Clinical trial NCT02999100
Conditions: Postpartum Hemorrhage
Keywords: oxytocin non-pregnant pregnant Postpartum Hemorrhage
Sponsor: GlaxoSmithKline
Start date: 2016-11-23; Completion date: 2019-03-04
Enrollment: 31 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Detailed description:

Arms: arm 1: Women with an uncomplicated pregnancy in third stage of labour will be enrolled in the arm. Subjects will receive 400 micrograms (mcg) IH oxytocin. Subjects will be followed up in-person or via telephone within approximately 24 hr post dose and once between 7 days to 14 days arm 2: Women with an uncomplicated pregnancy in third stage of labour will be enrolled in the arm. Subjects will receive 10 I.U. IM oxytocin. Subjects will be followed up in-person or via telephone within approximately 24 hr post dose and once between 7 days to 14 days arm 3: Group 2 will enrol healthy, non-pregnant, non-lactating female subjects of childbearing potential, and each subject will participate in 2 dosing sessions. Group 2 will be divided into two cohorts: Cohort A will enrol women on a combined oral contraceptive, and Cohort B will enrol women who are not using a hormonal form of contraceptive. Group 2 subjects will randomized to receive IH oxytocin, and IV oxytocin in a cross fashion. Subjects will be followed up in-person once between 7 days to 21 days
Interventions: intervention 1: IH Oxytocin intervention 2: IM Oxytocin intervention 3: IV Oxytocin intervention 4: ROTAHALER
Intervention descriptions: intervention 1: 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). intervention 2: 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 intervention 3: 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. intervention 4: ROTAHALER DPI device is a high airflow resistance capsule-based inhaler. It will be used to deliver IH oxytocin

Protocol documents:
Prot_000.pdf: 
2016N281575_03
CONFIDENTIAL
The GlaxoSmithKline group of companies
205920
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
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
Compound Number:
GR121619
Development Phase:
I
Effective Date:
30-MAY-2018
Protocol Amendment Number: 03
Author (s):
 
Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2016N281575_00
2016-AUG-22
Original
2016N281575_01
2016-OCT-10
Amendment No. 1
Section 6.2: Inclusion of information on CE marking
2016N281575_02
2018-JAN-04
Amendment No. 2
Update to PK collection procedures and implementation of in-stream PK data analysis.
Update to location of Secondary Medical Monitor contact information
2016N281575_03
30-MAY-2018
Amendment No. 3
Modification to informal interim and Group 2 analysis plans.
Copyright 2018 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
2019N402257_00
PPD


 
2019N402257_00
PPD
PPD


2016N281575_03
CONFIDENTIAL
205920
3
MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information: 
Role
Name
Day Time Phone Number 
and email address
After-hours 
Phone/Cell/
Pager 
Number
Fax 
Number
Site 
Address
Primary 
Medical 
Monitor 
GSK
Gunnels 
Wood 
Road
Stevenage
SG1 2NY
UK
Secondary 
Medical 
Monitor
Name and 
contact 
details 
available in 
Study 
Reference 
Manual
SAE contact  
information 
Medical 
monitor as 
above 
Sponsor Legal Registered Address:
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline (GSK)
Affiliate Company (or designee). If applicable, the details of the alternative Sponsor and 
contact person in the territory will be provided to the relevant regulatory authority as part 
of the clinical trial application.   
Regulatory Agency Identifying Number(s): EudraCT 2016-002672-27
 
2019N402257_00
PPD


2016N281575_03
CONFIDENTIAL
205920
4
INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number 205920:
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
5
TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 205920........................................................9
2.
INTRODUCTION....................................................................................................13
2.1.
Study Rationale ..........................................................................................14
2.2.
Brief Background ........................................................................................15
2.2.1.
IH Oxytocin FTIH Study 201558 ..................................................16
2.2.2.
PK Specimen Stability as Observed in 205920 ............................16
3.
OBJECTIVES AND ENDPOINTS...........................................................................17
3.1.
Group 1: Women in TSL .............................................................................17
3.2.
Group 2: Non-pregnant, non-lactating females of child bearing 
potential......................................................................................................18
3.3.
Groups 1 and 2: Women in TSL and Non-pregnant, non-lactating 
females of child bearing potential................................................................19
4.
STUDY DESIGN ....................................................................................................19
4.1.
Overall Design ............................................................................................19
4.1.1.
Study Schematic Group 1: Women in TSL...................................19
4.1.2.
Study Schematic Group 2: Non-pregnant, non-lactating 
females of child bearing potential.................................................19
4.1.3.
Study Design Detail .....................................................................19
4.1.3.1.
Pregnant Females (Group 1)......................................20
4.1.3.2.
Non-pregnant Females (Group 2)...............................20
4.1.4.
ROTAHALER Inhaler Training .....................................................21
4.1.5.
Length of Stay for All Subjects.....................................................21
4.2.
Treatment Arms and Duration.....................................................................22
4.3.
Type and Number of Subjects.....................................................................23
4.4.
Design Justification.....................................................................................23
4.5.
Dose Justification........................................................................................23
4.6.
Benefit:Risk Assessment ............................................................................26
4.6.1.
Risk Assessment .........................................................................26
4.6.2.
Immunogenicity Risk....................................................................29
4.6.3.
Benefit Assessment and Overall Benefit:Risk Conclusion............29
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............30
5.1.
Inclusion Criteria.........................................................................................30
5.2.
Exclusion Criteria........................................................................................33
5.3.
Screening/Baseline/Run-in Failures............................................................35
5.3.1.
Re-screening ...............................................................................35
5.4.
Withdrawal/Stopping Criteria.......................................................................35
5.4.1.
Pregnancy Complication Stopping Criteria (Group 1 Only) ..........35
5.4.2.
Anaphylaxis Stopping Criteria......................................................36
5.4.3.
QTc Stopping Criteria (Group 2 Only)..........................................36
5.4.4.
Blood Pressure Stopping Criteria (Group 2 Only).........................36
5.4.5.
Liver Chemistry Stopping Criteria ................................................36
5.4.6.
Plasma oxytocin concentration stopping criteria...........................37
5.5.
Subject and Study Completion....................................................................37
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
6
6.
STUDY TREATMENT ............................................................................................37
6.1.
Investigational Product and Other Study Treatment....................................37
6.2.
Medical Devices..........................................................................................38
6.3.
Treatment Assignment................................................................................38
6.4.
Planned Dose Adjustments.........................................................................39
6.4.1.
Dose Adjustment .........................................................................39
6.5.
Blinding.......................................................................................................40
6.6.
Packaging and Labeling..............................................................................40
6.7.
Preparation/Handling/Storage/Accountability..............................................40
6.8.
Compliance with Study Treatment Administration.......................................41
6.9.
Treatment of Study Treatment Overdose....................................................42
6.10.
Treatment after the End of the Study ..........................................................43
6.11.
Lifestyle and/or Dietary Restrictions............................................................43
6.11.1.
Meals and Dietary Restrictions ....................................................43
6.11.2.
Caffeine and Alcohol....................................................................43
6.11.3.
Activity .........................................................................................44
6.12.
Concomitant Medications and Non-Drug Therapies....................................44
6.12.1.
Permitted Medications and Non-Drug Therapies..........................44
6.12.2.
Prohibited Medications and Non-Drug Therapies.........................44
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................45
7.1.
Time and Events Table...............................................................................46
7.1.1.
Time and Events Table – General Overview................................46
7.1.2.
Time and Events – Main Phase Procedures ................................48
7.2.
Screening and Critical Baseline Assessments ............................................50
7.3.
Safety .........................................................................................................50
7.3.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........50
7.3.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................50
7.3.1.2.
Method of Detecting AEs and SAEs ...........................51
7.3.1.3.
Follow-up of AEs and SAEs........................................51
7.3.1.4.
Regulatory Reporting Requirements for SAEs............51
7.3.2.
Adverse Events of Special Interest (AESI)...................................52
7.3.3.
Pregnancy ...................................................................................52
7.3.4.
Medical Device Incidents (Including Malfunctions).......................52
7.3.4.1.
Time Period for Detecting Medical Device 
Incidents.....................................................................52
7.3.4.2.
Follow-up of Medical Device Incidents........................52
7.3.4.3.
Prompt Reporting of Medical Device Incidents 
to GSK........................................................................53
7.3.4.4.
Regulatory Reporting Requirements for 
Medical Device Incidents............................................53
7.3.5.
Physical Exams ...........................................................................53
7.3.6.
Vital Signs....................................................................................53
7.3.7.
Documentation of Labour Events.................................................53
7.3.8.
Electrocardiogram (ECG) (Group 2 Only) ....................................54
7.3.9.
Continuous Cardiac Telemetry (Group 2 Only) ............................54
7.3.10.
Device Acceptability Questionnaire (Group 1 Only) .....................54
7.3.11.
Clinical Safety Laboratory Assessments ......................................54
7.4.
Pharmacokinetics .......................................................................................56
7.4.1.
Blood Sample Collection..............................................................56
7.4.2.
Sample Analysis ..........................................................................56
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
7
7.5.
Biomarkers .................................................................................................57
7.5.1.
Pharmacodynamic Markers .........................................................57
7.5.2.
Immunogenicity............................................................................57
8.
DATA MANAGEMENT ...........................................................................................57
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................57
9.1.
Hypotheses.................................................................................................57
9.2.
Sample Size Considerations.......................................................................58
9.2.1.
Sample Size Sensitivity................................................................58
9.2.2.
Sample Size Re-estimation or Adjustment...................................59
9.3.
Data Analysis Considerations .....................................................................59
9.3.1.
Analysis Populations....................................................................59
9.3.2.
Interim Analyses ..........................................................................59
9.3.2.1.
Informal Interim Reviews ............................................60
9.3.2.2.
In-Stream Analysis of Group 1....................................60
9.3.2.3.
Analysis of Group 2 ....................................................60
9.4.
Key Elements of Analysis Plan ...................................................................60
9.4.1.
Primary Analyses.........................................................................60
9.4.1.1.
Safety Analysis...........................................................60
9.4.1.2.
Pharmacokinetic Analysis...........................................60
9.4.2.
Secondary Analyses ....................................................................61
9.4.2.1.
Pharmacokinetic Analysis...........................................61
9.4.3.
Exploratory Analyses ...................................................................61
9.4.3.1.
Pharmacokinetic Analysis...........................................61
9.4.3.2.
Device Acceptability Questionnaire ............................61
10. STUDY GOVERNANCE CONSIDERATIONS........................................................62
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............62
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................62
10.3.
Quality Control (Study Monitoring) ..............................................................62
10.4.
Quality Assurance.......................................................................................63
10.5.
Study and Site Closure ...............................................................................63
10.6.
Records Retention......................................................................................64
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publicly Available Clinical Trials Registers and Publication....................65
11. REFERENCES.......................................................................................................66
12. APPENDICES........................................................................................................68
12.1.
Appendix 1: Abbreviations and Trademarks................................................68
12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................71
12.3.
Appendix 3: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................73
12.3.1.
Definition of Adverse Events........................................................73
12.3.2.
Definition of Serious Adverse Events...........................................74
12.3.3.
Definition of Cardiovascular Events .............................................75
12.3.4.
Recording of AEs and SAEs ........................................................76
12.3.5.
Evaluating AEs and SAEs............................................................76
12.3.6.
Reporting of SAEs to GSK...........................................................78
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
8
12.4.
Appendix 4: Definition of and Procedures for Documenting Medical 
Device Incidents .........................................................................................79
12.4.1.
Definitions of a Medical Device Incident.......................................79
12.4.2.
Documenting Medical Device Incidents .......................................80
12.5.
Appendix 5: List of Acceptable Methods for Avoiding Pregnancy in 
FRP and Collection of Pregnancy Information ............................................81
12.5.1.
Group 2, Cohort B Only:  List of Acceptable Non-hormonal 
Methods for Avoiding Pregnancy in Females of 
Reproductive Potential (FRP) ......................................................81
12.5.2.
Collection of Pregnancy Information ............................................81
12.5.3.
References ..................................................................................82
12.6.
Appendix 6: Country Specific Requirements...............................................83
12.7.
Appendix 7: Device Acceptability Questionnaire .........................................84
12.8.
Appendix 8: Protocol Changes....................................................................85
12.8.1.
Protocol Amendment 01 ..............................................................85
12.8.2.
Protocol Amendment 02 ..............................................................86
12.8.3.
Protocol Amendment 03 ..............................................................90
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
9
1.
PROTOCOL SYNOPSIS FOR STUDY 205920
Rationale
Post-partum hemorrhage is one of the main causes of maternal mortality in the 
developing world. The World Health Organization (WHO) lists oxytocin on its list of 
‘Essential Medicines’ for Humanity as a preventative treatment for post-partum 
hemorrhage; however, because of its cold-chain storage requirement and parenteral 
administration route, high-quality oxytocin is not always available in resource-poor 
settings. GlaxoSmithKline (GSK) has developed a stable, dry-powder formulation of 
oxytocin to address this unmet need, with the goal of reducing post-partum hemorrhage 
morbidity and mortality in these settings.
This study is being conducted to further assess safety and tolerability of inhaled oxytocin, 
and to characterize the pharmacokinetic (PK) profile of inhaled oxytocin 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 inhaled 
(IH) or intramuscular (IM) oxytocin as active management of the third stage of labour. 
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.
Objectives/Endpoints
Group 1 – Women in Third Stage of Labour (TSL)
Objectives
Endpoints
Primary

To characterize the pharmacokinetics of 
single doses of IH oxytocin and 
10 International Units (I.U.) IM oxytocin in 
women in TSL.

