Clinical trial NCT02999100: Comparison of Inhaled Oxytocin (IH) With Intramuscular (IM) Oxytocin in Pregnant Women and With Intravenous (IV) Oxytocin in Healthy Non-pregnant Women
Official 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Postpartum Hemorrhage
Keywords: oxytocin
non-pregnant
pregnant
Postpartum Hemorrhage
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
Collaborators: name: InVentiv Clinique
name: Monash University
First posted: 2016-12-21
Enrollment: 31
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

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.

Primary outcomes:
measure: Part 1: Plasma Concentration Time Profile of Oxytocin
timeFrame: 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
measure: Part 1: Maximum Observed Plasma Concentration (Cmax) of Oxytocin
timeFrame: 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
measure: Part 1: Observed Plasma Concentration (Cp) 10 of Oxytocin
timeFrame: 10 minutes post dose Day 1
measure: Part 1: Observed Plasma Concentration (Cp) 20 of Oxytocin
timeFrame: 20 minutes post dose Day 1
measure: Part 1: Observed Plasma Concentration (Cp) 30 of Oxytocin
timeFrame: 30 minutes post dose Day 1
measure: Part 1: Time to Reach Maximum Observed Concentration (Tmax) of Oxytocin
timeFrame: 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
measure: Part 1: Area Under the Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC[0-t]) of Oxytocin
timeFrame: 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
measure: Part 1: Terminal Phase Half-life (t1/2) of Oxytocin
timeFrame: 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
measure: Part 2: Number of Participants With Non-serious Adverse Events (Non-SAEs) and Serious Adverse Events (SAEs)
timeFrame: Up to 37 days
measure: Part 2: Absolute Values of Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
timeFrame: Pre-dose, 5 minutes, 15 minutes, 30 minutes, 1 hour and 4 hours post dose
measure: Part 2: Change From Baseline in SBP and DBP
timeFrame: Baseline (Day 1, pre-dose), 5 minutes, 15 minutes, 30 minutes, 1 hour and 4 hours post dose
measure: Part 2: Change From Baseline in Heart Rate
timeFrame: Baseline (Day 1, pre-dose), 5 minutes, 15 minutes, 30 minutes, 1 hour and 4 hours post dose
measure: Part 2: Absolute Values of Heart Rate
timeFrame: Pre dose, 5 minutes, 15 minutes, 30 minutes, 1 hour and 4 hours post dose
measure: 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
timeFrame: Pre-dose, 2 minutes, 10 minutes, 20 minutes, 30 minutes, 1 hour and 4 hours post dose
measure: Part 2: Number of Participants With Abnormal Respiratory Events
timeFrame: Up to Day 37
measure: Part 2: Forced Expiratory Volume at 1 Minute (FEV1)
timeFrame: Pre dose and 1 hour post dose on Day1
measure: Part 2: Percent Oxygen in Blood
timeFrame: Pre dose, 5 minutes, 15 minutes, 30 minutes, 1 hour and 4 hours post-dose
measure: Part 2: Absolute Values of Respiration Rate
timeFrame: Pre dose, 5 minutes, 15 minutes, 30 minutes, 1 hour and 4 hours post-dose
measure: Part 2: Plasma Concentration Time Profile of Oxytocin.
timeFrame: -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
measure: Part 2: Maximum Observed Plasma Concentration (Cmax) of Oxytocin
timeFrame: -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
measure: Part 2: Observed Plasma Concentration (Cp)10 of Oxytocin
timeFrame: 10 minutes post dose
measure: Part 2: Observed Plasma Concentration (Cp)20 of Oxytocin
timeFrame: 20 minutes post dose
measure: Part 2: Observed Plasma Concentration (Cp)30 of Oxytocin
timeFrame: 30 minutes post dose
measure: Part 2: Time to Reach Maximum Observed Concentration (Tmax) of Oxytocin
timeFrame: -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
measure: Part 2: Area Under the Concentration-time Curve From Time Zero Extrapolated to Time 't' (AUC[0-t]) of Oxytocin
timeFrame: -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
measure: Part 2: Plasma Clearance (CL) of Oxytocin for IV Route Only
timeFrame: -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
measure: Part 2: Volume of Distribution (VOD) of Oxytocin for IV Route Only
timeFrame: -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
measure: Part 2: Time to Reach Terminal Phase Half-life (t1/2) of Oxytocin
timeFrame: -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:
measure: Part 1: Number of Participants With Non-SAEs and SAEs
timeFrame: Up to 15 days
measure: Part 1: Absolute Values for Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
timeFrame: 30 minutes and 2 hours post dose
measure: Part 1: Absolute Values of Heart Rate
timeFrame: 30 minutes and 2 hours post dose
measure: Part 1: Absolute Values of Respiration Rate
timeFrame: 30 minutes and 2 hours post dose
measure: Part 1: Absolute Values of Temperature
timeFrame: 30 minutes and 2 hours post dose
measure: Part 1: Change From Baseline in SBP and DBP
timeFrame: Baseline (Day 1, pre-dose), 30 minutes and 2 hours post dose
measure: Part 1: Change From Baseline in Heart Rate
timeFrame: Baseline (Day 1, pre-dose), 30 minutes and 2 hours post dose
measure: Part 1: Change From Baseline in Respiration Rate
timeFrame: Baseline (Day 1, pre-dose), 30 minutes and 2 hours post dose
measure: Part 1: Change From Baseline in Body Temperature
timeFrame: Baseline (Day 1, pre-dose), 30 minutes and 2 hours post dose
measure: Part 1: Area Under the Concentration-time Curve From Time Zero (Pre-dose) to Three Hours (AUC ([0-3]) of Oxytocin
timeFrame: Predose, 3 minutes, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 1 hour, 2 hours, 2.5 hours and 3 hours post dose on Day 1
Other outcomes:
Locations:
city: Clayton
country: Australia
facility: GSK Investigational Site
state: Victoria
city: Cambridge
country: United Kingdom
facility: GSK Investigational Site
state: Cambridgeshire
city: Cambridge
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: