Comparison of Inhaled Oxytocin (IH) With Intramuscular (IM) Oxytocin in Pregnant Women and With Intravenous (IV) Oxytocin in Healthy Non-pregnant Women
Condition: Postpartum Hemorrhage
MeSH terms: Postpartum Hemorrhage; Hemorrhage
Intervention: IH Oxytocin; IM Oxytocin; IV Oxytocin; ROTAHALER
Intervention description: 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).; 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; 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.; ROTAHALER DPI device is a high airflow resistance capsule-based inhaler. It will be used to deliver IH oxytocin
Intervention MeSH terms: Oxytocin
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 31.0
Sex: Female
Minimum age: 18 Years
Maximum age: 40 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: oxytocin; non-pregnant; pregnant; Postpartum Hemorrhage

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.