Plasma concentration time profile for IH 
oxytocin and 10 I.U. IM oxytocin.

PK parameters: Maximum observed plasma 
concentration (Cmax), Observed plasma 
concentrations at 10 minutes (min) post-
dose (Cp10), Observed plasma 
concentrations at 20 min post-dose (Cp20), 
Observed plasma concentrations at 30 min 
post-dose (Cp30), Time to Cmax (tmax), 
Area under concentration-time curve (AUC), 
and Terminal phase half-life (t1/2) will be 
calculated as data permit.
Secondary

To evaluate the safety and tolerability of 
inhaled oxytocin.

General safety parameters: adverse events
(AE); absolute values and changes over 
time of vital signs (blood pressure, heart 
rate, respiratory rate, temperature).

To compare pharmacokinetics of IH 
oxytocin to 10 I.U. IM oxytocin in women in 
TSL.

Cmax, Cp10, Cp20, Cp30, Area under the 
concentration-time curve from time zero 
(pre-dose) to three hours (h) (AUC[0-3h]) 
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
10
Objectives
Endpoints
will be compared as data permit.
Exploratory 

Pharmacodynamic effect of IH oxytocin 
and 10 I.U. IM oxytocin in women in TSL.

Pre and post-delivery haemoglobin. 

Participant feedback regarding ease of 
use, instructions, and perceived ability of 
patients to use the ROTAHALER.

Questionnaire results from participants.
Group 2 – Non-pregnant, non-lactating females of child bearing potential
Objectives
Endpoints
Primary

To evaluate the safety and tolerability of IH 
and IV oxytocin.

General safety parameters: adverse events; 
absolute values and changes over time of 
vital signs (blood pressure, heart rate) and 
12-lead electrocardiogram (ECG) 
parameters (PR, QRS, QT, Corrected QT 
interval [QTc] intervals) from pre-dose 
values. 

Specific respiratory safety parameters: 
adverse respiratory events as monitored by 
spirometry including Forced expiratory 
volume at 1 minute (FEV1.0), respiratory 
rate, and pulse oximetry.

To characterize the pharmacokinetics of 
single doses of IH oxytocin and 5 I.U. IV 
oxytocin.

Plasma concentration time profile for IH 
oxytocin and 5 I.U. IV oxytocin.

PK parameters: Cmax, Cp10, Cp20, Cp30, 
tmax, AUC, Plasma clearance (CL), volume 
of distribution and t1/2 will be calculated as 
data permit.
Exploratory 

To evaluate endogenous plasma oxytocin 
concentrations in non-pregnant females in 
the presence and absence of the combined 
oral contraceptive.

Pre-dose plasma concentrations of 
oxytocin.

To compare the IH pharmacokinetics of 
oxytocin between Cohort A (subjects on 
combined oral contraceptive) and Cohort B 
(subjects using a non-hormonal form of 
contraception).

Cp10, Cp20, Cp30, Cmax, AUC(0-3h), 
Area under the concentration-time curve 
from time zero to infinity (AUC[0-∞]) and
t1/2, will be compared as data permit.

To compare the IV pharmacokinetics of 
oxytocin between Cohort A and Cohort B.

Cmax, AUC, t1/2, CL and Volume of 
distribution (VOD) will be compared as 
data permit.
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
11
Groups 1 and 2 – Women in TSL and Non-pregnant, non-lactating females of child bearing 
potential
Objectives
Endpoints
Exploratory 

To compare pharmacokinetics of IH 
oxytocin between Group 1 and Group 2

Cp10, Cp20, Cp30, Cmax, AUC(0-3h) 
AUC(0-∞), and t1/2 will be compared as 
data permit.
Overall Design
Group 1 – Women in TSL
Group 2 – Non-pregnant, non-lactating females of child bearing potential
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
12
Treatment Arms and Duration
Screening
Group 1: All screening assessments to be completed after the 18th
week of pregnancy (based on estimated date of delivery).
Group 2: All screening assessments to be completed within 28 days
prior to the first dose.
Treatment Session
Group 1: Each subject will take part in 1 dosing session.
Group 2: Each subject will take part in 2 dosing sessions.
Treatment Arms1
Group 1: Subjects will be randomised to receive one of the following 
study treatments:

400 micrograms (mcg) IH oxytocin

10 I.U. IM oxytocin
Group 2: Subjects will receive both of the following study treatments 
over the course of two dosing sessions:

400 mcg IH oxytocin

5 I.U. IV oxytocin
Follow-up
Group 1: Follow Up 1 – Within approximately 24 h post dose.
Group 1: Follow Up 2 –  At least 7 days and no greater than 14 days 
after study drug administration.
Both visits may be conducted in-person or via telephone.
Group 2: At least 7 days and no greater than 21 days after last study 
drug administration.
This visit will be conducted in-person.
If warranted, additional follow-up visits may be scheduled for both 
Groups.
Total Duration
Group 1: Screening after 18th week of pregnancy (i.e. within 168 days of 
1 dosing session) + follow up of 7 - 14 days = approximately 183 days
Group 2: Screening within 28 days of dosing session 1 + 2 dosing 
sessions with a maximum of 14 days between dosing + follow-up of 7 –
21 days = 64 days
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
13
Type and Number of Subjects
Sufficient subjects will be screened such that approximately 20 subjects complete all 
study procedures in Group 1, and approximately 10 subjects complete all study 
procedures in Group 2 (approximately 5 in each cohort of Group 2). 
If subjects prematurely discontinue the study, additional replacement subjects may be 
recruited and assigned to the same treatment sequence at the discretion of the Sponsor. 
Replacement subjects will complete all study procedures.
If the PK variability between subjects in Group 1 is higher than expected, it may be 
required to increase the sample size up to a maximum of 10 additional subjects per 
treatment group for inhaled and intramuscular oxytocin. In the event of this, sufficient 
subjects will be screened such that a maximum of 50 subjects complete Group 1.
If a dose adjustment is required in either group, additional subjects may be recruited such 
that a full 10 subjects receive the final IH or IV dose.
Analysis
The primary objective of this study is to characterize pharmacokinetics of IH oxytocin 
and IM oxytocin in women in the third stage of labour.
No formal hypotheses will be tested, however, comparisons of interest, within Group 1,
and between Group 1 and Group 2 and between Cohorts A and B in Group 2 will be 
made and the point estimates and corresponding two-sided 90% confidence intervals (CI)
will be presented to provide the range of plausible values for the comparisons. 
2.
INTRODUCTION
Maternal mortality associated with postpartum hemorrhage (PPH) is one of the major 
public health problems in the developing world. Approximately half a million women 
worldwide die annually from causes directly related to pregnancy and childbirth, and up 
to one third of these deaths in Africa and Asia are caused by complications as a result of 
PPH [Khan, 2006; WHO, 2010]. A Cochrane Review meta-analysis of the data from 
multiple preventative trials with oxytocin at 10 international units (I.U.) given via the 
intramuscular (IM) route has confirmed this specific uterotonic, and this particular route 
of administration, to be the gold standard prophylactic therapy for PPH [Mousa, 2014].
For this reason, the World Health Organization (WHO) has designated oxytocin as one of 
its ‘Essential Medicines’ for humanity [WHO Model List of Essential Medicines 18th list, 
April 2013 (WHO, 2013); WHO Model List of Essential Medicines for Children 4th list, 
April 2013 (WHO, 2013)].
However, in resource-poor settings within the developing world, the 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 
[Mousa, 2014]. Although single-use, oxytocin prefilled, syringes for IM injection are 
available in many developing countries (e.g. UNIJECT device), the development of a 
needle-free and self-administered inhaled (IH) oxytocin product, which delivers 
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
14
comparable systemic exposure to 10 I.U. IM, would be a major step-change in the 
administration of this life-saving medicine to pregnant women in resource-poor regions 
of the developing world. This would be particularly relevant in rural areas where the 
mother has no routine access to a trained HCP and/or where there is no reliable electricity 
supply to permit refrigerated storage of oxytocin injection vials. 
We have developed a stable, dry-powder formulation of oxytocin to be administered via 
the oral inhaled pulmonary route (compared to 10 I.U. of IM oxytocin) using a 
GlaxoSmithKline (GSK)-manufactured medical device (or device manufactured for GSK 
by a third party) which is a capsule-based inhaler (Modified Air Inlet ROTAHALERTM
Dry Powder Inhaler (DPI) device, hereafter referred to as ROTAHALER). This 
formulation and delivery method has the potential to be used in settings where effective 
oxytocin is currently unavailable to women in the third stage of labour (TSL).
2.1.
Study Rationale
This study will be the second investigation of oxytocin in humans via the IH route, which 
follows the first time in human (FTIH) study, 201558 [GlaxoSmithKline Document 
Number 2015N234711_01, 2015; see Section 2.2.1 for more information on the FTIH 
trial]. Published literature on the pharmacokinetics (PK) of oxytocin in non-pregnant and 
pregnant women is limited.  There is some evidence to suggest that the metabolic 
clearance of oxytocin may increase during pregnancy; potentially related to degradation 
by the circulating aminopeptidase, oxytocinase, and/or pregnancy related changes in 
hepatic and renal function [Syntocinon Summary of Product Characteristics, Novartis, 
2014; Thornton, 1990].  In addition, endogenous oxytocin plasma concentrations have 
been reported to either increase or remain constant after the delivery of the fetal anterior 
shoulder [Thornton, 1988]. As a result of these pregnancy related changes, systemic 
exposure to oxytocin may differ between healthy non-pregnant women and women in the 
TSL for a given dose and route of administration of oxytocin. To further understand the 
effect of pregnancy on the PK of oxytocin, this study will investigate the PK of oxytocin 
in pregnant women in TSL following either IH (400 micrograms [mcg]) or 10 I.U. IM 
(17 mcg) administration. A greater understanding of the PK of oxytocin in TSL will help 
facilitate extrapolation of data obtained in healthy non-pregnant women to women in 
TSL. An additional group of  non-pregnant non-lactating female volunteers will also be 
included as a control group and will receive 400 mcg IH oxytocin and 5 I.U. intravenous 
(IV) oxytocin. This second group will enrol one cohort of subjects taking the combined 
oral contraceptive (COC), and another cohort using a non-hormonal form of 
contraception. This will assess if women need to be on an oral contraceptive vs. other 
methods of birth control in future clinical studies, since although the COC is believed to 
suppress endogenous oxytocin levels the literature is not consistent about this 
observation. As the requirement to be taking the COC makes recruitment more of a 
challenge it will be helpful to know if this inclusion is essential, or if women using non-
hormonal forms of birth control might also have sufficiently low systemic oxytocin levels 
suitable for PK studies.
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
15
2.2.
Brief Background
Oxytocin is a nonapeptide which is produced by the hypothalamus and released into the 
systemic circulation by the posterior pituitary gland. Within the brain, oxytocin, like most 
hypothalamic synthesized hormones, acts as a neurotransmitter. In human pregnancy,
during the later phases of the third trimester, increasing circulating levels of oxytocin act 
as a potent endogenous uterotonic which facilitates the initiation of labour. Furthermore, 
a neurohormonal positive feedback loop exists between dilatation of the cervico-vaginal 
canal by fetal passage and the hypothalamus (i.e. Fergusson reflex) which augments 
oxytocin production, thus increasing uterine contraction intensity and frequency which 
facilitates vaginal delivery. However, once the fetus is delivered, plasma oxytocin levels 
rapidly diminish probably due to a combination of increased circulating levels of 
oxytocinase (the principal oxytocin deactivating enzyme), in the plasma, an overall 
reduction in hypothalamic oxytocin synthesis (Figure 1), and a reduction in uterine 
oxytocin receptor (OTR) density. This oxytocin-depleted, relatively auterotonic, 
physiological environment puts the mother at risk of PPH during the subsequent placental 
delivery phase (i.e. TSL). 
Figure 1
Oxytocin During Physiological Fetal Delivery
Oxytocin receptors are constitutively expressed in smooth muscle cells (SMCs) in the 
uterine myometrium, muscular walls of the bronchi and upper digestive tract, 
myoepithelial cells of the breast duct which are essential for the oxytocin-dependent 
postpartum breast milk let-down reflex, and in different regions of the brain.  Although 
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
16
uterine OTR expression increases during the later stages of pregnancy, it is not known 
whether pregnancy increases OTR expression at non-uterine sites, such as the maternal 
brain, where neuronal oxytocin signalling has been implicated in postpartum bonding 
behaviour with the baby. Within the kidney, oxytocin is known to bind to vasopressin 
(V2) receptors, rather than OTR, in the medullary renal collecting duct which triggers an 
antidiuretic effect.
Binding of oxytocin to OTR triggers an increase in intracellular calcium (Ca2+), which is 
partly mediated through oxytocin-dependent up-regulation of prostaglandin F (PGF)2α 
synthesis, which in the uterine myometrium leads to physiological uterine contractions 
during 3rd-stage labour.
More recent research has shown oxytocin to be present in broncho-alveloar lavage fluid 
collected from the respiratory tract of adult humans of both sexes, but oxytocinase 
expression was not assessed. In an in vivo pharmacology study [Prankerd, 2013] in
pregnant ewes intratracheal insufflation of a dry-powder formulation of oxytocin was 
associated with poor absolute bioavailability (ca 5%), but despite low systemic exposure, 
this still caused a pharmacodynamic response that was manifested by increased electrical 
uterine activity measured by electromyography, probably as a result of increased OTR 
stimulation in the pregnant uterus.
2.2.1.
IH Oxytocin FTIH Study 201558
Study 201558 [GlaxoSmithKline Document Number 2016N277949_00] was the FTIH 
study to evaluate safety, tolerability, and characterize the PK profile of 4 dose strengths 
of IH oxytocin compared to oxytocin 10 I.U. IM. The study enrolled 16 healthy, non-
pregnant, premenopausal female subjects. One subject was withdrawn prior to IH 
oxytocin dosing due to inability to cannulate. Subjects were administered 10 I.U. IM 
oxytocin, IH placebo containing (only) the excipients found in the IH oxytocin 
formulation, and IH oxytocin. A minimum washout period of 48 hours (h) was required 
between each dose of active drug. This dose escalation study evaluated 4 doses of IH 
oxytocin: 50 mcg, 200 mcg, 400 mcg, and 600 mcg. The most frequently reported 
Adverse Event (AE) was headache, and occurred in at least one subject in each treatment 
arm. In general, IH oxytocin was well-tolerated, no safety concerns with IH dosing were 
identified, no clinically significant effect on respiratory parameters were observed, and 
no Serious Adverse Events (SAEs) were reported. The PK profile of the 400 mcg IH 
oxytocin dose was similar to that of 10 I.U. IM, and has been selected for further 
evaluation. See Section 4.5 for further information on PK characteristics.
2.2.2.
PK Specimen Stability as Observed in 205920
Prior to the initiation of the current trial, a sample-handling process was developed using 
blood from pregnant subjects of at least 37 weeks gestation to ensure ex-vivo oxytocin 
stability in specimens collected from Group 1 TSL subjects. 
Per protocol, after 10 subjects had completed all procedures in Group 1, an informal 
interim PK analysis was conducted. It was observed that in the majority of the plasma 
samples collected from TSL subjects, oxytocin concentrations were below the limit of 
quantification (BLQ) or at very low concentrations (approximately 3pg/mL) approaching 
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
17
the lower limit of quantification (LLQ) of the assay (2pg/mL). This was seen across both 
IM and IH routes of administration. This was an unexpected finding which has been 
confirmed by re-analysis of selected samples. As such, it is considered that it may be due 
to ex-vivo oxytocin instability related to uninhibited oxytocinase and peptidases, which 
are believed to be at increased concentrations in the plasma of postpartum women 
compared with non-pregnant women, and women at 37 weeks gestation. This finding 
resulted in a temporary halt to the trial.
3.
OBJECTIVES AND ENDPOINTS
3.1.
Group 1: Women in TSL
Objectives
Endpoints
Primary

