| For each dose, the 95% CIs for the mean differences for the test product versus the reference product were calculated. | ANOVA | 0.078 | Comparability demonstrated for p>0.05 | Mean Difference (Final Values) | 0 | 2-Sided | 95 | -0.302 | 0.016 | Comparability confirmed if confidence interval includes zero. | Equivalence | Comparability confirmed if confidence interval includes zero. |
| For each dose, the 95% CIs for the mean differences for the test product versus the reference product were calculated. | ANOVA | 1.00 | Comparability demonstrated for p>0.05 | Mean Difference (Final Values) | 0 | 2-Sided | 95 | -4.7 | 4.7 | Comparability confirmed if confidence interval includes zero. | Equivalence | Comparability confirmed if confidence interval includes zero. |
| For each dose, the 95% CIs for the mean differences for the test product versus the reference product were calculated. | ANOVA | 0.016 | Comparability demonstrated for p>0.05 | Mean Difference (Final Values) | -2 | 2-Sided | 95 | -10.6 | -1.1 | Comparability confirmed if confidence interval includes zero. | Equivalence | Comparability confirmed if confidence interval includes zero. |