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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT02999100




Registration number
NCT02999100
Ethics application status
Date submitted
1/11/2016
Date registered
21/12/2016
Date last updated
29/03/2019

Titles & IDs
Public title
Comparison of Inhaled Oxytocin (IH) With Intramuscular (IM) Oxytocin in Pregnant Women and With Intravenous (IV) Oxytocin in Healthy Non-pregnant Women
Scientific title
A Randomized, Open-label Study to Characterize the Pharmacokinetics of Inhaled Oxytocin (GR121619) Compared With IM Oxytocin in Women in the Third Stage of Labour, and With IV Oxytocin in Non-pregnant, Non-lactating Women of Childbearing Potential
Secondary ID [1] 0 0
2016-002672-27
Secondary ID [2] 0 0
205920
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Postpartum Hemorrhage 0 0
Condition category
Condition code
Reproductive Health and Childbirth 0 0 0 0
Fetal medicine and complications of pregnancy

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - IH Oxytocin
Treatment: Drugs - IM Oxytocin
Treatment: Drugs - IV Oxytocin
Treatment: Devices - ROTAHALER

Experimental: Group 1 -IH oxytocin - 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

Experimental: Group 1 -IM oxytocin - 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

Experimental: Group 2 (IH and IV oxytocin) - 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


Treatment: Drugs: IH Oxytocin
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).

Treatment: Drugs: IM Oxytocin
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

Treatment: Drugs: IV Oxytocin
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.

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

Intervention code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Treatment: Devices
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Group 1: Plasma concentration time profile for IH oxytocin
Timepoint [1] 0 0
Blood samples will be collected at the following time points: Predose, and post dose at 3 minutes (min), 5 min, 10 min, 15 min, 20 min, 30 min, 1 hour (hr), 2 hr, 2.5 hr, 3 hr, 4 hr on Day 1
Primary outcome [2] 0 0
Group 1: Plasma concentration time profile for IM oxytocin.
Timepoint [2] 0 0
Blood samples will be collected at the following time points: Predose, and post dose at 3 min, 5 min, 10 min, 15 min, 20 min, 30 min, 1 hr, 2 hr, 2.5 hr, 3 hr, 4 hr on Day 1
Primary outcome [3] 0 0
Group 1: Maximum observed plasma concentration (Cmax) for IH oxytocin and IM oxytocin
Timepoint [3] 0 0
Blood samples will be collected at the following time points: Predose, and post dose at 3 min, 5 min, 10 min, 15 min, 20 min, 30 min, 1 hr, 2 hr, 2.5 hr, 3 hr, 4 hr on Day 1
Primary outcome [4] 0 0
Group 1: Observed plasma concentrations at defined time intervals post-dose (Cp) for IH oxytocin and IM oxytocin - Cp will be reported for observed plasma concentrations at 10 min post-dose (Cp10), observed plasma concentrations at 20 min post-dose (Cp20), and observed plasma concentrations at 30 min post-dose (Cp30).
Timepoint [4] 0 0
Blood samples will be collected at the following time points: post dose at 10 min, 20 min, and 30 min on Day 1
Primary outcome [5] 0 0
Group 1: Time to Cmax (tmax) for IH oxytocin and IM oxytocin
Timepoint [5] 0 0
Blood samples will be collected at the following time points: Predose, and post dose at 3 min, 5 min, 10 min, 15 min, 20 min, 30 min, 1 hr, 2 hr, 2.5 hr, 3 hr, 4 hr on Day 1
Primary outcome [6] 0 0
Group 1: Area under concentration-time curve (AUC) for IH oxytocin and IM oxytocin
Timepoint [6] 0 0
Blood samples will be collected at the following time points: Predose, and post dose at 3 min, 5 min, 10 min, 15 min, 20 min, 30 min, 1 hr, 2 hr, 2.5 hr, 3 hr, 4 hr on Day 1
Primary outcome [7] 0 0
Group 2: Number of subjects with adverse events
Timepoint [7] 0 0
Maximum up to 64 days
Primary outcome [8] 0 0
Group 2: Absolute values of blood pressure - Blood pressure will be measured at screening, on Day 1 at pre-dose, and at 5 min, 15 min, 30 min, 1 hr and 4 hrs post dose.
Timepoint [8] 0 0
Day 1
Primary outcome [9] 0 0
Group 2: Absolute values of heart rate - Heart rate will be measured at screening, on Day 1 at pre-dose, and at 5 min, 15 min, 30 min, 1 hr and 4 hrs post dose.
Timepoint [9] 0 0
Day 1
Primary outcome [10] 0 0
Group 2: Change from Baseline over time in blood pressure - Blood pressure will be measured at screening, on Day 1 at pre-dose, and at 5 min, 15 min, 30 min, 1 hr and 4 hrs post dose.
Timepoint [10] 0 0
Baseline and up to Day 1
Primary outcome [11] 0 0
Group 2: Change from Baseline over time in heart rate - Heart rate will be measured at screening, on Day 1 at pre-dose, and at 5 min, 15 min, 30 min, 1 hr and 4 hrs post dose.
Timepoint [11] 0 0
Baseline and up to Day 1
Primary outcome [12] 0 0
Group 2: Absolute values of 12-lead electrocardiogram (ECG) parameters - ECG parameters will include PR, QRS, QT, Corrected QT interval [QTc] intervals. ECG will be measured at screening, on Day 1 at pre-dose, and at 2 min, 10 min, 20 min, 30 min, 1 hr and 4 hrs post dose.
Timepoint [12] 0 0
Day 1
Primary outcome [13] 0 0
Group 2: Change from Baseline over time in 12-lead electrocardiogram (ECG) parameters - ECG parameters will include PR, QRS, QT, Corrected QT interval [QTc] intervals. ECG will be measured at screening, on Day 1 at pre-dose, and at 2 min, 10 min, 20 min, 30 min, 1 hr and 4 hrs post dose.
Timepoint [13] 0 0
Baseline and up to Day 1
Primary outcome [14] 0 0
Group 2: Number of subjects with adverse respiratory events - Adverse respiratory events will be monitored using spirometry on Day 1 at pre-dose and 1 hr post dose.
Timepoint [14] 0 0
Day 1
Primary outcome [15] 0 0
Group 2: Forced expiratory volume at 1 minute (FEV1.0) - The FEV 1.0 will be measured using spirometry on Day 1 at pre-dose and 1 hr post dose.
Timepoint [15] 0 0
Day 1
Primary outcome [16] 0 0
Group 2: Respiratory rate - Respiratory rate will be measured using spirometry on Day 1 at pre-dose and 1 hr post dose.
Timepoint [16] 0 0
Day 1
Primary outcome [17] 0 0
Group 2: Pulse oximetry - Pulse oximetry will be measured using spirometry on Day 1 at pre-dose and 1 hr post dose.
Timepoint [17] 0 0
Day 1
Primary outcome [18] 0 0
Group 1: Time to Terminal phase half-life (t1/2) for IH oxytocin and IM oxytocin
Timepoint [18] 0 0
Blood samples will be collected at the following time points: Predose, and post dose at 3 min, 5 min, 10 min, 15 min, 20 min, 30 min, 1 hr, 2 hr, 2.5 hr, 3 hr, 4 hr on Day 1