To characterize the pharmacokinetics of 
single doses of IH oxytocin and 10 I.U. IM 
oxytocin in women in TSL.

Plasma concentration time profile for IH 
oxytocin and 10 I.U. IM oxytocin.

PK parameters: Maximum observed plasma 
concentration (Cmax), Observed plasma 
concentrations at 10 minutes (min) post-
dose (Cp10), Observed plasma 
concentrations at 20 min post-dose (Cp20), 
Observed plasma concentrations at 30 min 
post-dose (Cp30), Time to Cmax (tmax), 
Area under concentration-time curve (AUC), 
and Terminal phase half-life (t1/2) will be 
calculated as data permit.
Secondary

To evaluate the safety and tolerability of 
inhaled oxytocin.

General safety parameters: adverse events; 
absolute values and changes over time of 
vital signs (blood pressure, heart rate, 
respiratory rate, temperature).

To compare pharmacokinetics of IH 
oxytocin to 10 I.U. IM oxytocin in women in 
TSL.

Cmax ,Cp10, Cp20, Cp30, Area under the 
concentration-time curve from time zero 
(pre-dose) to three hours (h) (AUC[0-3h])
will be compared as data permit.
Exploratory 

Pharmacodynamic effect of IH oxytocin 
and 10 I.U. IM in women in TSL.

Pre and post-delivery haemoglobin. 

Participant feedback regarding ease of 
use, instructions, and perceived ability of 
patients to use the ROTAHALER.

Questionnaire results from participants.
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
18
3.2.
Group 2: Non-pregnant, non-lactating females of child 
bearing potential
Objectives
Endpoints
Primary

To evaluate the safety and tolerability of IH 
and IV oxytocin.

General safety parameters: adverse events; 
absolute values and changes over time of 
vital signs (blood pressure, heart rate) and 
12-lead electrocardiogram (ECG) 
parameters (PR, QRS, QT, Corrected QT 
interval [QTc] intervals) from pre-dose 
values. 

Specific respiratory safety parameters: 
adverse respiratory events as monitored by 
spirometry including Forced expiratory 
volume at 1 minute (FEV1.0), respiratory 
rate, and pulse oximetry.

To characterize the pharmacokinetics of 
single doses of IH oxytocin and 5 I.U. IV 
oxytocin.

Plasma concentration time profile for IH 
oxytocin and 5 I.U. IV oxytocin.

PK parameters: Cmax, Cp10, Cp20, Cp30, 
tmax, AUC, Plasma clearance (CL), volume 
of distribution and t1/2 will be calculated as 
data permit.
Exploratory 

To evaluate endogenous plasma oxytocin 
concentrations in non-pregnant females in 
the presence and absence of the combined 
oral contraceptive.

Pre-dose plasma concentrations of 
oxytocin.

To compare the IH pharmacokinetics of 
oxytocin between Cohort A (subjects on 
combined oral contraceptive) and Cohort B 
(subjects using a non-hormonal form of 
contraception).

Cp10, Cp20, Cp30, Cmax, AUC(0-3h), 
Area under the concentration-time curve 
from time zero to infinity (AUC[0-∞]) and 
t1/2, will be compared as data permit.

To compare the IV pharmacokinetics of 
oxytocin between Cohort A and Cohort B.

Cmax, AUC, t1/2, CL and Volume of 
distribution (VOD) will be compared as 
data permit.
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
19
3.3.
Groups 1 and 2: Women in TSL and Non-pregnant, non-
lactating females of child bearing potential
Objectives
Endpoints
Exploratory 

To compare pharmacokinetics of IH 
oxytocin between Group 1 and Group 2.

Cp10, Cp20, Cp30, Cmax, AUC(0-3h) 
AUC(0-∞), and t1/2 will be compared as 
data permit.
4.
STUDY DESIGN
4.1.
Overall Design
4.1.1.
Study Schematic Group 1: Women in TSL
4.1.2.
Study Schematic Group 2: Non-pregnant, non-lactating females 
of child bearing potential
4.1.3.
Study Design Detail
This study will enrol two groups. 
Group 1 - Women in TSL
Group 1 will enrol women with an uncomplicated pregnancy, and main phase procedures 
will occur during TSL. Subjects will be randomized to receive either IH or IM oxytocin 
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
20
as active management of TSL.  The specific timing of this dose will be as per local 
standard of care.1
Group 2 - Non-pregnant, non-lactating females of child bearing potential
Group 2 will enrol healthy, non-pregnant, non-lactating female subjects of childbearing 
potential, and each subject will participate in 2 dosing sessions. Group 2 will be divided 
into two cohorts: Cohort A will enrol women on a combined oral contraceptive, and 
Cohort B will enrol women who are not using a hormonal form of contraceptive. Group 2 
subjects will receive IH oxytocin at one dosing session, and IV oxytocin at the other 
dosing session; the order of IH versus IV oxytocin administration will be randomly 
assigned.
PK samples will be analysed periodically throughout the study duration to enable 
development of the population PK model and derivation of PK parameters via non-
compartmental methods, as data permits.
No formal interim analysis is planned, however, PK samples will be analysed and 
preliminary PK parameters derived following completion of approximately 5 women on 
each treatment group: IH, IM in Group 1 and IH in Group 2 Cohort A in order to assess if 
dose escalation is required.  
4.1.3.1.
Pregnant Females (Group 1)
Subjects will review the study information and if they agree to participate, sign the
informed consent form. For most subjects this is expected to take place at an outpatient
antenatal visit, or additional study-specific screening visit. If a subject meets all 
inclusion/exclusion criteria for the study, she will be eligible for enrolment in the study.
To facilitate recruitment, and provide subjects ample time to consider participation, 
screening may occur any time after 18 weeks gestation (based on estimated date of 
delivery). See time and events (T&E) table in Section 7.1 for details.
4.1.3.2.
Non-pregnant Females (Group 2)
Subjects will review the study information and if they agree to participate, sign the 
informed consent form. If a subject meets all inclusion/exclusion criteria for the study, 
she will be enrolled in the study.
Screening may occur within 28 days prior to randomization for non-pregnant volunteers. 
If a subject falls outside this window prior to randomization and enrolment, she must be 
re-screened. Certain screening procedures may not be required to be repeated; see T&E 
(Section 7.1) for details.
                                                
1 For information only: Standard of care at proposed clinical site is to administer the oxytocic drug by IM 
injection with the birth of the anterior shoulder, or immediately after the birth of the baby and before the 
cord is clamped and cut.
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
21
Group 2 subjects will take part in 2 dosing sessions, which must be conducted a 
minimum of 48 hours apart. It is recommended that subjects complete Session 2 within 
14 days of Session 1. Subjects will be randomized to receive either IH or IV oxytocin 
during Session 1, and to receive the other treatment during Session 2, such that all 
subjects in Group 2 receive both treatments over the course of the 2 sessions.
4.1.4.
ROTAHALER Inhaler Training
The investigator/designee will be trained to load the ROTACAPS powder capsule into 
the device, prime the dose and instruct the subjects to inhale from the ROTAHALER 
inhaler in the appropriate manner (refer to Section 6.7). Subjects will be instructed by the 
investigator/designee to use an inspiration technique (2 inhalations) that enables maximal 
inhalation of the ROTACAPS powder capsule contents (refer to Section 6.7 for full 
details). This will ensure optimal and consistent drug delivery (full instructions available 
in the Study Reference Manual [SRM]). 
4.1.5.
Length of Stay for All Subjects
Group 1 - Women in TSL
Subjects in Group 1 will be admitted to hospital during labour as part of their routine 
care, and will be required to remain inpatient for a minimum of 4 hours after receiving 
any study-related dose of oxytocin. After final PK collection, subjects will be finished 
with study procedures and the main phase of the study will be considered complete. 
Discharge from hospital will be determined by the subject’s medical provider. 
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
22
Group 2 - Non-pregnant, non-lactating females of child bearing potential
Subjects in Group 2 will be admitted to the clinical unit prior to dosing on Day 1 and are 
to remain inpatient until at least 4 hours after dosing. Discharge will occur at the 
discretion of the investigator.
4.2.
Treatment Arms and Duration
Screening
Group 1: All screening assessments to be completed after the 18th
week of pregnancy (based on estimated date of delivery)
Group 2: All screening assessments to be completed within 28 days
prior to the first dose
Treatment Session
Group 1: Each subject will take part in 1 dosing session.
Group 2: Each subject will take part in 2 dosing sessions
Treatment Arms1
Group 1: Subjects will be randomised to receive one of the following 
study treatments:

