Increasing access to oxytocin for the prevention of postpartum haemorrhage: Inhaled Oxytocin A Phase I Study Disala Fernando, MD
The following clinical trial (NCT02542813) was funded entirely by the pharmaceutical company GSK and conducted at the GSK Clinical Trials unit in Addenbrooke s Hospital, Cambridge, UK. The speaker of this presentation Dr. Disala Fernando is an employee and a shareholder of GSK. RCOG World Congress Cape Town 2017 2
RCOG World Congress Cape Town 2017 3
Unpublished studies: Monash University and GSK internal data RCOG World Congress Cape Town 2017 4
200 mcg 400 mcg 600 mcg 10 IU IM IH Placebo 50 mcg IH Placebo IH Placebo IH Placebo RCOG World Congress Cape Town 2017 5
Median oxytocin plasma concentration-time profile RCOG World Congress Cape Town 2017 6
Next Steps RCOG World Congress Cape Town 2017 7
Project Partners Monash University (Innovator and Development Partner) GlaxoSmithKline (Development Partner, Co-Funder) Current Funding Partners McCall MacBain Foundation Saving Lives at Birth RHSC Innovation Fund Previous Funding Partners Bill & Melinda Gates Foundation ANZ Partners UN Commission Innovation Working Group Grand Challenges Canada Planet Wheeler Foundation 8
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Increasing access to oxytocin for the prevention of postpartum haemorrhage in resource-limited settings: Phase I data for a heat-stable, dry-powder formulation of inhaled oxytocin in healthy, non-pregnant volunteers Disala Fernando 1, Sarah Siederer 2, Sunita Singh 3, Ian Schneider 1, Kimberley Hacquoil 4, Marcy Powell 5, Michelle P. McIntosh 7, Peter Lambert 7, Pauline Williams 6, Duncan Richards 6 Author Conflict of Interest (COI) and academic and /or employment affiliations: 1 GSK Clinical Unit Cambridge, Addenbrooke s Hospital NHS Trust, Cambridge, UK; 2 Clinical Pharmacology Modelling and Simulation Department, GSK, Stevenage, UK; 3 Clinical operations, GSK, Stevenage, UK; 4 Clinical Statistics, GSK, Stevenage, UK; 5 Clinical safety, GSK, Research Triangle Park, NC, USA; 6 Alternative Discovery and Development, GSK, Stevenage, UK; 7 Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia Objective Reducing maternal mortality is a key UN Sustainable Development Goal. However, over 300,000 women still die from complications of pregnancy and childbirth every year; the vast majority in developing countries. 1 Postpartum Haemorrhage (PPH), accounts for 19.7% of these maternal deaths. 2 Intramuscular (IM) oxytocin is the gold standard for prevention of PPH, but access in developing countries is limited by formulation stability and availability of trained professionals to administer injections. A heat-stable, inhaled (IH) formulation delivered via a simple inhaler (Modified Air Inlet ROTAHALER TM Dry Powder Inhaled Device [Figure 1]) provides an opportunity to offer women in resource poor settings access to this gold standard treatment. Here we report the first IH oxytocin clinical study which was conducted in healthy non-pregnant volunteers, and designed to assess the safety, tolerability and pharmacokinetics (PK) of IH oxytocin compared to IM oxytocin. Study Design This was a single-blind, dose-escalation, fixed-sequence study in healthy, pre-menopausal, non-pregnant, non-lactating women aged 18 45 years. In dosing session 1 (S1), subjects received IM oxytocin 10 IU on day 1, IH placebo on day 2 and IH oxytocin 50 μg on day 3. In dosing Session 2 (S2) to Session 4 (S4), subjects were randomized to receive either IH placebo or ascending doses of IH oxytocin (200, 400, 600 µg). [Figure 2] Plasma PK profiles were compared for each IH dose vs IM oxytocin focusing on rate and extent of systemic exposure, specifically quantified concentration at 10 and 30 min (Cp10 and Cp30) post dose and area under concentration-time curve over 3h post dose (AUC 0 