Secondary outcome [1] 0 0
Group 1: Number of subjects with adverse events (AE) - An AE is any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.
Timepoint [1] 0 0
Maximum up to 14 days
Secondary outcome [2] 0 0
Group 1: Absolute values of blood pressure - Blood pressure will be measured at screening and Day 1 post dose at 30 min and 2 hr
Timepoint [2] 0 0
Baseline (Day -1) and up to Day 1
Secondary outcome [3] 0 0
Group 1: Absolute values of heart rate - Heart rate will be measured at screening and Day 1 post dose at 30 min and 2 hr
Timepoint [3] 0 0
Day 1
Secondary outcome [4] 0 0
Group 1: Absolute values of respiratory rateGroup 1: Absolute values of respiratory rate - Respiratory rate will be measured at screening and Day 1 post dose at 30 min and 2 hr
Timepoint [4] 0 0
Day 1
Secondary outcome [5] 0 0
Group 1: Absolute values of temperature - Temperature will be measured at screening and Day 1 post dose at 30 min and 2 hr
Timepoint [5] 0 0
Day 1
Secondary outcome [6] 0 0
Group 1: Change from Baseline over time in blood pressure - Blood pressure will be measured at screening and Day 1 post dose at 30 min and 2 hr
Timepoint [6] 0 0
Baseline and up to Day 1
Secondary outcome [7] 0 0
Group 1: Change from Baseline over time in heart rate - Heart rate will be measured at screening and Day 1 post dose at 30 min and 2 hr
Timepoint [7] 0 0
Baseline and up to Day 1
Secondary outcome [8] 0 0
Group 1: Change from Baseline over time in respiratory rate - Respiratory rate will be measured at screening and Day 1 post dose at 30 min and 2 hr
Timepoint [8] 0 0
Baseline and up to Day 1
Secondary outcome [9] 0 0
Group 1: Change from Baseline over time in temperature - Temperature will be measured at screening and Day 1 post dose at 30 min and 2 hr
Timepoint [9] 0 0
Baseline and up to Day 1
Secondary outcome [10] 0 0
Group 1: Comparison of Cmax between IH oxytocin and IM oxytocin
Timepoint [10] 0 0
Blood samples will be collected at the following time points: Predose, and post dose at 3 min, 5 min, 10 min, 15 min, 20 min, 30 min, 1 hr, 2 hr, 2.5 hr, 3 hr, 4 hr on Day 1
Secondary outcome [11] 0 0
Group 1: Comparison of Cp between IH oxytocin and IM oxytocin - Cp will be reported for Cp10, Cp20, and Cp30.
Timepoint [11] 0 0
Blood samples will be collected at the following time points: post dose at 10 min, 120 min, and 30 min on Day 1
Secondary outcome [12] 0 0
Group 1: Comparison of Area under the concentration-time curve from time zero (pre-dose) to three hours (AUC[0-3h]) between IH oxytocin and IM oxytocin
Timepoint [12] 0 0
Blood samples will be collected at the following time points: Predose, and post dose at 3 min, 5 min, 10 min, 15 min, 20 min, 30 min, 1 hr, 2 hr, 2.5 hr, 3 hr, 4 hr on Day 1
Secondary outcome [13] 0 0
Group 2: Plasma concentration time profile for IH oxytocin and IV oxytocin
Timepoint [13] 0 0
Blood samples will be collected at the following time points: Pre-dose, and post dose at 2 min, 3 min, 5 min, 8 min, 10 min, 15 min, 20 min, 30 min, 45 min, 1 hr, 1.5 hr, 2 hr, 2.5 hr, 3 hr, and 4 hr on Day 1
Secondary outcome [14] 0 0
Group 2: Cmax for IH oxytocin and IV oxytocin - Cmax, Cp10, Cp20, Cp30
Timepoint [14] 0 0
Blood samples will be collected at the following time points: Pre-dose, and post dose at 2 min, 3 min, 5 min, 8 min, 10 min, 15 min, 20 min, 30 min, 45 min, 1 hr, 1.5 hr, 2 hr, 2.5 hr, 3 hr, and 4 hr on Day 1
Secondary outcome [15] 0 0
Group 2: Cp for IH oxytocin and IV oxytocin - Cp will be reported for Cp10, Cp20, and Cp30.
Timepoint [15] 0 0
Blood samples will be collected at the following time points: post dose at 10 min, 120 min, and 30 min on Day 1.
Secondary outcome [16] 0 0
Group 2: Tmax for IH oxytocin and IV oxytocin
Timepoint [16] 0 0
Blood samples will be collected at the following time points: Pre-dose, and post dose at 2 min, 3 min, 5 min, 8 min, 10 min, 15 min, 20 min, 30 min, 45 min, 1 hr, 1.5 hr, 2 hr, 2.5 hr, 3 hr, and 4 hr on Day 1
Secondary outcome [17] 0 0
Group 2: AUC for IH oxytocin and IV oxytocin
Timepoint [17] 0 0
Blood samples will be collected at the following time points: Pre-dose, and post dose at 2 min, 3 min, 5 min, 8 min, 10 min, 15 min, 20 min, 30 min, 45 min, 1 hr, 1.5 hr, 2 hr, 2.5 hr, 3 hr, and 4 hr on Day 1
Secondary outcome [18] 0 0
Group 2: Plasma clearance (CL) for IH oxytocin and IV oxytocin
Timepoint [18] 0 0
Blood samples will be collected at the following time points: Pre-dose, and post dose at 2 min, 3 min, 5 min, 8 min, 10 min, 15 min, 20 min, 30 min, 45 min, 1 hr, 1.5 hr, 2 hr, 2.5 hr, 3 hr, and 4 hr on Day 1
Secondary outcome [19] 0 0
Group 2: T1/2 for IH oxytocin and IV oxytocin
Timepoint [19] 0 0
Blood samples will be collected at the following time points: Pre-dose, and post dose at 2 min, 3 min, 5 min, 8 min, 10 min, 15 min, 20 min, 30 min, 45 min, 1 hr, 1.5 hr, 2 hr, 2.5 hr, 3 hr, and 4 hr on Day 1

Eligibility
Key inclusion criteria
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.

- Subject clinical chemistry and haematology values within an acceptable range for the
population recruited and not of abnormal clinical significance. A subject with a
clinical abnormality or laboratory parameter(s) which is/are not specifically listed
in the inclusion or exclusion criteria, outside the reference range for the population
being studied may be included only if the investigator in consultation with the
Medical Monitor (if required) agree and document that the finding is unlikely to
introduce additional risk factors and will not interfere with the study procedures.

- 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:

Is of reproductive potential and agrees to use the same combined estrogen and progestogen
oral contraceptive from 3 months prior to the first dose of study medication and until the
follow-up contact.

This method of contraception is only effective when used consistently, correctly and in
accordance with the product label. The investigator is responsible for ensuring that
subjects understand how to properly use their method of contraception

- Group 2, Cohort B 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 hCG test), not lactating,
and one of the following conditions applies:

Is of reproductive potential and has been using the same non-hormonal contraceptive method
from 3 months prior to the first dose of study medication and until the follow-up contact.

Would be of reproductive potential, but has undergone bilateral tubal ligation or occlusion
or bilateral salpingectomy at least 12 months prior to first dose of study medication.

Is of reproductive potential with only same sex partners or who are and will continue to be
abstinent from penile-vaginal intercourse on a long term and persistent basis, when this is
their preferred and usual lifestyle. Periodic abstinence (e.g. calendar, ovulation,
symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of
contraception.

These methods of contraception are only effective when used consistently, correctly and in
accordance with the product label. The investigator is responsible for ensuring that
subjects understand how to properly use their method(s) of contraception.

Of Note: Group 2, Cohort B will enrol women of reproductive potential if they agree to use
a nonhormonal contraceptive method from at least one month prior to receiving study drug
and until the follow-up assessment. Although condoms with spermicide are not considered a
highly effective method of contraception, the risk of receiving study drug during pregnancy
is minimal for the following reasons:

Pregnancy testing must be negative at screening and on the first day of dosing. Dosing is
completed no greater than 14 days from the start of dosing. Oxytocin has a well established
rapid half-life. If a patient happened to conceive during the time of dosing, study drug
would be eliminated before implantation would occur.