400 mcg IH oxytocin

10 I.U. IM oxytocin
Group 2: Subjects will receive both of the following study treatments 
over the course of two dosing sessions:

400 mcg IH oxytocin

5 I.U. IV oxytocin
Follow-up
Group 1: Follow Up 1 – Within approximately 24 hours post dose.
Group 1: Follow Up 2 –  At least 7 days and no greater than 14 days 
after study drug administration.
Both visits may be conducted in-person or via telephone. Group 2: At 
least 7 days and no greater than 21 days after last study drug 
administration.
This visit will be conducted in-person.
If warranted, additional follow-up visits may be scheduled for both 
Groups.
Total Duration
Group 1: Screening after 18th week of pregnancy (i.e. within 168 days of 
1 dosing session) + follow up of 7 - 14 days = approximately 183 days
Group 2: Screening within 28 days of dosing session 1 + 2 dosing 
sessions with a maximum of 14 days between dosing + follow-up of 7 –
21 days = 64 days
1 See Section 6.4 for possible dose adjustment to IH oxytocin.
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
23
4.3.
Type and Number of Subjects
Sufficient subjects will be screened such that approximately 20 subjects complete all 
study procedures in Group 1, and approximately 10 subjects complete all study 
procedures in Group 2 (approximately 5 in each cohort of Group 2). Refer to Section 6.3
for treatment assignment information.
If subjects prematurely discontinue the study, additional replacement subjects may be 
recruited and assigned to the same treatment at the discretion of the Sponsor. 
Replacement subjects will complete all study procedures as outlined in Section 7.1.
If the PK variability between subjects in Group 1 is higher than expected, it may be 
required to increase the sample size up to a maximum of 10 additional subjects per 
treatment group for IH and IM.  In the event of this, sufficient subjects will be screened 
such that a maximum of 50 subjects complete Group 1.
If a dose adjustment is required in either group, additional subjects may be recruited such 
that a full 10 subjects receive the final IH or IV dose. See Section 6.4.1 for more details.
4.4.
Design Justification
Group 1 - Women in TSL
This trial uses a randomized, single-dose approach to assign women in TSL to receive 
oxytocin by one of two routes: IM or IH. No placebo is being used, as the current 
standard of care is to administer oxytocin as active management of TSL to prevent PPH.
Group 2 - Non-pregnant, non-lactating females of child bearing potential
A group of non-pregnant, non-lactating women of childbearing potential will receive IH 
and IV oxytocin. This group will be divided into two cohorts: Cohort A will enrol women 
on the combined oral contraceptive. This cohort will serve as a control group, as they 
most closely resemble the population enrolled in the FTIH study. Cohort B will enrol 
women using a non-hormonal form of contraception. This comparison group will help 
characterize the effect of oral contraceptives on endogenous oxytocin production and the 
PK profile of oxytocin.
Blinding
This study uses an open-label design. 
4.5.
Dose Justification
Single inhaled doses of oxytocin (50-600 mcg) have been generally well tolerated in the 
FTIH study, with no emerging safety signals, in healthy, non-pregnant, premenopausal 
female subjects (Study 201558) [GlaxoSmithKline Document Number 
2016N277949_00; see also Section 2.2.1].  Following inhaled administration oxytocin 
was rapidly absorbed into the systemic circulation (tmax ranging from 0.05 to 0.50 h) 
with systemic exposure (Cmax and AUC) increasing with inhaled dose in an 
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
24
approximately proportional manner between 200 and 600 mcg.  In general, the shape of 
the observed oxytocin concentration-time profile following inhaled administration was 
consistent with that following IM administration.
Based on the data from the FTIH study, and assuming that the PK characteristics of IH 
and IM oxytocin are similar in TSL compared with non-pregnant women, the 400 mcg 
inhaled dose is predicted to be an effective dose in women in TSL by ensuring that the 
systemic exposure (Cp10, Cp30 and AUC(0-3 h) following IH dosing is at least that 
following IM administration at the approved dose of 10 I.U. This would be based on the
adjusted geometric mean ratio (90% Confidence Interval [CI]) treatment comparisons for
Cp10, Cp30 and AUC (0-3 h) following 400 mcg IH compared with 10 I.U. IM, namely 
1.10 (0.85,1.43), 1.65 (1.30, 2.09) and 1.27 (1.07, 1.50) respectively in study 201558. 
The PK parameters (Cp10, Cp30 and AUC(0-3 h)) have been selected to ensure onset and 
duration of action of the IH product is at least comparable to IM.
The clinical safety and reported AEs with oxytocin correlates to Cmax, with the Cmax of 
10 I.U. IV representing the upper bounds of what could be considered safe in current 
clinical practice (AEs include flushing, which can cause a transient decrease in blood 
pressure and reflex tachycardia; see the Oxytocin Summary of Product Characteristics for 
more information). The recommendation in the United Kingdom (UK) in clinical practice 
has been to reduce the IV dose to 5 I.U. IV or administer by a controlled IV infusion 
[Bolton, 2003].
Minimising the risk of high Cmax levels of oxytocin following the IH administration is 
therefore important.  Based on a comparison of  model predicted systemic exposure 
following IV administration to non-pregnant, premenopausal female subjects with 
observed PK profiles following 400 mcg IH oxytocin, it is anticipated that Cmax 
following administration of the 400 mcg dose will not markedly exceed values following 
5 I.U. IV bolus oxytocin (Figure 2). The inclusion of the 5 I.U. IV dose will allow an 
assessment of the potential safety and PK of the inhaled formulation compared to IV 
route of administration.
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
25
Figure 2
Model predicted profiles (median (95%PI)) following IM (10 I.U. and 
IV bolus (5 I.U. administration of oxytocin overlaid with observed 
plasma concentrations of oxytocin following 400 mcg IH oxytocin to 
healthy non-pregnant females
Whilst published literature on the PK of oxytocin in non-pregnant and pregnant women is 
limited there is some evidence to suggest that the metabolic clearance of oxytocin may 
increase during pregnancy. This may be related to degradation by the circulating 
aminopeptidase, oxytocinase, and/or pregnancy-related changes in hepatic and renal 
function [Syntocinon, 2014; Thornton, 1990]. In addition, there may be circulating levels 
of endogenous oxytocin in the plasma in women in TSL [Thornton, 1988] and increases 
in blood volume (40-50%) and total body water [Costantine, 2014]. As a result of these 
pregnancy related changes, systemic exposure to oxytocin may differ between healthy 
non-pregnant women and women in TSL for a given dose and route of administration of 
oxytocin. However, given that any pregnancy-related changes in systemic clearance, 
and/or distribution and baseline oxytocin levels, are considered to equally impact on each 
route of administration (IV, IM and IH), it is considered that the relative ratio of IV to IM 
and IH exposure observed in non-pregnant women is likely to be maintained in 
pregnancy. The only exception may be if pregnancy results in marked changes in 
absorption profiles.  However, in a study of inhalation profiles of non-pregnant and 
women in the third stage of labour, the inhalation endpoints appeared to be broadly 
similar across the two cohorts and any small changes are not considered to markedly 
impact the delivery of an inhaled product in the third stage of labour [GlaxoSmithKline 

