Comparison of Inhaled Oxytocin (IH) With Intramuscular (IM) Oxytocin in Pregnant Women and With Intravenous (IV) Oxytocin in Healthy Non-pregnant Women

NCT02999100 | Terminated Phase 1 Results

• 2 other identifiers: 2059202016-002672-27
• Study Type: interventional
• Target: 31
• Locations: 2 countries
• Sites: 3

Brief Summary

The study will evaluate a stable, dry-powder formulation of oxytocin, with the goal of reducing post-partum hemorrhage morbidity and mortality in resource poor settings. This study is being conducted to further assess safety and tolerability of inhaled oxytocin, and to characterize the drug levels of inhaled (IH) oxytocin when compared to oxytocin administered as standard of care. Two groups of subjects will be enrolled. Group 1 will enroll pregnant women, who will be randomized to receive either IH or intramuscular (IM) oxytocin as active management of the third stage of labour (after the baby is born). Group 2 will enroll non-pregnant women of childbearing potential, who will receive IH oxytocin and intravenous (IV) oxytocin in a cross over design over two dosing sessions This group will evaluate the safety and tolerability of IH and IV oxytocin.

Conditions

Postpartum Hemorrhage

Keywords

oxytocin; non-pregnant; pregnant; Postpartum Hemorrhage

Outcome Measures

Primary Outcomes (28)

• Part 1: Plasma Concentration Time Profile of Oxytocin

  Blood samples were collected at indicated time points to evaluate concentration of oxytocin. Pharmacokinetic parameters were calculated by standard non-compartmental analysis.

  Predose, 3 minutes, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 1 hour, 2 hours, 2.5 hours, 3 hours and 4 hours post dose Day 1

• Part 1: Maximum Observed Plasma Concentration (Cmax) of Oxytocin

  Blood samples were collected at indicated time points to evaluate Cmax of oxytocin. Pharmacokinetic parameters were calculated by standard non-compartmental analysis.

  Predose, 3 minutes, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 1 hour, 2 hours, 2.5 hours, 3 hours and 4 hours post dose Day 1

• Part 1: Observed Plasma Concentration (Cp) 10 of Oxytocin

  Blood samples were collected at indicated time points to evaluate observed plasma concentration of oxytocin. Pharmacokinetic parameters were calculated by standard non-compartmental analysis.

  10 minutes post dose Day 1

• Part 1: Observed Plasma Concentration (Cp) 20 of Oxytocin

  Blood samples were collected at indicated time points to evaluate observed plasma concentration of oxytocin. Pharmacokinetic parameters were calculated by standard non-compartmental analysis.

  20 minutes post dose Day 1

• Part 1: Observed Plasma Concentration (Cp) 30 of Oxytocin

  Blood samples were collected at indicated time points to evaluate observed plasma concentration of oxytocin. Pharmacokinetic parameters were calculated by standard non-compartmental analysis.

  30 minutes post dose Day 1

• Part 1: Time to Reach Maximum Observed Concentration (Tmax) of Oxytocin

  Blood samples were collected at indicated time points to evaluate Tmax of oxytocin. Pharmacokinetic parameters were calculated by standard non-compartmental analysis.

  Predose, 3 minutes, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 1 hour, 2 hours, 2.5 hours, 3 hours and 4 hours post dose Day 1

• Part 1: Area Under the Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC[0-t]) of Oxytocin

  Blood samples were collected at indicated time points to evaluate AUC (0-t) of oxytocin. Pharmacokinetic parameters were calculated by standard non-compartmental analysis.

  Predose, 3 minutes, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 1 hour, 2 hours, 2.5 hours, 3 hours and 4 hours post dose on Day 1

• Part 1: Terminal Phase Half-life (t1/2) of Oxytocin

  Blood samples were collected at indicated time points to evaluate t1/2 of oxytocin.

  Predose, 3 minutes, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 1 hour, 2 hours, 2.5 hours, 3 hours and 4 hours post dose on Day 1

• Part 2: Number of Participants With Non-serious Adverse Events (Non-SAEs) and Serious Adverse Events (SAEs)

  An adverse event (AE) is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. As SAE is defined as any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent disability/incapacity; is a congenital anomaly/birth defect; other situation according to medical or scientific judgment or is associated with liver injury and impaired liver function. Safety Population includes participants who received at least one dose of study medication.

  Up to 37 days

• Part 2: Absolute Values of Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)

  Blood pressure of participants were measured at indicated time points in semi-supine position after 5 minutes rest.

