Postpartum Hemorrhage
Conditions
Keywords
Pharmacokinetics, safety, tolerability, oxytocin
Brief summary
Intramuscular (IM) oxytocin is the gold standard prophylactic therapy for post partum haemorrhage (PPH). However, in resource-poor settings within the developing world, the stability and therefore effectiveness of prophylactic IM oxytocin is diminished by a lack of appropriate refrigeration facilities and availability of trained health care professionals (HCPs) to administer IM injections. This study will be the first investigation of oxytocin in humans via the inhaled (IH) route and is designed to evaluate the safety and tolerability of inhaled oxytocin and the five non-pharmacologically active components in the placebo, and to establish the PK characteristics of up to four fixed escalating doses of inhaled oxytocin. In this single blind ascending dose-escalation study, the systemic exposure from up to four proposed escalating inhaled fixed-dose levels (50 micrograms \[mcg\], 200 mcg, 400 mcg and 600 mcg) will be compared with the systemic exposure following 10 international units (IU) of IM oxytocin in healthy premenopausal females.. A total of 15 subjects will be enrolled after screening sufficient number of healthy female subjects and the subjects will be assigned to one of the two treatment sequences. The total duration of this study is approximately 20 weeks.
Interventions
DRUGIM oxytocin 10 IU
IM oxytocin 10 IU is a colourless and clear sterile solution in a 1 mL ampoule containing 10 IU of oxytocin, which is administered intramuscularly
DRUGIH oxytocin 50 mcg
IH oxytocin 50 mcg is a powder blend for inhalation in a hard capsule containing 50 mcg of oxytocin, which is administered by oral inhalation.
DRUGIH oxytocin 200 mcg
IH oxytocin 200 mcg is a powder blend for inhalation in a hard capsule containing 200 mcg of oxytocin, which is administered by oral inhalation.
DRUGIH oxytocin 400 mcg
IH oxytocin 400 mcg is a powder blend for inhalation in a hard capsule containing 400 mcg of oxytocin, which is administered by oral inhalation.
DRUGIH oxytocin 600 mcg
IH oxytocin 600 mcg is a powder blend for inhalation in a hard capsule containing 600 mcg of oxytocin, which is administered by oral inhalation.
DRUGPlacebo
Placebo is a powder blend for inhalation in a hard capsule containing five inactive components, which is administered by oral inhalation.
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Between 18 and 45 years of age inclusive, at the time of signing the informed consent. * Premenopausal women on an oestrogen-containing oral contraceptive pill (OCP) for a 12 month minimum period and to continue their current OCP schedule for the duration of the clinical study and until completion of the follow-up visit. * Physically capable of using an oral inhalation dry powder inhaler (DPI) device without physical assistance. * FEV1.0 within normal range at screening. * Healthy as determined by the investigator or medically qualified designee based on a medical evaluation including medical history, physical examination, laboratory tests and 12-lead ECG. 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. * Body mass index (BMI) within the range 18 - 30 kilogram (kg)/square meter (m\^2) (inclusive). * Only females may participate. A female subject is eligible to participate if she is not pregnant (as confirmed by a negative serum human chorionic gonadotrophin (hCG) test), not lactating, and at least one of the following conditions applies: The investigator is responsible for ensuring that subjects are reminded during the study of the importance of maintaining compliance to oral contraception. * 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Composite PK parameters for 10 IU IM oxytocin: Cmax, Clast, tmax, AUC and t1/2 | Day 1, 2, and 3 of dosing session 1, and Day 1 of dosing session 2, 3, and 4 | Blood samples will be withdrawn from subjects at pre dose, 3 mins, 5 mins, 10 mins, 20 mins, 0.5 h, 0.75 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, and 8 h. |
| Absolute values and changes over time of urinalysis from pre-dose values as a measure of safety and tolerability | Up to 20 weeks | Dipstick method will be used to measure pH, glucose, protein, blood and ketones. |
| Absolute values and changes over time of blood pressure from pre-dose values as a measure of safety and tolerability | Up to 20 weeks | Three readings of blood pressure will be taken at screening (single readings at all other time-points). |