= Observed 400 mcg IH oxytocin plasma concentration in study 
5  I.U. IV oxytocin
10 I.U. IM oxytocin
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
26
Document Number 2015N239682_00]. In addition, in a pre-clinical sheep model the ratio 
IH:IV was generally similar in non-pregnant and post-partum ewes (Data on file 
Monash). In the event of enhanced pulmonary absorption in pregnancy, the selected 
400 mcg inhaled dose is predicted to have an approximate 2-fold safe cover for Cmax 
compared with an 10 I.U. IV bolus oxytocin (assumes linearity from 5 -10 I.U. IV). 
4.6.
Benefit:Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
GR121619 can be found in the Investigator’s Brochure [GlaxoSmithKline Document 
Number 2015N240749_01] and oxytocin for parenteral administration [Syntocinon, 
2014]. The following section outlines the risk assessment and mitigation strategy for this 
protocol:  
4.6.1.
Risk Assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
Investigational Product (IP) – Inhaled Oxytocin – GR121619 
Bronchospasm, cough and 
dyspnoea, with increased 
theoretical risk in asthmatic 
subjects.
Oxytocin receptors are known 
to be expressed in human 
bronchial smooth muscle and 
up regulated by interleukin 
(IL)-13. Therefore, there is a 
hypothetical risk of 
bronchospasm, cough and 
dyspnoea. 
See Section 5.2 for exclusion 
criteria.
The oxytocin summary of 
product characteristics (SPC) 
does not list asthma as a 
contraindication to 
administration. 
Symptomatic wheezing may 
be treated with bronchodilator 
at the discretion of the 
investigator.
Forced expiratory volume at 1 
minute (FEV1) monitoring for 
both paradoxical and oxytocin 
induced bronchospasm
Subjects with asthma or 
known pulmonary disease are 
excluded.
Hypotension, tachycardia and 
prolongation of QTc interval
Transient flushing, 
hypotension and tachycardia 
could be observed if the IH PK 
profile is comparable to an IM
or IV oxytocin profile. 
Effects of oxytocin on the 
Cardiovascular system (CVS) 
is unclear and contradictory in 
Ongoing assessments of study 
subjects’ cardiovascular 
function including blood 
pressure (BP), heart rate (HR) 
and ECG.
Only single-dose IH, IM, or 
5 IU IV bolus injection routes 
of administration will be used 
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
27
Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
the literature but IV 
administered oxytocin can 
have a vasodilatory and 
negative inotropic effect in 
humans. Hypotension is 
thought to arise as a result of 
vascular smooth muscle 
relaxation and oxytocin 
binding to cardiac atrial OTR 
which leads to atrial natriuetic 
peptide (ANP) being 
transiently released into the 
systemic circulation. 
Prolongation of the QTc 
interval has been reported at 
the time of caesarean delivery  
with 10 IU IV oxytocin 
administration, rather than IM 
injection, in susceptible 
individuals
as study treatment. Telemetry 
and frequent 12-lead ECGs 
will be used to monitor the 
healthy subject cohorts
The 5 IU IV dose of oxytocin is 
the standard dose 
administered at the Rosie 
Maternity hospital post 
Caesarean Section.
IV bolus will be given as a 
slow IV injection over 30 
seconds with the option to 
change to a 5 minute infusion 
if frequent CV adverse effects 
are observed
Exclusion of subjects with long 
QT syndrome, congenital 
cardiac abnormalities, and 
subjects taking anti-arrhythmic 
drugs.
12-lead ECG and telemetry 
covering Cmax in healthy 
subjects administered IH, IM 
and IV oxytocin
Insufficient uterotonic effect
The altered physiology and 
pharmacokinetics of women in 
the TSL my lead to a sub-
optimal dose of inhaled 
oxytocin, resulting in a 
reduced or absent uterotonic 
effect.
In this setting, women in TSL 
and post-delivery are 
intensively observed. 
Therefore, any adverse 
events, including excessive 
blood loss due to unenhanced 
uterine contraction, will be 
managed in accordance with 
current local practice 
guidelines. This will usually 
include administration of 
additional uterotonic agents in 
the first instance.
A follow-up within 24 h of 
discharge by the study team 
will be performed to 
specifically enquire if any late 
bleeding problems had 
occurred.
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
28
Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
An interim analysis of IH and 
IM PK in the TSL group will be 
performed to ensure that the 
PK is in the acceptable range 
for efficacy to be anticipated.
Reference Intervention - IM Oxytocin / IV Oxytocin
Hypotension, tachycardia and 
prolongation of QTc interval
See above section.
See above section.
Subjects receiving the IV 
Oxytocin are required to have 
a systolic BP ≥ 90 Millimeter of 
mercury (mmHg) prior to 
dosing.
Myocardial Ischaemia and ST 
change on ECG
ECG changes consistent with 
myocardial ischaemia have 
been observed with 10 IU 
oxytocin IV bolus in healthy 
women associated with 
hypotension and tachycardia.
Oxytocic cardiovascular effects 
appear to be transient
and persistent myocardial 
damage very rare and 
associated with 10 IU IV.
Study is only using 5 IU IV as a 
slow IV bolus which is 
associated with a short lived 
increase in heart rate and 
reduction in BP but not ST 
changes on ECG in women 
undergoing Caesarean 
Section.
Telemetry and 12-lead ECG 
monitoring in healthy subjects.
Abdominal pain
There is a hypothetical risk 
that IM oxytocin may trigger 
abdominal pain through 
contractions of the non-
pregnant uterus in healthy 
women. 
Given the short half-life of 
oxytocin (approximately 30 
minutes), the duration of a 
single abdominal pain episode 
would be expected to be brief, 
not sustained and not 
This is a theoretical possibility 
and not expected to occur. 
Ongoing assessments of study 
subjects’ well-being along with 
vital signs and laboratory
evaluations will be completed 
throughout the duration of the 
study.  
Abdominal pain which is 
clinically uncomfortable to the 
subject may be treated with 
paracetamol at the local 
investigator’s discretion.  
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
29
Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
recurrent in the absence of 
further oxytocin administration.
Furthermore, no abdominal 
pain was observed in the FTiH 
study.
4.6.2.
Immunogenicity Risk
The oxytocin material used in the inhaled product is produced synthetically and so does 
not include any other protein/cell impuritites which might be intrinsically immunogenic.
A review of the risk of immunogenicity of oxytocin and/or excipients was considered as 
part of the non-clinical safety studies but as the lymphoid tissues were not deemed to be 
pathologically affected and there were difficulties in generating a suitable assay, anti-
drug antibodies (ADAs) were not measured. The FTIH study involved repeat dosing, and 
did not reveal any unexpected differences in PK which may have signalled the 
development of ADAs.
Oxytocin is an endogenous human peptide with a short systemic half-life and there are no 
reports of immunogenicity with oxytocin via parenteral administration. Thus it is 
considered unlikely that inhaled delivery of a small molecular weight (MW) peptide 
molecule like oxytocin would invoke an immunogenic response.
However, blood samples will be retained for anti-oxytocin antibody analysis if required 
in the event of an anaphylactic / allergic reaction (refer to Section 5.4.2) or other 
observation which would suggest an immunogenic effect.
4.6.3.
Benefit Assessment and Overall Benefit:Risk Conclusion
Oxytocin has been administered to postpartum women for over 40 years via both the IM 
and IV routes, and has an established safety profile for each of these routes of 
administration. The FTIH study into IH oxytocin revealed no safety concerns for any of 
the subjects who received this new formulation. There are no direct clinical benefits to 
the volunteers within this study. The main contribution to their participation will be in the 
further development of a therapy (i.e. inhaled oxytocin) which may be ultimately used as 
a preventative therapy for postpartum haemorrhage in women during TSL in resource 
poor settings. It is fundamental to the project to clearly understand the PK of oxytocin 
following IH and IM administration to women in TSL in order to confirm the dose level 
that delivers a PK profile comparable to that of 10 I.U. IM (i.e. current standard of care in 
the developed world setting). Taking into account the measures taken to minimize risk to 
subjects participating in this study, the potential risks identified in association with 
oxytocin (IH IM, and IV) are justified by the supporting data and overall benefit 
anticipated for women’s health worldwide.
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
30
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the investigator brochure for 
GR121619 [GlaxoSmithKline Document Number 2015N240749_01] and SPC for 
oxytocin administered IM or IV.
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
5.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
AGE
All Groups: 
1. Between 18 and 40 years of age inclusive, at the time of signing the informed 
consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
All Groups: 
2. 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.
Note: At time of randomisation, investigator or designee should confirm the subject 
feels fit and well, and is safely able to participate in the study.
3. Subject clinical chemistry and haematology values within an acceptable range for the 
population recruited and not of abnormal clinical significance.
Note: Additional laboratory tests beyond those which are done as part of routine care 
(e.g. 28-week visit) are not required for subjects in Group 1. The 
investigator/designee may use his/her judgment in deciding whether to perform 
additional laboratory assessments to determine eligibility.
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. 
4. Adequate peripheral venous access for cannulation.
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
31
Group 1 Only: 
5. Currently pregnant, with an uncomplicated pregnancy as determined by the 
investigator or designee.
6. Estimated date of delivery within 24 weeks of screening.
7. Planned spontaneous vaginal birth and considered by investigator at low risk for PPH.
8. Planned birth in between the 37th and 42nd week of pregnancy.
Note: Subjects can only receive study treatment if the onset of labour is between 
approximately 37 and 42 weeks estimated gestation. If a subject goes into labour 
before or after this timeframe, she should not receive study treatment.
9. Women who qualify for oxytocin as appropriate for active management of TSL and 
who agree to have active management.
Group 2 Only:
10. ECG normal, or abnormal and not clinically significant.
11. FEV1 >80% of predicted.
12. Systolic blood pressure ≥90 mmHg.
WEIGHT
Group 2 Only:
13. Body mass index (BMI) within the range 18 – 32 Kilogram (kg)/ meter (m)2
(inclusive).
SEX
14. 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:
a.
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.
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
32
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:
a.
Is of reproductive potential and has been using the same non-hormonal 
contraceptive method (see List of Acceptable Nonhormonal Methods for Avoiding 
Pregnancy in Females of Reproductive Potential [see Appendix 5] from 3 months
prior to the first dose of study medication and until the follow-up contact.
b.
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.
c.
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.  
INFORMED CONSENT
All Groups:
15. Capable of giving signed informed consent as described in Section 10.2 which 
includes compliance with the requirements and restrictions listed in the consent form 
and in this protocol.
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
33
5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL) 
All Groups: 
1. Postmenopausal as defined by gynaecological history.
2. Chronic lung condition of any etiology including asthma, Chronic obstructive 
pulmonary disease (COPD), emphysema, interstitial lung disease or active 
Tuberculosis (TB).
      Note: Childhood asthma (resolved) is not exclusionary.
3. Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones).
4. Blood pressure >140 systolic or >90 diastolic.
Group 1 Only:
5. Females with planned Caesarean Section.
6. Females with significant medical complications as determined by investigator.
Group 2 Only:
7. Currently breastfeeding or lactating.
8. QT duration corrected for heart rate by Fridericia’s formula (QTcF) 
>450 milliseconds (msec).
9. 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%).
10. Subjects with highly-active or symptomatic gynaecological disorders (such as large 
symptomatic fibroids).
CONCOMITANT MEDICATIONS
All Groups: 
11. Prescription or non-prescription drugs not approved by the investigator (refer to 
Section 6.12.1 for approved medications).
12. Oxytocin for any reason (including, but not limited to, induction or augmentation of 
labour) prior to administration of study-related oxytocin.
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
34
RELEVANT HABITS
All Groups: 
13. 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 (~240 milliliter [ml]) of beer, 1 glass (125 ml) of 
wine or 1 (25 ml) measure of spirits. 
14. 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.
a.
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.
CONTRAINDICATIONS 
All Groups: 
15. 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).
16. Participation in another clinical trial, which in the opinion of the investigator, 
jeopardizes the subject’s safety or study outcomes.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
All Groups: 
17. Where participation in the study would result in donation of blood or blood products 
in excess of 500 mL within 56 days.
18. 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).
19. Exposure to more than four new chemical entities within 12 months prior to the first 
dosing day.
Group 2 Only: 
20. Presence of hepatitis B surface antigen or positive hepatitis C antibody test result.
21. A positive Human Immunodeficiency Virus (HIV) antibody test.
22. A positive pre-study drugs of abuse test (not explained by diet or approved 
concomitant medications).
23. A positive alcohol breath test.
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
35
5.3.
Screening/Baseline/Run-in Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomized. In order to ensure transparent reporting of screen 
failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and respond to queries from Regulatory authorities, a minimal 
set of screen failure information is required including Demography, Screen Failure 
details, Eligibility Criteria, and Serious Adverse Events (see Section 7.3.1.4).
5.3.1.
Re-screening
If a subject fails screening, she may be rescreened one additional time.
5.4.
Withdrawal/Stopping Criteria
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as 
soon as possible. 

The site must counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or should 
continue in the study. 

In cases where the subject is deemed ‘lost to follow up’, the investigator or 
designee must make every effort to regain contact with the subject (where 
possible, 3 telephone calls and if necessary a certified letter to the subject’s last 
known mailing address or local equivalent methods). These contact attempts 
should be documented in the subject’s medical record. 

Should the subject continue to be unreachable, only then will she be considered to 
have withdrawn from the study with a primary reason of “Lost to Follow-up”. 
A subject may withdraw from study treatment at any time at her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioural or 
administrative reasons. If a subject withdraws from the study, she may request 
destruction of any samples taken, and the investigator must document this in the site 
study records. 
5.4.1.
Pregnancy Complication Stopping Criteria (Group 1 Only)
Any complication requiring clinical intervention which no longer allows for a vaginal 
delivery or safe completion of study procedures will be cause for immediate withdrawal 
from the study. Investigators should continue to manage any pregnancy complication per 
local guidelines, and record any associated AE/SAE or concomitant medication. This 
includes the need for additional uterotonic administration.
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
36
5.4.2.
Anaphylaxis Stopping Criteria
Clinical signs or symptoms of anaphylaxis / allergic reaction to IH oxytocin will be an 
automatic stopping criterion. Stored serum samples will be analysed for anti-oxytocin 
antibody analysis for affected subjects as detailed in Section 7.5.2. The samples will be 
analysed for Immunoglobulin E (IgE)/ Immunoglobulin G (IgG) anti-oxytocin titres 
biochemical markers of mast cell degranulation (e.g. tryptase) in the event of an 
anaphylactic / allergic reaction occurring.  
5.4.3.
QTc Stopping Criteria (Group 2 Only)

The same QT correction formula must be used for each individual subject to 
determine eligibility for and discontinuation from the study.  This formula may 
not be changed or substituted once the subject has been enrolled.

For example, if a subject is eligible for the protocol based on QTcF, then QTcF
must be used for discontinuation of this individual subject as well.

Once the QT correction formula has been chosen for a subject’s eligibility, the 
same formula must continue to be used for that subject for all QTc data being 
collected for data analysis.  Safety ECGs and other non-protocol specified 
ECGs are an exception.  

The QTc should be based on single or averaged QTc values of triplicate 
electrocardiograms obtained over a brief (e.g., 5-10 minute) recording period.  
QTcF is proposed to be used for this study. If a subject meets either of the following 
bulleted criterion below, she will be withdrawn from the study.  