  Pre-dose, 5 minutes, 15 minutes, 30 minutes, 1 hour and 4 hours post dose

• Part 2: Change From Baseline in SBP and DBP

  SBP and DBP of participants were measured at indicated time points in semi-supine position after 5 minutes rest. Baseline was defined as the latest pre-dose assessment with a non-missing value at Day 1 (Pre-dose). Change from Baseline value is calculated as the value at the post-dose visit minus the Baseline value.

  Baseline (Day 1, pre-dose), 5 minutes, 15 minutes, 30 minutes, 1 hour and 4 hours post dose

• Part 2: Change From Baseline in Heart Rate

  Heart rate of participants were measured at indicated time points in semi-supine position after 5 minutes rest. Baseline was defined as the latest pre-dose assessment with a non-missing value at Day 1 (Pre-dose). Change from Baseline value is calculated as the value at the post-dose visit minus the Baseline value.

  Baseline (Day 1, pre-dose), 5 minutes, 15 minutes, 30 minutes, 1 hour and 4 hours post dose

• Part 2: Absolute Values of Heart Rate

  Heart rate was measured in semi-supine position after 5 minutes rest

  Pre dose, 5 minutes, 15 minutes, 30 minutes, 1 hour and 4 hours post dose

• Part 2: Absolute Values of PR Interval, QRS Duration, Corrected QT Interval Using Bazett's (QTcB) Formula and Corrected QT Interval Using Fredericia's Formula (QTcF) Interval

  Triplicate 12-lead electrocardiograms (ECGs) were recorded pre-dose and post-dose with participant in semi-supine position after 5 minutes rest. At each time point ECG was taken using an ECG machine that automatically measured PR interval, QRS duration, QTcB interval, and QTcF interval.

  Pre-dose, 2 minutes, 10 minutes, 20 minutes, 30 minutes, 1 hour and 4 hours post dose

• Part 2: Number of Participants With Abnormal Respiratory Events

  Number of participants with abnormal respiratory events has been presented

  Up to Day 37

• Part 2: Forced Expiratory Volume at 1 Minute (FEV1)

  FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. FEV1 measurements were taken electronically by spirometry on Day 1. At each time point, three best measurements were recorded.

  Pre dose and 1 hour post dose on Day1

• Part 2: Percent Oxygen in Blood

  Percent oxygen in blood was measured using pulse oximetry in a semi-supine position after 5 minutes rest. Pulse oximeter is a device that measures oxygen saturation of arterial blood in participants by utilizing a sensor attached typically to a finger, toe, or ear to determine the percentage of oxyhemoglobin in blood pulsating through a network of capillaries

  Pre dose, 5 minutes, 15 minutes, 30 minutes, 1 hour and 4 hours post-dose

• Part 2: Absolute Values of Respiration Rate

  Respiration rate was measured in semi-supine position after 5 minutes rest

  Pre dose, 5 minutes, 15 minutes, 30 minutes, 1 hour and 4 hours post-dose

• Part 2: Plasma Concentration Time Profile of Oxytocin.

  Blood samples were collected at indicated time points to evaluate concentration of oxytocin. Pharmacokinetic parameters were calculated by standard non-compartmental analysis.

  -1 hour,-30 minutes,-15 minutes pre-dose, 2 minutes, 3 minutes, 5 minutes, 8 minutes,10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours and 4 hours post dose

• Part 2: Maximum Observed Plasma Concentration (Cmax) of Oxytocin

  Blood samples were collected at indicated time points to evaluate Cmax of oxytocin. Pharmacokinetic parameters were calculated by standard non-compartmental analysis.

  -1 hour,-30 minutes,-15 minutes pre-dose, 2 minutes, 3 minutes, 5 minutes, 8 minutes,10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours and 4 hours post dose

• Part 2: Observed Plasma Concentration (Cp)10 of Oxytocin

  Blood samples were collected at indicated time points to evaluate observed plasma concentration of oxytocin. Pharmacokinetic parameters were calculated by standard non-compartmental analysis.

  10 minutes post dose

• Part 2: Observed Plasma Concentration (Cp)20 of Oxytocin

  Blood samples were collected at indicated time points to evaluate observed plasma concentration of oxytocin. Pharmacokinetic parameters were calculated by standard non-compartmental analysis.

  20 minutes post dose

• Part 2: Observed Plasma Concentration (Cp)30 of Oxytocin

  Blood samples were collected at indicated time points to evaluate observed plasma concentration of oxytocin. Pharmacokinetic parameters were calculated by standard non-compartmental analysis.