| Absolute values and changes over time of pulse rate from pre-dose values as a measure of safety and tolerability | Up to 20 weeks | Three readings of pulse rate will be taken at screening (single readings at all other time-points). |
| Number of subjects with adverse events (AEs) | Up to 16 weeks | 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. |
| Absolute values and changes over time of haematology from pre-dose values as a measure of safety and tolerability | Up to 20 weeks | Hematology assessments will be performed for the following parameters: platelet count, red blood cell (RBC) count, hemoglobin, hematocrit, white blood cells (WBC) (absolute), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), neutrophils, lymphocytes, monocytes, eosinophils, and basophils. |
| Absolute values and changes over time of clinical chemistry from pre-dose values as a measure of safety and tolerability | Up to 20 weeks | Clinical chemistry assessments will be performed for the following parameters: blood urea nitrogen (BUN), creatinine, glucose, potassium, sodium, calcium, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, total and direct bilirubin, total protein, and albumin. |
| Absolute values and changes over time of heart rate from pre-dose values as a measure of safety and tolerability | Up to 20 weeks | Absolute values and changes over time of heart rate from pre-dose values as a measure of safety and tolerability. |
| Absolute values and changes over time of 12-lead electrocardiogram (ECG) parameters (PR, QRS, QT, corrected QT [QTc] intervals) from pre-dose values as a measure of safety and tolerability | Up to 20 weeks | Triplicate 12-lead ECGs will be obtained screening and predose (predose IM oxytocin), and single 12-lead ECGs at all other time-points during the study using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals. |
| Number of subjects with adverse respiratory events as monitored by spirometry including forced expiratory volume in 1 second (FEV1.0) and pulse oximetry as a measure of specific respiratory safety | Up to 16 weeks | FEV1 is the volume exhaled during the first second of a forced expiratory maneuver started from the level of total lung capacity. Pulse oximetry is a procedure used to measure the oxygen level (or oxygen saturation) in the blood. |
| Plasma concentration profile for IH oxytocin | Day 1, 2, and 3 of dosing session 1, and Day 1 of dosing session 2, 3, and 4 | Blood samples will be withdrawn from subjects at pre dose, 3 minutes (mins), 5 mins, 10 mins, 20 mins, 0.5h, 0.75h, 1 hour (h), 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 8 h, and 24 h (24 h post dose assessments only applicable to Dosing Session 1, Group 1 and the first 3 subjects at each new dose level \[Dosing Sessions 2 -4\]). |
| Plasma concentration profile for 10 IU IM oxytocin | Day 1, 2, and 3 of dosing session 1, and Day 1 of dosing session 2, 3, and 4 | Blood samples will be withdrawn from subjects at pre dose, 3 mins, 5 mins, 10 mins, 20 mins, 0.5 h, 0.75 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, and 8 h. |
| Composite PK parameters for IH oxytocin: maximum plasma concentration (Cmax), last quantifiable concentration (Clast), time to Cmax (tmax), area under the plasma concentration-time curve (AUC) and terminal phase half-life (t1/2) | Day 1, 2, and 3 of dosing session 1, and Day 1 of dosing session 2, 3, and 4 | Blood samples will be withdrawn from subjects at pre dose, 3 mins, 5 mins, 10 mins, 20 mins, 0.5 h, 0.75 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 8 h, and 24 h (24 h post dose assessments only applicable to Dosing Session 1, Group 1 and the first 3 subjects at each new dose level \[Dosing Sessions 2 -4\]). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Composite of PK parameters: Cmax and AUC will be compared as data permit | Day 1, 2, and 3 of dosing session 1, and Day 1 of dosing session 2, 3, and 4 | For IM oxytocin: Blood samples will be withdrawn from subjects at pre dose, 3 mins, 5 mins, 10 mins, 20 mins, 0.5 h, 0.75 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, and 8 h.For IH oxytocin: Blood samples will be withdrawn from subjects at pre dose, 3 mins, 5 mins, 10 mins, 20 mins, 0.5 h, 0.75 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 8 h, and 24 h (24 h post dose assessments only applicable to Dosing Session 1, Group 1 and the first 3 subjects at each new dose level \[Dosing Sessions 2 -4\]). |
Countries
United Kingdom
Outcome results
None listed