QTcF > 500 msec,

Change from baseline: Increase in QTcF >60 msec.
Withdrawal of subjects is to be based on an average QTcF value of triplicate ECGs.  If an 
ECG demonstrates a prolonged QT interval, then obtain 2 more ECGs over a brief period 
of time and then use the averaged QTcF values of the 3 ECGs to determine whether the 
subject should be withdrawn from the study.
5.4.4.
Blood Pressure Stopping Criteria (Group 2 Only)
Subjects with a pre-dose systolic blood pressure of <90 mm Hg should not be dosed until 
systolic blood pressure is ≥90 mm Hg.
5.4.5.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
37
Study treatment will be discontinued for a subject if liver chemistry stopping criteria are 
met:
Phase I Liver Chemistry Stopping Criteria – Liver Stopping Event Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
*INR value not applicable to subjects on anticoagulants 
ALT ≥3xULN 
No
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments  section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in
Appendix 2.
5.4.6.
Plasma oxytocin concentration stopping criteria
Per Section 9.3.2.2, the plasma oxytocin concentrations in up to 5 subjects in Group 1 
will be analysed in real time. If the plasma oxytocin concentration is BLQ or sufficiently 
low to prohibit interpretation in these 5 subjects irrespective of treatment, the study will 
be halted and reviewed.
5.5.
Subject and Study Completion
A completed subject is one who has completed all phases of the study including the 
follow-up visit(s).
6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design. Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments.
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
38
Table 1
Study Treatment Information
Study Treatment
Product name:
Oxytocin  (GR121619 
capsule for inhalation)
Oxytocin
Oxytocin
Formulation 
description:
Powder Blend for Inhalation
Solution for Infusion
Solution for Infusion
Dosage form:
Inhalation powder, hard 
capsule
1ml ampoule
1ml ampoule
Unit dose 
strengths:
400 mcg
200 mcg
5 I.U./mL, or 10 
I.U./mL
5 I.U./mL, or 10 
I.U./mL
Route of 
Administration
For oral inhalation
Intramuscular (thigh)
Intravenous
Dosing 
instructions:
Capsule unit dose 
dispensed by ROTAHALER 
inhaler 
Standard 
intramuscular injection
Adminster as a 30-
second bolus
Physical 
description:
Colourless and clear 
HPMC capsules 
containing a white 
powder
Colourless and clear 
sterile solution
Colourless and clear 
sterile solution
Device:
ROTAHALER inhaler
Needle/Syringe 
Intravenous Infusion 
Device
6.2.
Medical Devices
The GSK manufactured medical device (or device manufactured for GSK by a third 
party) provided for use in this study is a high airflow resistance capsule-based inhaler 
(Modified Air Inlet ROTAHALER DPI device). Although this investigational device 
bears a CE mark, it has not been CE marked in accordance with the Medical 
Devices Directive 93/42/EEC.
Instructions for medical device use are provided in Section 6.7. Further details on use of 
the device are provided in the SRM.
GSK medical device incidents, including those resulting from malfunctions of the device, 
must be detected, documented, and reported by the investigator throughout the study –
see Section 12.4.
6.3.
Treatment Assignment
Subjects in Group 1 will be assigned to one of two treatments (IH oxytocin or IM 
oxytocin). Subjects in Group 2 will receive both IH and IV oxytocin in separate dosing 
sessions in a cross over design. Treatment assignment in Group 1, and order of dosing in 
Group 2, will be done in accordance with the randomization schedule generated by 
Clinical Statistics, prior to the start of the study, using validated internal software.
A description of each regimen is provided in Table 2:
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
39
Table 2
Treatment Assignment
Group
Session
Treatment 1
Number of Subjects2
Group 1
1
400 mcg IH oxytocin
10
10 I.U. IM Oxytocin
10
Group 2, Cohort A
1
400 mcg IH oxytocin or 
5 I.U. IV oxytocin
5
2
400 mcg IH oxytocin or 
5 I.U. IV oxytocin
Group 2, Cohort B
1
400mcg IH oxytocin or 
5 I.U. IV oxytocin
5
2
400 mcg IH oxytocin or 
5 I.U. IV oxytocin
1 See Section 6.4 for possible dose adjustment.
2 See Section 9.2.2 for possible adjustment to subject numbers to Group 1
If deemed necessary or if there is a new site identified for conducting and/or continuing 
the clinical trial, then a new randomization schedule may be generated by Clinical
Statistics, prior to the start of the study at the new site, using validated internal software.
6.4.
Planned Dose Adjustments
There is no plan to adjust the dose of IH oxytocin in this study. However, if systemic 
exposure seen in 400 mcg IH oxytocin in TSL subjects is less than expected and not 
comparable to the 10 I.U. IM profile, a consideration to escalate the dose to 600 mcg may 
be made as detailed in Section 6.4.1.
For Group 2, if an exaggerated physiological response is seen with the IV dose, such as 
increased heart rate and decreased blood pressure, then consideration will be given to 
changing to a 5-minute infusion.
6.4.1.
Dose Adjustment
The decision to adjust the IH dose in women in TSL will be determined by the GSK 
study team based on Group 1 PK data in TSL and Group 2, Cohort A PK data.  After a 
minimum of n=5 women in TSL have received 400 mcg IH and 10 I.U. IM and a 
minimum of n=5 non-pregnant women on the combined oral contraceptive (Group 2, 
Cohort A) have received 400 mcg IH oxytocin, PK samples will be analysed and PK 
parameters derived (including but not limited to Cp10, Cp30 and AUC(0-3h)).  
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
40
The median Cp10 will be estimated for women in TSL for each dose group (IH or IM) 
and the median ratio (IH/IM; n=5) derived.  Based on the estimated ratio, the dose of IH 
oxytocin to be administered to women in TSL will either remain at 400 mcg or be 
increased per the criteria described in Table 3:
Table 3
Dose Adjustment Decision Criteria
Median Ratio IH/IM
Decision
< 0.5
Consider study halt and review data.
≥ 0.5 to <0.7
Consider dose adjust to 600 mcg IH in women in TSL.
≥ 0.7
Continue with 400 mcg IH dose.
If a decision to increase the dose is made, additional subjects will be enrolled into Group 
1 such that 10 subjects receive the 600 mcg IH oxytocin dose.
6.5.
Blinding
This will be an open-label study.
6.6.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
6.7.
Preparation/Handling/Storage/Accountability

The investigator/designee will be trained to load the ROTACAPS powder capsule 
into the device, prime the dose and instruct the subjects to inhale from the 
ROTAHALER inhaler in the appropriate manner. The investigator/designee will 
always load and prime the ROTACAPS powder capsule in the device before the 
subject self-administers an IH oxytocin dose

All subjects will be taught by the investigator/designee to use the device in the 
“full-tilt” position and to use a “fast and deep” inspiration technique per 
inhalation, to achieve two rapidly consecutive maximal inhalations for IH 
oxytocin administration. This will ensure optimal and consistent treatment 
delivery. For subjects, the training session will be at any time during the 28-day 
Screening Period, as deemed appropriate by the investigator/designee. 

ROTACAPS powder capsules should be kept in their sealed packaging at room 
temperature (15-25°Centigrade [C]). The packaging should only be opened 
immediately prior to use.

ROTAHALER inhaler devices will be supplied in bulk and unlabelled to the site.
After dosing all ROTAHALER inhaler devices will be uniquely labelled and 
retained after each dosing session. The devices (which should not be opened up at 
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
41
the clinical study site) will be stored until further instruction from the sponsor is 
received.

The investigator or designee must confirm appropriate temperature conditions 
have been maintained during transit for all study treatment received and any 
discrepancies are reported and resolved before use of the study treatment.

Only subjects enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment.  All study 
treatments must be stored in a secure environmentally controlled and monitored 
(manual or automated) area in accordance with the labelled storage conditions 
with access limited to the investigator and authorized site staff. 

The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (i.e. receipt, reconciliation and final disposition records).  

Further guidance and information for final disposition of unused study treatment 
are provided in the SRM. 

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff. Take adequate precautions to 
avoid direct eye or skin contact and the generation of aerosols or mists. In the case 
of unintentional occupational exposure notify the monitor, Medical Monitor 
and/or GSK study contact.

A Material Safety Data Sheet (MSDS)/equivalent document describing 
occupational hazards and recommended handling precautions either will be 
provided to the investigator, where this is required by local laws, or is available 
upon request from GSK.
6.8.
Compliance with Study Treatment Administration
Per ROTACAPS powder capsule dose, each subject will be asked to inhale twice from 
the ROTAHALER inhaler to reduce the possibility of inadequate administration due to a 
single poor inhalation manoeuvre. If failure of the ROTACAPS powder capsule 
actuation is suspected by the investigator (i.e. due to failure to open the capsule during 
device priming), the investigator is permitted to rechallenge the individual with a 
maximum of two further administrations at the same dose using the same capsule. 
When subjects are dosed at the site, they will receive study treatment directly from the 
investigator or designee, under medical supervision.  The date and time of each dose 
administered in the clinic will be recorded in the source documents.  The dose of study 
treatment and study subject identification will be confirmed at the time of dosing by a 
member of the study site staff other than the person administering the study treatment.  
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
42
Group 1 – Women in TSL
Following randomisation and any pre-dose procedures, subjects will receive a single 
study treatment as active management of TSL. The specific timing of this dose will be as 
per local standard of care.2
Administration will be documented in the source documents and reported in the Case 
report form (CRF).
Group 2 – Non-pregnant, non-lactating females of child bearing potential
Following randomisation and all pre-dose procedures, subjects will receive two doses of 
oxytocin, separated by at least 48 hours. Randomisation will determine the order in which 
the IH and IV formulation is administered. 
Administration will be documented in the source documents and reported in the Case 
report form (CRF).
6.9.
Treatment of Study Treatment Overdose
For this study, any dose of the following compounds will be considered an overdose 
when administered as part of study procedures: 

IH oxytocin > 400 mcg 
o
If study dose is increased to 600 mcg, then an overdose will be considered 
any dose > 600 mcg.

Oxytocin > 10 I.U. IM 

Oxytocin > 5 I.U. IV
Note: Group 1 subjects may receive additional doses of oxytocin (IM or IV) when 
required as part of their general care and as clinically indicated. Additional doses of 
oxytocin will be recorded as concomitant medications, as will any related AEs.
General medical management consists of supportive care. 
GSK does not recommend specific treatment for an overdose.
In the event of a study drug overdose the investigator or treating physician should:
1.
Contact the Medical Monitor immediately.
                                                
2 For information only: Standard of care at proposed clinical site is to administer the oxytocic drug by IM 
injection with the birth of the anterior shoulder, or immediately after the birth of the baby and before the 
cord is clamped and cut.
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
43
2. Closely monitor the subject for adverse events (AEs)/serious adverse events (SAEs) 
and laboratory abnormalities until oxytocin can no longer be detected systemically (at 
least 4 hours).
3. Obtain an additional plasma sample for pharmacokinetic (PK) analysis if requested 
by the Medical Monitor (determined on a case-by-case basis).
4. Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the subject.
6.10.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study because either only healthy volunteers are eligible for study participation, or there 
are other treatment options are available.
The investigator is responsible for ensuring that consideration has been given to the post-
study care of postpartum subjects’ medical conditions, whether or not GSK is providing 
specific post-study treatment.
6.11.
Lifestyle and/or Dietary Restrictions
6.11.1.
Meals and Dietary Restrictions
There are no dietary restrictions for subjects in either cohort.
6.11.2.
Caffeine and Alcohol
Group 1 – Women in TSL

There are no restrictions for Group 1.
Group 2 – Non-pregnant, non-lactating females of child bearing potential

During each dosing session, subjects will abstain from ingesting caffeine- or 
xanthine-containing products (e.g., coffee, tea, cola drinks and chocolate) for 
12 hours prior to the start of dosing until collection of the final pharmacokinetic 
sample during each session. 

During each dosing session, subjects will abstain from alcohol for 12 hours prior to 
the start of dosing until collection of the final pharmacokinetic sample during each 
session. 
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
44
6.11.3.
Activity
Group 1 – Women in TSL
There are no activity restrictions.
Group 2 – Non-pregnant, non-lactating females of child bearing potential
Subjects will abstain from strenuous exercise for 48 hours prior to each blood collection 
for clinical laboratory tests.  Subjects may participate in light recreational activities 
during studies (e.g., watch television, read).
6.12.
Concomitant Medications and Non-Drug Therapies
6.12.1.
Permitted Medications and Non-Drug Therapies
Paracetamol, at doses equal to or below the maximum recommended daily dose, is 
permitted for use during the screening period or at any time deemed necessary by the 
investigator or subject. All concomitant medication related to routine care during 
pregnancy and delivery is allowed (including pain relief [e.g. gas/air mixture] and 
epidural), and other medication may be considered on a case by case basis by the 
investigator or designee (in consultation with the Medical Monitor if required). 
The start and stop time of any concomitant medications administered at any time during 
labour (including nitrous oxide gas/air mixtures) should be documented on the CRF.
6.12.2.
Prohibited Medications and Non-Drug Therapies
Use of the following medications will result in immediate withdrawal of subject:

Oxytocin for any reason (including, but not limited to, induction or augmentation 
of labour) before or after administration of study-related oxytocin.
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
45
7.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct.
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Table in Section 7.1.
The following points must be noted: 

If assessments are scheduled for the same nominal time, THEN the assessments 
are recommended to occur in the following order:
1. 12-lead ECG
2. vital signs
3. blood draws
Note: The timing of the assessments should allow the blood draw to occur at the 
exact nominal time.