  30 minutes post dose

• Part 2: Time to Reach Maximum Observed Concentration (Tmax) of Oxytocin

  Blood samples were collected at indicated time points to evaluate Tmax of oxytocin. Pharmacokinetic parameters were calculated by standard non-compartmental analysis.

  -1 hour,-30 minutes,-15 minutes pre-dose, 2 minutes, 3 minutes, 5 minutes, 8 minutes,10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours and 4 hours post dose

• Part 2: Area Under the Concentration-time Curve From Time Zero Extrapolated to Time 't' (AUC[0-t]) of Oxytocin

  Blood samples were collected at indicated time points to evaluate AUC (0-t) of oxytocin. Pharmacokinetic parameters were calculated by standard non-compartmental analysis.

  -1 hour,-30 minutes,-15 minutes Pre-dose, 2 minutes, 3 minutes, 5 minutes, 8 minutes,10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours and 4 hours post dose

• Part 2: Plasma Clearance (CL) of Oxytocin for IV Route Only

  Blood samples were collected at indicated time points to evaluate plasma clearance of oxytocin IV bolus and infusion. Pharmacokinetic parameters were calculated by standard non-compartmental analysis.

  -1 hour,-30 minutes,-15 minutes Pre-dose, 2 minutes, 3 minutes, 5 minutes, 8 minutes,10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours and 4 hours post dose

• Part 2: Volume of Distribution (VOD) of Oxytocin for IV Route Only

  Blood samples were collected at indicated time points to evaluate volume of distribution of oxytocin IV bolus and infusion. Pharmacokinetic parameters were calculated by standard non-compartmental analysis.

  -1 hour,-30 minutes,-15 minutes Pre-dose, 2 minutes, 3 minutes, 5 minutes, 8 minutes,10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours and 4 hours post dose

• Part 2: Time to Reach Terminal Phase Half-life (t1/2) of Oxytocin

  Blood samples were collected at indicated time points to evaluate t1/2 of oxytocin. Pharmacokinetic parameters were calculated by standard non-compartmental analysis.

  -1 hour,-30 minutes,-15 minutes pre-dose, 2 minutes, 3 minutes, 5 minutes, 8 minutes,10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours and 4 hours post dose

Secondary Outcomes (10)

• Part 1: Number of Participants With Non-SAEs and SAEs

  Up to 15 days

• Part 1: Absolute Values for Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)

  30 minutes and 2 hours post dose

• Part 1: Absolute Values of Heart Rate

  30 minutes and 2 hours post dose

• Part 1: Absolute Values of Respiration Rate

  30 minutes and 2 hours post dose

• Part 1: Absolute Values of Temperature

  30 minutes and 2 hours post dose

Study Arms (3)

Group 1 -IH oxytocin

EXPERIMENTAL

Women with an uncomplicated pregnancy in third stage of labour will be enrolled in the arm. Subjects will receive 400 micrograms (mcg) IH oxytocin. Subjects will be followed up in-person or via telephone within approximately 24 hr post dose and once between 7 days to 14 days

Drug: IH Oxytocin; Device: ROTAHALER

Group 1 -IM oxytocin

EXPERIMENTAL

Women with an uncomplicated pregnancy in third stage of labour will be enrolled in the arm. Subjects will receive 10 I.U. IM oxytocin. Subjects will be followed up in-person or via telephone within approximately 24 hr post dose and once between 7 days to 14 days

Drug: IM Oxytocin

Group 2 (IH and IV oxytocin)

EXPERIMENTAL

Group 2 will enrol healthy, non-pregnant, non-lactating female subjects of childbearing potential, and each subject will participate in 2 dosing sessions. Group 2 will be divided into two cohorts: Cohort A will enrol women on a combined oral contraceptive, and Cohort B will enrol women who are not using a hormonal form of contraceptive. Group 2 subjects will randomized to receive IH oxytocin, and IV oxytocin in a cross fashion. Subjects will be followed up in-person once between 7 days to 21 days

Drug: IH Oxytocin; Drug: IV Oxytocin; Device: ROTAHALER

Interventions

IH Oxytocin DRUG

Oxytocin will be supplied as colourless and clear hard capsule with powder blend for inhalation with unit dose strength 400 mcg and 200 mcg. It will be administered using ROTAHALER dry powder inhaler (DPI).