- All Groups: Capable of giving signed informed consent as described in Protocol which
includes compliance with the requirements and restrictions listed in the consent form
and in this protocol.
Minimum age
18 Years
Maximum age
40 Years
Gender
Females
Can healthy volunteers participate?
Yes
Key exclusion criteria
All Groups:

- Postmenopausal as defined by gynaecological history.

- Chronic lung condition of any etiology including asthma, Chronic obstructive pulmonary
disease (COPD), emphysema, interstitial lung disease or active Tuberculosis (TB).

- Current or chronic history of liver disease, or known hepatic or biliary abnormalities
(with the exception of Gilbert's syndrome or asymptomatic gallstones).

- Blood pressure >140 systolic or >90 diastolic.

Group 1 Only:

- Females with planned Caesarean Section.

- Females with significant medical complications as determined by investigator.

Group 2 Only:

- Currently breastfeeding or lactating.

- QT duration corrected for heart rate by Fridericia's formula (QTcF) >450 milliseconds
(msec).

- Alanine aminotransferase (ALT) and bilirubin >1.5 Upper Limit of Normal (ULN)
(isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct
bilirubin <35%).

- Subjects with highly-active or symptomatic gynaecological disorders (such as large
symptomatic fibroids).

All Groups:

- Prescription or non-prescription drugs not approved by the investigator.

- Oxytocin for any reason (including, but not limited to, induction or augmentation of
labour) prior to administration of study-related oxytocin.

- History of regular alcohol consumption within 6 months of the study defined as: An
average weekly intake of >14 units. One unit is equivalent to 8 grams (g) of alcohol:
a half-pint (approximately 240 milliliter [ml]) of beer, 1 glass (125 ml) of wine or 1
(25 ml) measure of spirits.

- Current smokers or subjects with a history of smoking within 6 months of screening, or
with a total pack year history of >5 pack years. Confirmatory use via a Smokerlyzer is
at the discretion of the local investigator, but is advised if the subject's recent
smoking history is in doubt.

- History of sensitivity to any of the study medications, or components thereof, or a
history of drug or other allergy that, in the opinion of the investigator or Medical
Monitor, contraindicates their participation (e.g. allergy to any previous inhaler
use).

- Participation in another clinical trial, which in the opinion of the investigator,
jeopardizes the subject's safety or study outcomes.

- Where participation in the study would result in donation of blood or blood products
in excess of 500 mL within 56 days.

- The subject has participated in a clinical trial and has received an investigation
product within the following time period prior to the first dosing day in the current
study: 30 days or twice the duration of the biological effect of the investigational
product (whichever is longer).

- Exposure to more than four new chemical entities within 12 months prior to the first
dosing day.

Group 2 Only:

- Presence of hepatitis B surface antigen or positive hepatitis C antibody test result.

- A positive Human Immunodeficiency Virus (HIV) antibody test.

- A positive pre-study drugs of abuse test (not explained by diet or approved
concomitant medications).

- A positive alcohol breath test.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Terminated
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 0 0
GSK Investigational Site - Clayton
Recruitment postcode(s) [1] 0 0
3168 - Clayton
Recruitment outside Australia
Country [1] 0 0
United Kingdom
State/province [1] 0 0
Cambridgeshire
Country [2] 0 0
United Kingdom
State/province [2] 0 0
Cambridge

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
GlaxoSmithKline
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
InVentiv Clinique
Address [1] 0 0
Country [1] 0 0
Other collaborator category [2] 0 0
Other
Name [2] 0 0
Monash University
Address [2] 0 0
Country [2] 0 0

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/show/NCT02999100
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
GSK Clinical Trials
Address 0 0
GlaxoSmithKline
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT02999100