The timing and number of planned study assessments, including safety, 
pharmacokinetic, pharmacodynamic, immunogenic or other assessments may be 
altered during the course of the study based on newly available data (e.g., to 
obtain data closer to the time of peak plasma concentrations) to ensure 
appropriate monitoring. 

The change in timing or addition of time points for any planned study 
assessments must be documented in a Note to File which is approved by the
relevant GSK study team member and then archived in the study sponsor and 
site study files, but this will not constitute a protocol amendment. 

The Institutional Review Board (IRB)/ Independent Ethics Committee (IEC)
will be informed of any safety issues that require alteration of the safety 
monitoring scheme or amendment of the Informed Consent Form. 

No more than 500 mL of blood will be collected over the duration of the study, 
including any extra assessments that may be required.
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
46
7.1.
Time and Events Table
7.1.1.
Time and Events Table – General Overview
Group 1
Study Day
Procedure
Screening4
Main Phase 
Follow – Up 1 (approx. 24 
hours post dose)
Follow – Up 2 (7-14 days post dose)
Informed Consent and Demography
X
Brief Physical Examination
X
Medical history (incl. substance abuse)
X
Inhaler device training / education session
X
Laboratory assessments1
X
Vital signs2
X
X
Pharmacokinetic blood sample
X
Oxytocin Administration (IM/IH)
X
Full blood count
X
Labour Events Documentation
X
Device acceptability questionnaire3
X
Prior / concomitant medication review
X
X
X
X
AE review
------------------------------ continuous review ------------------------------------------------------
SAE review
 ---------------------------------------------------------------- continuous review  -------------------------------------------------
1.
Only required if done as part of routine care. Additional study-specific laboratory assessments not required.
2.
Includes blood pressure, heart rate, temperature, respiratory rate
3.
Only to be used when randomized to IH oxytocin
4.
To be completed after 18th week of pregnancy (based on estimated date of delivery).
 
 
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
47
Group 2
Study Day
Procedure
Screening5
Main Phase
Follow - Up (7-21
days post 
dose)
Informed Consent and Demography
X
Brief Physical Examination
X
X
Medical history
X
Pregnancy test 
X
X
Alcohol Breath Test, Smokerlyzer, Urine Drug Screen1 
X
X
HIV, Hep B and Hep C screen2
X
Inhaler device training / education session
X
Laboratory assessments (including liver chemistries)
X
X
Immunogenicity sample
X
X
12-lead ECG
X4
X
CardiacTelemetry
X
Vital signs3
X
X
Spirometry (FEV-1)4
X
X
Admission to unit
X
Pharmacokinetic blood sample
X
X
Oxytocin Administration (IH or IV)
X
Prior / concomitant medication review
X
X
X
AE review
------ continuous review -----------------------------------
SAE review
 ----------------------------------- continuous review  --------------------------------
Discharge from unit
X
1.
Smokerlyzer at PI/designee discretion if smoking history in question.
2.
If test otherwise performed within 3 months prior to first dose of study treatment, repeat testing at screening is not required.
3.
Includes blood pressure, heart rate, temperature, respiratory rate, and SpO2.
4.
Performed in triplicate.
5.
To be completed within 28 days of randomization.
 
 
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
48
7.1.2.
Time and Events – Main Phase Procedures
Group 1 
Time post dose
Procedure
Pre-
dose
3 min
5 min
10 
min
15 min
20 
min
30 
min
1 hr
2 hr
2.5 hr
3 hr
4 hr
Vital signs1
X
X
Pharmacokinetic blood sample
X2
X
X
X
X
X
X
X
X
X
X
X
Prior  medication review
X
Concomitant  medication review
---------------------------------------------------------- continuous review  ---------------------------------------------------
AE review
--------------------------------------------------------- continuous review  ---------------------------------------------------
SAE Review
------------------------------------------------------------------------ continuous review  -----------------------------------------------------
Device Acceptability Questionnaire3
X
Full Blood Count
X
X
1.
Includes blood pressure, heart rate, temperature, respiratory rate
2.
Predose PK sample to be taken immediately prior to administration of study treatment 
3.
Only to be administered when randomized to IH oxytocin
 
 
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
49
Group 2 – Sessions 1 and 2
Time Post Dose
Procedure
Pre-
dose
2 
min
3 
min
5 
min
8 
min
10 
min
15 
min
20 
min
30 
min
45 
min
1 hr
1.5 hr
2 hr
2.5 hr
3 hr
4 hr
Brief Physical Exam
X
Pregnancy Test
X
Alcohol Breath Test, Smokerlyzer, Urine 
Drug Screen1
X
Vital signs2
X
X
X
X
X
X
12-lead ECG
X
X
X
X
X
X
X
CardiacTelemetry
---------------------------------------------Continuous-----------------------------------------------
Spirometry3
X
X
Pharmacokinetic blood sample
X5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Immunogenicity Sample
X
Laboratory assessments (including liver 
chemistries)
X
X
Prior medication review
X
Concomitant medication review
------------------------------------------------------------ continuous review  ----------------------------------------------------
AE review
----------------------------------------------------------- continuous review  ----------------------------------------------------
SAE Review
------------------------------------------------------------------------- continuous review  ----------------------------------------------------
Discharge from unit4
X
1.
Smokerlyzer at Principal Investigator (PI)/designee discretion if smoking history in question.
2.
Includes blood pressure, heart rate, temperature, respiratory rate, and SpO2
3.
FEV 1.0 will be performed in triplicate at each time point. Record all three values on source document, and record best effort in eCRF.
4.
Discharge at PI discretion, no sooner than 4-hours post-dose.
5.
3 pre-dose samples: approximately 1 hr pre-dose, 30 minutes pre-dose, and 15 minutes pre-dose
 
 
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
50
7.2.
Screening and Critical Baseline Assessments
Cardiovascular medical history/risk factors (as detailed in the CRF) will be assessed at 
screening.
The following demographic parameters will be captured: year of birth, sex, race and 
ethnicity.
Medical/medication/family history will be assessed as related to the inclusion/exclusion 
criteria listed in Section 5.  
Procedures conducted as part of the subject’s routine clinical management [e.g. brief 
physical exam, laboratory assessments] and obtained prior to signing of informed consent 
may be utilized for Screening or baseline purposes provided the procedure meets the 
protocol-defined criteria and has been performed within the timeframe defined in the 
Time and Events Schedule.
7.3.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1).  Additional time points for safety tests (such as vital signs, physical exams 
and laboratory safety tests) may be added during the course of the study based on newly 
available data to ensure appropriate safety monitoring.
7.3.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 3 (see Section 12.3).
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 
7.3.1.1.
Time period and Frequency for collecting AE and SAE information

Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK 
product will be recorded from the time a subject consents to participate in the 
study up to and including any follow-up contact. 

AEs will be collected from the start of Study Treatment until the follow-up 
contact (see Section 7.3.1.3), at the timepoints specified in the Time and Events 
Table (Section 7.1).

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the CRF or appropriate source document.

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in
Appendix 3.

Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects. However, if the investigator learns of any SAE, including a death, at any 
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
51
time after a subject has been discharged from the study, and she considers the 
event reasonably related to the study treatment or study participation, the 
investigator must promptly notify GSK.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Appendix 3.
7.3.1.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:

“How are you feeling?” 

“Have you had any (other) medical problems since your last visit/contact?”

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?” 
7.3.1.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All SAEs, and non-serious AEs of special interest 
(as defined in Section 4.6.1) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up 
(as defined in Section 5.4). Further information on follow-up procedures is given in
Appendix 3.
7.3.1.4.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK of SAEs related to study treatment (even 
for non- interventional post-marketing studies) is essential so that legal obligations and 
ethical responsibilities towards the safety of subjects and the safety of a product under 
clinical investigation are met. 
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, IRB/ IEC and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the Investigators Brochure (IB) and will notify the IRB/IEC, if appropriate according to 
local requirements.
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
52
7.3.2.
Adverse Events of Special Interest (AESI)
Any problem related to the delivery of the placenta or postpartum haemorrhage should be 
documented as an AESI using the appropriate case report form (CRF). 
7.3.3.
Pregnancy
Group 2 Only:

Details of all pregnancies will be collected after the start of dosing and until 
follow-up.

If a pregnancy is reported then the investigator should inform GSK within 2 
weeks of learning of the pregnancy and should follow the procedures outlined in
Appendix 5.
7.3.4.
Medical Device Incidents (Including Malfunctions)
GSK medical devices are being provided for use in this study.  In order to fulfil 
regulatory reporting obligations worldwide the investigator is responsible for the 
detection and documentation of events meeting the definitions of incident or malfunction 
that occur during the study with such devices. 
The definition of a Medical Device Incident can be found in Section 12.4.
NOTE: Incidents fulfilling the definition of an AE/SAE will also follow the processes 
outlined in Section 12.3.6 and Appendix 3 of the Protocol. 
7.3.4.1.
Time Period for Detecting Medical Device Incidents

Medical device incidents or malfunctions of the device that result in an incident will 
be detected, documented and reported during all periods of the study in which the 
GSK medical devices are available for use. 

If the investigator learns of any incident at any time after a subject has been 
discharged from the study, and such incident is reasonably related to a GSK medical 
device provided for the study, the investigator will promptly notify GSK.
NOTE: The method of documenting Medical Device Incidents is provided in 
Appendix 4.
7.3.4.2.
Follow-up of Medical Device Incidents

All medical device incidents involving an AE will be followed until resolution of the 
event, until the condition stabilizes, until the condition is otherwise explained, or 
until the subject is lost to follow-up (as defined in Section 5.4). This applies to all 
subjects, including those withdrawn prematurely. 
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
53

The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as may be indicated to elucidate as completely as practical the nature 
and/or causality of the incident.

New or updated information will be recorded on the originally completed form with 
all changes signed and dated by the investigator.
7.3.4.3.
Prompt Reporting of Medical Device Incidents to GSK

Medical device incidents will be reported to GSK within 24 hours once the 
investigator determines that the event meets the protocol definition of a medical 
device incident.

Facsimile transmission of the "Medical Device Incident Report Form" is the 
preferred method to transmit this information to the Medical Monitor or SAE 
coordinator.

The same individual will be the contact for receipt of medical device reports and 
SAEs.

In the absence of facsimile equipment, notification by telephone is acceptable for
incidents, with a copy of the "Medical Device Incident Report Form" sent by 
overnight mail. 
7.3.4.4.
Regulatory Reporting Requirements for Medical Device Incidents

The investigator will promptly report all incidents occurring with any GSK medical 
device provided for use in the study in order for GSK to fulfil the legal responsibility 
to notify appropriate regulatory bodies and other entities about certain safety 
information relating to medical devices being used in clinical studies.

The investigator, or responsible person according to local requirements (e.g., the 
head of the medical institution in Japan), will comply with the applicable local 
regulatory requirements relating to the reporting of incidents to the IRB/IEC.
7.3.5.
Physical Exams

A brief physical examination will include, at a minimum assessments of the lungs, 
cardiovascular system, and abdomen (liver and spleen if palpable).

Investigators should pay special attention to clinical signs related to previous 
serious illnesses
7.3.6.
Vital Signs
Vital signs will be measured in semi-supine position after 5 minutes rest and will 
include temperature, systolic and diastolic blood pressure, pulse rate and respiratory 
rate (unless otherwise specified in T&E). 
7.3.7.
Documentation of Labour Events
The time that the following labour events occurred will be collected:
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
54

Time of crowning

Time of birth

Time of delivery of placenta
7.3.8.
Electrocardiogram (ECG) (Group 2 Only)

Triplicate 12-lead ECGs will be obtained at screening as listed in Section 7.1.1.

Single 12-lead ECGs will be obtained at each timepoint as listed in Section 7.1.2
using an ECG machine that automatically calculates the heart rate and measures 
PR, QRS, QT, and QTc intervals.  Refer to Section 5.4.3 for QTc withdrawal 
criteria and additional QTc readings that may be necessary.

