Single Blind Cross-over Dose Response Study in Subjects of Two Inhalers of Salmeterol and Fluticasone Propionate

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.

• Salmeterol (Drug), also known as Sirdupla, Seretide Evohaler: A, D 2 puffs; B, E 6 puffs; C, F 12 puffs
• fluticasone propionate (Drug), also known as Sirdupla, Seretide Evohaler: A, D 2 puffs; B, E 6 puffs; C, F 12 puffs

Primary outcomes

• Relative Potency Max Heart Rate [Baseline, up to 6 hrs]: 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 QTcB Interval [Baseline up to 6 hrs]: 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.

Secondary outcomes

• Max Heart Rate [Baseline through 6 hours]: max heart rate at the 2, 6, or 12 inhalations dose, assessed at multiple times over 6 hours
• Plasma Potassium Level [baseline through 6 hours]: maximum plasma levels of potassium at 2, 6 or 12 inhalations dose inhalations dose, assessed a multiple times over 6 hours.
• Max Plasma Glucose Level [baseline through 6 hours]: maximum levels of glucose at the 2, 6 or 12 inhalations dose, assessed at multiple times over 6 hours.
• Max QTcB [Baseline through 6 hours]: For each dose, the 95% CIs for the mean difference for the test product versus the reference product were calculated.

Sex: All, ages: 18 Years to 55 Years, accepts healthy volunteers

Inclusion Criteria:

* Healthy Volunteer
* Willing and able to give informed consent
* Willing to withhold all alcoholic beverages for 48 hours and all xanthine- containing foods and beverages for 24 hours prior to reporting to clinic
* Male and female subjects aged 18 to 55 years (inclusive)
* Subjects must agree to use an adequate method of contraception from admission through 12 weeks after last administration

Exclusion Criteria:

* Evidence or history of clinically significant abnormalities or disease or chronic respiratory disorders
* Any presence or history of a clinically significant allergy including any adverse reaction to study drug
* History of drug or alcohol abuse within the past 2 years
* Smoked tobacco within the past 6 months or have a history of more than 10- pack years (number of packs smoked per day x number of years smoked)
* Donation or loss of greater than 400 mL of blood within the previous 3 months
* Have received any prescription medication within 4 weeks or investigational medication within 12 weeks of study (exception: contraceptives are permitted)
* Have received any non-prescription medication within 14 days prior to dosing (exception: paracetamol use within 2 days)
* Upper respiratory tract infection (excluding otitis media) within 14 days of the first study day, or lower respiratory tract infection within the last 3 months
* If female, nursing, lactating or pregnant
* Regular alcohol consumption in males >21 units per week and females >14 units per week (1 unit = ½ pint beer, 25 mL of 40% spirit or a 125 mL glass of wine)
* Surgery scheduled during the study or within 3 weeks after last dose
* History of familial long QT syndrome or history of sudden death in family members aged < 30 years

Participant flow

Outcome results

• Relative Potency Max Heart Rate (Primary), Number, unitless: Test B and C vs Reference E and F 0.8619 (0.7209 to 1.00) (p >0.10)
• Relative Potency QTcB Interval (Primary), Number, unitless: Test A and B vs Reference D and E 1.0760 (0.8206 to 1.4238) (p >0.10)
• Max Heart Rate (Secondary), Mean, bpm: Test Product A 65.1 +/- 10.9; Reference Product D 65.5 +/- 10.1; Test Product B 68.9 +/- 11.0; Reference Product E 69.9 +/- 12.2; Test Product C 75.3 +/- 13.3; Reference Product F 76.8 +/- 14.8 (p 0.55)
• Plasma Potassium Level (Secondary), Mean, mmol/L: Test Product A 3.82 +/- 0.19; Reference Product D 3.78 +/- 0.16; Test Product B 3.76 +/- 0.20; Reference Product E 3.75 +/- 0.19; Test Product C 3.63 +/- 0.24; Reference Product F 3.61 +/- 0.26 (p 0.26)
• Max Plasma Glucose Level (Secondary), Mean, mmol/L: Test Product A 5.31 +/- 0.49; Reference Product D 5.31 +/- 0.40; Test Product B 5.53 +/- 0.65; Reference Product E 5.62 +/- 0.54; Test Product C 5.88 +/- 0.66; Reference Product F 5.98 +/- 0.65 (p 0.93)
• Max QTcB (Secondary), Mean, ms: Test Product A 422.3 +/- 22.4; Reference Product D 422.1 +/- 23.7; Test Product B 430.0 +/- 23.1; Reference Product E 430.2 +/- 21.4; Test Product D 441.0 +/- 20.5; Reference Product F 444.0 +/- 26.7 (p 0.71)

Adverse events

Time frame: Adverse events were collected for up to 2 months for each subject. The duration of the clinical phase of the study was 4 months.

Other adverse events by term

Limitations and caveats: There are no limitations or caveats.

• Results publication: 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. PMID 28626983

• Pui Leung, MD, Principal investigator, Quotient Clinical Ltd