3h ). Adverse events (AEs), laboratory tests, vital signs, electrocardiograms, physical exams, telemetry and spirometry were assessed. Day 1 Day 2 Day 3 Figure 2 - Study Schematic Dosing Session 1 Dosing Session 2 Dosing Session 3 Dosing Session 4 Group 1 (n=3) Oxytocin 10IU IM Inhaled Placebo Group 1+2, n=15 Group 1+2, n=15 Group 1+2, n=15 Inhaled Oxytocin Inhaled Oxytocin Inhaled Oxytocin Inhaled Oxytocin 50mcg * 200mcg / Placebo * 400mcg / Placebo * 600mcg / Placebo Day 1 Day 1 Day 1 Group 2 (n=12) Oxytocin 10IU IM Day 1 Inhaled Placebo Day 2 Inhaled Oxytocin Day 3 50mcg Up to -28 days Wk1 Wk2 Wk4 Wk6 Wk9 Wk12 Wk14-15 Approximate Timings Screening Treatment F/Up * Dose escalation meeting Figure 1 ROTAHALER Device Results 15 of 16 randomised females completed the study. * In general, the shape of the observed PK concentration-time profile following IH oxytocin was consistent with the IM profile [Figure 3]. There was rapid absorption of oxytocin into plasma following both routes of administration. Median Tmax (0.17 h) after IM oxytocin was consistent with median Tmax (0.14-0.33h) following IH oxytocin over the dose range of 50-600 µg. Thereafter, plasma concentration fell with estimates of the apparent terminal elimination half-life consistent across routes (IH vs IM) and doses. Adjusted mean ratios for PK parameters were >1.0 for Cp10, Cp30 and AUC(0-3) following 400 and 600 µg IH oxytocin and <1 for the lower doses [Table 1]. No serious AEs were reported. No clinically significant findings were observed for any safety parameter. *One subject was withdrawn at the investigator s discretion. Table 1 - Summary of Statistical Analysis of oxytocin PK Parameters Parameter Comparison Adj. geometric mean (test/ref) Adj. geometric mean ratio (90% CI) Cp10 (pg/ml) 50 µg IH vs 10 IU IM 12.0/171.2 0.07 (0.05, 0.09) 200 µg IH vs 10 IU IM 72.7/171.2 0.42 (0.33, 0.55) 400 µg IH vs 10 IU IM 188.1/171.2 1.10 (0.85, 1.43) 600 µg IH vs 10 IU IM 258.3/171.2 1.51 (1.16, 1.96) Cp30 (pg/ml) 50 µg IH vs 10 IU IM 9.6/82.2 0.12 (0.09, 0.15) 200 µg IH vs 10 IU IM 58.6/82.1 0.71 (0.56, 0.91) 400 µg IH vs 10 IU IM 135.6/82.2 1.65 (1.30, 2.09) 600 µg IH vs 10 IU IM 191.0/82.2 2.32 (1.83, 2.95) AUC 0-3h(pg.h/mL) 50 µg IH vs 10 IU IM 14.8/127.6 0.12 (0.10, 0.14) 200 µg IH vs 10 IU IM 69.8/127.6 0.55 (0.46, 0.65) 400 µg IH vs 10 IU IM 161.8/127.6 1.27 (1.07, 1.50) 600 µg IH vs 10 IU IM 234.9/127.6 1.84 (1.56, 2.18) Figure 3 - Plot of Median oxytocin plasma concentration-time profile Note: LLQ=2 pg/ml Linear Scale Conclusion & Long-Term Goals Preliminary plasma PK data suggest that similar oxytocin systemic exposure can be achieved with IM and IH administration routes with no new safety concerns. A second study enrolling pregnant women is currently underway in Cambridge, UK evaluating the PK of IH oxytocin compared to IM oxytocin during the third stage of labour. Future studies will aim to confirm the final dose, and explore safety in sub-populations such as asthmatics and smokers. The inhalation route may offer the opportunity to deliver an effective oxytocin dose to women giving birth in resource poor settings. REFERENCES Logarithmic Scale 1. Trends in Maternal Mortality: 1990 to 2015, WHO (2015) http://www.who.int/reproductivehealth/publications/monitoring/maternalmortality-2015/en/ 2. Say et al. (2014). Global causes of maternal death: a WHO systematic analysis. Lancet Global Health. http://dx.doi.org/10.1016/ S2214-109X(14)70227-X GlaxoSmithKline Document Number 2016N277949_00. Study ID 201558 Clinical Study Report. 30-JUN-2016. GlaxoSmithKline Document Number 2016N288552_00. Study ID IVF116828; 29-NOV-2016. GlaxoSmithKline Document Number 2015N247262_00. Study ID 145136ALPG; 12-JUL-2015. RCOG World Congress Cape Town 2017 Analysis entirely funded by GlaxoSmithKline, plc; (NCT02542813) Creation Date: 02-FEB-2017