Group 1 -IH oxytocin; Group 2 (IH and IV oxytocin)

IM Oxytocin DRUG

Oxytocin will be supplied for solution for infusion in 1ml ampoule containing colourless and clear sterile solution with unit dose strength 5 I.U./mL, or 10 I.U./mL for IM administration

Group 1 -IM oxytocin

IV Oxytocin DRUG

Oxytocin will be supplied as solution for infusion in 1ml ampoule containing colourless and clear sterile solution to be administered as a 30-second IV bolus with unit dose strength 5 I.U./mL, or 10 I.U./mL.

Group 2 (IH and IV oxytocin)

ROTAHALER DEVICE

ROTAHALER DPI device is a high airflow resistance capsule-based inhaler. It will be used to deliver IH oxytocin

Group 1 -IH oxytocin; Group 2 (IH and IV oxytocin)

Eligibility Criteria

• Age: 18 Years - 40 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• All Groups:
• Between 18 and 40 years of age inclusive, at the time of signing the informed consent.
• Healthy as determined by the investigator or medically qualified designee based on a medical evaluation including medical history, physical examination, and laboratory tests as required per protocol.

You may not qualify if:

• Adequate peripheral venous access for cannulation.
• Group 1 Only:
• Currently pregnant, with an uncomplicated pregnancy as determined by the investigator or designee.
• Estimated date of delivery within 24 weeks of screening.
• Planned spontaneous vaginal birth and considered by investigator at low risk for post partum hemorrhage (PPH).
• Planned birth in between the 37th and 42nd week of pregnancy.
• Women who qualify for oxytocin as appropriate for active management of TSL and who agree to have active management.
• Group 2 Only:
• ECG normal, or abnormal and not clinically significant.
• FEV1 \>80% of predicted.
• Systolic blood pressure \>=90 millimeters of mercury (mmHg).
• Body mass index (BMI) within the range 18 - 32 Kilogram (kg)/square meter (m\^2) (inclusive).
• Sex-Female.
• Group 2, Cohort A Only:
• A female subject is eligible to participate if she is confirmed to be not pregnant at screening and on Day 1 (as confirmed by a negative serum or urine human chorionic gonadotrophin \[hCG\] test), not lactating, and the following condition applies:

Sponsors & Collaborators

• GlaxoSmithKline: lead
• InVentiv Clinique: collaborator
• Monash University: collaborator

Study Sites (3)

GSK Investigational Site

Clayton, Victoria, 3168, Australia

Location

GSK Investigational Site

Cambridge, Cambridgeshire, CB2 2GG, United Kingdom

Location

GSK Investigational Site

Cambridge, CB2 2GG, United Kingdom

Location

Related Publications (2)

• Oliver VL, Siederer S, Cahn A, Gajewska-Knapik K, Gibson RA, Goodall C, Kirkpatrick C, Murray J, Nguyen TH, Schneider I, Lambert P, McIntosh MP, Parry S. Exploring the role of ex vivo metabolism on blood and plasma measurements of oxytocin among women in the third stage of labour: A post hoc study. Br J Clin Pharmacol. 2023 Dec;89(12):3669-3680. doi: 10.1111/bcp.15865. Epub 2023 Aug 24.

  PMID: 37522415 DERIVED

• Gajewska-Knapik K, Kumar S, Sutton-Cole A, Palmer KR, Cahn A, Gibson RA, Kirkpatrick C, Parry S, Schneider I, Siederer S, Stylianou A, Hacquoil K, Powell M, Ellis M, McIntosh MP, Lambert P. Pharmacokinetics and safety of inhaled oxytocin compared with intramuscular oxytocin in women in the third stage of labour: A randomized open-label study. Br J Clin Pharmacol. 2023 Dec;89(12):3681-3689. doi: 10.1111/bcp.15860. Epub 2023 Aug 31.

  PMID: 37485589 DERIVED

MeSH Terms

Conditions

Postpartum Hemorrhage

Interventions

Oxytocin

Condition Hierarchy (Ancestors)

Obstetric Labor Complications; Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Puerperal Disorders; Uterine Hemorrhage; Hemorrhage; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Pituitary Hormones, Posterior; Pituitary Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptides; Amino Acids, Peptides, and Proteins

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 1, 2016
• First Posted: December 21, 2016
• Study Start: November 23, 2016
• Primary Completion: March 1, 2019
• Study Completion: March 4, 2019
• Last Updated: March 23, 2020
• Results First Posted: March 5, 2020

Record last verified: 2020-03

Locations

AU (1); GB (2)