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

NCT ID: NCT02542813

Last Updated: 2017-10-19

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 16 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-09-14
• Study Completion Date: 2015-12-16

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: FACTORIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

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

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

Group Type: EXPERIMENTAL

IM oxytocin 10 IU

Intervention Type: 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

IH oxytocin 50 mcg

Intervention Type: 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.

IH oxytocin 200 mcg

Intervention Type: 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.

IH oxytocin 400 mcg

Intervention Type: 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.

IH oxytocin 600 mcg

Intervention Type: 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.

Placebo

Intervention Type: 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)

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

Group Type: EXPERIMENTAL

IM oxytocin 10 IU

Intervention Type: 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

IH oxytocin 50 mcg

Intervention Type: 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.

Placebo

Intervention Type: DRUG

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

Interventions

IM 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

Intervention Type: DRUG

IH 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.

Intervention Type: DRUG

IH 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.

Intervention Type: DRUG

IH 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.

Intervention Type: DRUG

IH 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.

Intervention Type: DRUG

Placebo

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

Intervention Type: DRUG

Eligibility Criteria

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.

Exclusion Criteria

• 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).
• Corrected QT interval using Fridericia's formula (QTcF) >450 millisecond (msec) (based on triplicate ECGs).
• Prescription or non-prescription drugs not approved by the investigator, including vaginal prostaglandins within two weeks of dosing.
• History of regular alcohol consumption within 6 months of the study defined as: For United Kingdom (UK) sites: an average weekly intake of >14 units for females. 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.
• History or regular use of tobacco- or nicotine-containing products within one year prior to screening. 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 such as - Allergy to latex; allergy to any previous inhaler use.
• Positive pregnancy test at screening.
• Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment.
• A positive pre-study drug/alcohol screen.
• A positive test for human immunodeficiency virus (HIV) antibody.
• 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 investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives 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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 45 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: Yes

Sponsors

GlaxoSmithKline

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

GSK Clinical Trials

Role: STUDY_DIRECTOR

GlaxoSmithKline

Locations

GSK Investigational Site

Cambridge, , United Kingdom

Countries

United Kingdom

References

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.

Reference Type: DERIVED

PMID: 28781129 (View on PubMed)

Study Documents

Document Type: Statistical Analysis Plan

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Document Type: Annotated Case Report Form

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Document Type: Individual Participant Data Set

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Document Type: Study Protocol

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Document Type: Clinical Study Report

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Document Type: Informed Consent Form

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Document Type: Dataset Specification

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Other Identifiers

201558

Identifier Type: -

Identifier Source: org_study_id