Safety, Tolerability and Pharmacokinetics (PK) Study of Oxytocin (GR121619) Administered Via an Inhaled Route in Healthy Female Volunteers

NCT02542813 | Completed Phase 1

• 1 other identifier: 201558
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

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.

Conditions

Postpartum Hemorrhage

Keywords

Pharmacokinetics; safety; tolerability; oxytocin

Outcome Measures

Primary Outcomes (13)

• Number of subjects with adverse events (AEs)

  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.

  Up to 16 weeks

• Absolute values and changes over time of haematology from pre-dose values as a measure of safety and tolerability

  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.

  Up to 20 weeks

• Absolute values and changes over time of clinical chemistry from pre-dose values as a measure of safety and tolerability

  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.

  Up to 20 weeks

• Absolute values and changes over time of urinalysis from pre-dose values as a measure of safety and tolerability

  Dipstick method will be used to measure pH, glucose, protein, blood and ketones.

  Up to 20 weeks

• Absolute values and changes over time of blood pressure from pre-dose values as a measure of safety and tolerability

  Three readings of blood pressure will be taken at screening (single readings at all other time-points).

  Up to 20 weeks

• Absolute values and changes over time of pulse rate from pre-dose values as a measure of safety and tolerability

  Three readings of pulse rate will be taken at screening (single readings at all other time-points).

  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 heart rate from pre-dose values as a measure of safety and tolerability.

  Up to 20 weeks

• 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

  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.

  Up to 20 weeks

• 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

  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.

  Up to 16 weeks

• Plasma concentration profile for IH oxytocin

  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 \[Dosing Sessions 2 -4\]).

  Day 1, 2, and 3 of dosing session 1, and Day 1 of dosing session 2, 3, and 4

• Plasma concentration profile for 10 IU 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.

  Day 1, 2, and 3 of dosing session 1, and Day 1 of dosing session 2, 3, and 4

• 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)

  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 \[Dosing Sessions 2 -4\]).

  Day 1, 2, and 3 of dosing session 1, and Day 1 of dosing session 2, 3, and 4

• Composite PK parameters for 10 IU IM oxytocin: Cmax, Clast, tmax, AUC and t1/2

  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.

  Day 1, 2, and 3 of dosing session 1, and Day 1 of dosing session 2, 3, and 4

Secondary Outcomes (1)

• 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

Study Arms (2)

IM oxytocin - IH placebo/IH oxytocin (50, 200, 400, 600)

EXPERIMENTAL

Subjects will receive IM oxytocin, IH placebo/IH oxytocin at doses of 50, 200, 400, 600 mcg.

Drug: IM oxytocin 10 IU; Drug: IH oxytocin 50 mcg; Drug: IH oxytocin 200 mcg; Drug: IH oxytocin 400 mcg; Drug: IH oxytocin 600 mcg; Drug: Placebo

IM oxytocin - IH placebo/IH oxytocin (50)

EXPERIMENTAL

Subjects will receive IM oxytocin and IH placebo and/or IH oxytocin at 50 mcg.

Drug: IM oxytocin 10 IU; Drug: IH oxytocin 50 mcg; Drug: Placebo

Interventions

IM oxytocin 10 IU DRUG

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

IM oxytocin - IH placebo/IH oxytocin (50); IM oxytocin - IH placebo/IH oxytocin (50, 200, 400, 600)

IH oxytocin 50 mcg DRUG

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.

IM oxytocin - IH placebo/IH oxytocin (50); IM oxytocin - IH placebo/IH oxytocin (50, 200, 400, 600)

IH oxytocin 200 mcg DRUG

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.

IM oxytocin - IH placebo/IH oxytocin (50, 200, 400, 600)

IH oxytocin 400 mcg DRUG

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.

IM oxytocin - IH placebo/IH oxytocin (50, 200, 400, 600)

IH oxytocin 600 mcg DRUG

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.

IM oxytocin - IH placebo/IH oxytocin (50, 200, 400, 600)

Placebo DRUG

Placebo is a powder blend for inhalation in a hard capsule containing five inactive components, which is administered by oral inhalation.

IM oxytocin - IH placebo/IH oxytocin (50); IM oxytocin - IH placebo/IH oxytocin (50, 200, 400, 600)

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• Postmenopausal female as defined by gynaecological history.
• Chronic lung condition of any aetiology including adult asthma, chronic obstructive pulmonary disease (COPD), emphysema and interstitial lung diseases.
• Previous or current clinical history of proven pulmonary or systemic tuberculosis (TB).
• Proven or suspected respiratory tract infection / pneumonia of any aetiology within 4 weeks of screening.
• Current history of smoking and previous smokers within one year of the screening visit (if unsure about cessation of smoking status please refer to guidance below in "Relevant Habits".
• History of pulmonary embolus, pulmonary hypertension of any aetiology, and peripheral venous thromboembolism.
• Average baseline systolic blood pressure (SBP) \<=100 millimeter of mercury (mmHg) at three separate readings.
• Use of an intrauterine device (IUD) within last 3 months.
• Any pregnancy within last 12 months.
• Gynaecological disorders or other diseases which can increase the risk of pelvic fibrosis are excluded, since acute uterine rupture after administration of oxytocin in postpartum women has been associated with a history of Caesarean section, possibly caused by intrauterine / pelvic scarring: a) Previous ectopic pregnancy, b) Previous pelvic, abdominal or lower spinal radiotherapy for any indication, c) Previous laparotomy for any abdominal or gynaecological indication, except no more than two previous caesarean-section(s), Previous gynaecological or urological history including endometrosis, adenomyosis, fibroids, or local bladder surgery.
• ALT and bilirubin \>1.5x upper limit of normal (ULN) (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (1)

GSK Investigational Site

Cambridge, CB2 2GG, United Kingdom

Location

Related Publications (1)

• Fernando D, Siederer S, Singh S, Schneider I, Gupta A, Powell M, Richards D, McIntosh MP, Lambert P, Fowles S. Safety, Tolerability and Pharmacokinetics of Single Doses of Oxytocin Administered via an Inhaled Route in Healthy Females: Randomized, Single-blind, Phase 1 Study. EBioMedicine. 2017 Aug;22:249-255. doi: 10.1016/j.ebiom.2017.07.020. Epub 2017 Jul 22.

  PMID: 28781129 DERIVED

Related Links

• Results for study 201558 can be found on the GSK Clinical Study Register.

MeSH Terms

Conditions

Postpartum Hemorrhage

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

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 3, 2015
• First Posted: September 7, 2015
• Study Start: September 14, 2015
• Primary Completion: December 16, 2015
• Study Completion: December 16, 2015
• Last Updated: October 19, 2017

Record last verified: 2017-10

Data Sharing

• IPD Sharing: Will share

Locations

GB (1)