At all single 12-lead ECG time-points if QTc >450, repeat twice and take average 
reading.
7.3.9.
Continuous Cardiac Telemetry (Group 2 Only)
Continuous cardiac telemetry will be started at least 10 minutes pre-dose (to obtain a 
stable reading) and continue until at least the first hour after IV and IH placebo / 
oxytocin administration and then as deemed necessary by the investigator.  Full 
disclosures will be reviewed in detail and the review maintained as part of the 
subject’s source documents.
7.3.10.
Device Acceptability Questionnaire (Group 1 Only)
A device acceptability questionnaire will be administered to subjects in Group 1 
following use of the ROTAHALER (Appendix 7). 
7.3.11.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as required by Section 7.1 and defined in 
Table 4, must be conducted in accordance with the Laboratory Manual, and Protocol 
Time and Events Schedule. Laboratory requisition forms must be completed and samples 
must be clearly labelled with the subject number, protocol number, site/centre number, 
and visit date. Details for the preparation and shipment of samples will be provided by 
the laboratory and are detailed in the SRM. Reference ranges for all safety parameters 
will be provided to the site by the laboratory responsible for the assessments.
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the CRF.
Refer to the SRM for appropriate processing and handling of samples to avoid duplicate 
and/or additional blood draws.
All study-required laboratory assessments will be performed by a central laboratory, apart 
from:
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
55

Tests performed as part of routine care in Group 1.
NOTE:  Local laboratory results are only required in the event that the central laboratory
results are not available in time for either a treatment and/or response evaluation to be 
performed. Additionally if the local laboratory results are used to make either a treatment 
or response evaluation, the results must be entered into the CRF.
Subjects in Group 1 are not required to undergo additional laboratory assessments beyond 
those done as part of their routine care. However, the investigator/designee may conduct 
any of the tests listed in Table 4 in order to confirm eligibility. Haematology, clinical 
chemistry, and additional parameters to be tested in all Group 2 subjects are listed in 
Table 4.
Table 4
Protocol Required Safety Laboratory Assessments
Laboratory
Assessments
Parameters
Haematology
Platelet Count
RBC Indices:
White Blood Cell (WBC) count 
with Differential:
Red Blood Cell (RBC)
Count
Mean 
Corpuscular 
Volume 
(MCV)
Neutrophils
Hemoglobin
Mean 
Corpuscular 
Hemoglobin 
(MCH)
Lymphocytes
Hematocrit
Monocytes
Eosinophils
Basophils
Clinical 
Chemistry 1
Blood Urea 
Nitrogen 
(BUN)
Potassium
Aspartate 
aminotransferase 
(AST) (SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
Alanine 
aminotransferase 
(ALT) (SGPT)
Total Protein
Glucose 
Calcium
Alkaline phosphatise
Albumin
Other 
Screening 
Tests
HIV
Hepatitis B (HBsAg)
Hepatitis C (Hep C antibody)
Follicle Stimulating Hormone (FSH) and estradiol (as needed in women 
of suspected non-child bearing potential only)
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
56
Laboratory
Assessments
Parameters
Alcohol and drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines)
Serum or urine hCG Pregnancy test (Group 2 only) 2
NOTES :
1.
Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up 
Assessments after liver stopping or monitoring event are given in Section 12.2 and
Appendix 2
2.
Local urine testing will be standard for the protocol unless serum testing is required 
by local regulation or ethics committee.
All laboratory tests with values that are considered clinically significantly abnormal 
during participation in the study should be repeated until the values return to normal or 
baseline.  If such values do not return to normal within a period judged reasonable by the 
investigator, the etiology should be identified and the sponsor notified.
7.4.
Pharmacokinetics
7.4.1.
Blood Sample Collection
Blood samples for pharmacokinetic (PK) analysis of oxytocin will be collected at the 
time points indicated in Section 7.1, Time and Events Table.  The actual date and time of 
each blood sample collection will be recorded.  The timing of PK samples may be altered 
and/or PK samples may be obtained at additional time points to ensure thorough PK 
monitoring.  
At each time point, 4 mL of blood will be collected into study-specific tubes formulated 
to further inhibit peptidase activity. Additional details regarding collection/shipping 
procedures are provided in the SRM.
7.4.2.
Sample Analysis
Plasma analysis will be performed under the control of PTS-DMPK, GlaxoSmithKline, 
the details of which will be included in the SRM. Concentrations of oxytocin will be 
determined in plasma samples using the currently approved bioanalytical methodology.
Raw data will be archived at the bioanalytical site (detailed in the SRM). Once the 
plasma has been analyzed for oxytocin any remaining plasma may be analysed for 
metabolites of oxytocin and the results reported separately.
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
57
7.5.
Biomarkers
7.5.1.
Pharmacodynamic Markers
Pre and post-delivery full blood counts will be collected from Group 1 subjects to assess 
for a change in haemoglobin levels.
7.5.2.
Immunogenicity
Blood samples will be taken at the time points specified in the Time and Events Table 
(Section 7.1) to assess the immunogenicity of oxytocin.
Pre- and post-dose samples will be retained in the event that further immunologic tests 
are deemed necessary to support observations of unexpected anaphylaxis/
hypersensitivity, and / or a PK profile for IH oxytocin in any Dosing Session which is 
regarded by the GSK Study Team to be reasonably attributable to circulating anti-
oxytocin antibodies.
Details of the collection / shipping procedures are provided in the SRM.
8.
DATA MANAGEMENT

For this study subject data will be entered into GSK defined CRFs, transmitted 
electronically to GSK or designee and combined with data provided from other 
sources in a validated data system.  

Management of clinical data will be performed in accordance with applicable 
GSK standards and data cleaning procedures to ensure the integrity of the data, 
e.g., removing errors and inconsistencies in the data.

Adverse events and concomitant medications terms will be coded using MedDRA 
(Medical Dictionary for Regulatory Activities) and an internal validated 
medication dictionary, GSKDrug.  

CRFs (including queries and audit trails) will be retained by GSK, and copies will 
be sent to the investigator to maintain as the investigator copy.  Subject initials 
will not be collected or transmitted to GSK according to GSK policy.
9.
STATISTICAL CONSIDERATIONS AND DATA
ANALYSES
9.1.
Hypotheses
The primary objective of this study is to characterize the pharmacokinetics of 400 mcg IH 
oxytocin and 10 I.U. IM oxytocin in women in TSL. 
No formal hypotheses will be tested, however, the following comparisons are of interest,
within Group 1, (IH vs. IM) and between Group 1 and Group 2 (IH oxytocin comparison 
in TSL vs. non-pregnant women on oral contraception) and between Cohorts A and B in 
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
58
Group 2 (IH and IV oxytocin comparison in non-pregnant women in the presence and 
absence of oral contraceptive). For each PK endpoint of interest, point estimates and 
corresponding two-sided 90% confidence intervals will be constructed for the ratio of the 
geometric mean of the test treatment to the geometric mean of the reference treatment, 
μ(test)/μ(reference) to provide the range of plausible values for the comparisons of 
interest. 
9.2.
Sample Size Considerations
A sufficient number of subjects will be enrolled to ensure approximately 20 evaluable 
subjects (10 in each of the IM and IH groups) complete all dosing and critical 
assessments in Group 1, as well as 5 subjects in each cohort in Group 2. Whilst sample 
size is based on feasibility, precision calculation was also done to approximate the 
estimate of the expected half width of 90% CI around point estimate for the main 
comparison of interest (IH oxytocin to 10 I.U. IM oxytocin in women in TSL) using a t-
test. 
Table 5 illustrates the associated 90% CIs for the mean treatment ratios, assuming 
between subject SDs of 0.424 and 0.601 (SDs are based on log transformed data) for 
AUC (0-3h) and CP10 respectively, for the comparisons of interest detailed in Section 
9.1. Calculations are based on a symmetric two-tailed procedure on the loge scale and a 
type I error rate of 10%. These values represent estimates of the between-subject 
variability observed in the FTIH study 201558 [GlaxoSmithKline Document Number 
2016N277949_00].
Table 5
Estimated 90% Confidence Intervals for Treatment Ratios
N
Parameter
Between
Subject 
Standard 
Deviation 
(SD)
Estimated 
Treatment 
Ratio
Precision
Expected 
90% CI
10
AUC(0-3h)
0.424 
(CVb=44.35%)
1
38.30%
(0.72, 1.38)
10
Cp10
0.601 
(Cvb=65.96%)
1
58.20%
(0.63,1.58)
The precision estimates are deemed acceptable to assess the study objectives at this stage
of development.
9.2.1.
Sample Size Sensitivity
Considering the variability of AUC(0-3h) and Cp10, Table 6 shows the scenarios for 
different sample size and the precision estimates for IH vs. IM in Group 1.
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
59
Table 6
Estimated 90% Confidence Intervals for Treatment Ratios for Sample 
Size Sensitivity
%CVb
N
Precision
Assuming ratio 1, the 
confidence interval
44.35%
5
61.90%
(0.61, 1.61)
15
29.80%
(0.77,1.29)
65.96%
5
98.00%
(0.50, 1.98)
15
44.80%
(0.69, 1.44)
20
37.40%
(0.72,1.37)
85.35%*
5
131.90%
(0.43, 2.31)
10
75.90%
(0.56, 1.75)
15
57.60%
(0.63, 1.57)
20
48.00%
(0.67, 1.48)
* 85.35%  was the largest between subject CV for AUC(0-10) observed for FTIH study 201558 
[GlaxoSmithKline Document Number:2016N277949_00]
9.2.2.
Sample Size Re-estimation or Adjustment
No formal sample size re-estimation is planned for this study. However, if the variability 
is high (for example approaching 85%) then the sample size for Group 1 may be 
increased to a maximum of 10 additional subjects per treatment arm (IH and IM only).
9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations
Enrolled Population

Defined as all subjects who were enrolled for the trial 
irrespective of whether they were randomized or not and 
for whom a record exist on the study database. This 
population will be used for summarizing screening failure 
reasons.
All Subjects Population

Comprise of subjects who receive at least one dose of 
study medication. This population will be used for the 
study population and safety displays.
Pharmacokinetic 
Population

Subjects in the ‘All Subjects’ population for whom a 
pharmacokinetic sample was obtained and analysed.  PK 
population will be the population for reporting PK data.
9.3.2.
Interim Analyses
No formal interim analyses are planned. PK data will be reviewed per Section 9.3.2.1,
Section 9.3.2.2 and Section 9.3.2.3, and may be shared with any relevant third party to 
allow for discussion around future partnering opportunities for IH oxytocin.
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
60
9.3.2.1.
Informal Interim Reviews
PK samples will be analysed and preliminary PK parameters derived following 
completion of 5 women on each of the following treatments: 400 mcg IH and 10 I.U. IM 
to women in TSL (Group 1) and 400 mcg IH to non-pregnant women on the combined  
oral contraceptive (Group 2 Cohort A).  Based on the PK profiles the dose of IH oxytocin 
to be administered to women in TSL will either remain at 400 mcg or be increased (to 
600 mcg) (See Section 6.4.1). This decision will be made by the study team in 
collaboration with the Principal Investigator. 
This will be repeated after restart from the temporary halt for Group 1.
9.3.2.2.
In-Stream Analysis of Group 1
Following restart from temporary halt, PK specimens from each of up to 5 subjects in 
Group 1 will be analysed as soon as possible after collection. This will allow for 
confirmation that the revised specimen collection procedures allow for detection of 
adequate oxytocin PK profile. 
9.3.2.3.
Analysis of Group 2
An analysis of Group 2 (non-pregnant volunteers) will be performed once Group 2 has 
completed to allow for full reporting of non-pregnant volunteer data prior to completion 
of Group 1.
There will be no changes to the study design or Group 1 of the study as a result of this 
analysis. The Reporting and Analysis Plan (RAP) will describe the planned analysis in 
greater detail.
9.4.
Key Elements of Analysis Plan
9.4.1.
Primary Analyses
9.4.1.1.
Safety Analysis
Safety data will be presented in tabular and/or graphical format and summarized 
descriptively according to GSK’s Integrated Data Standards Library (IDSL) standards.
9.4.1.2.
Pharmacokinetic Analysis
Pharmacokinetics analysis will be the responsibility of the Clinical Pharmacokinetics 
Modeling & Simulation department within GlaxoSmithKline.  Plasma oxytocin
concentration-time data will be analyzed by non-compartmental methods with 
WinNonlin V6.3 or greater.  Calculations will be based on the actual sampling times 
recorded during the study. 
From the plasma concentration-time data, the following pharmacokinetic parameters will 
be determined, as data permit: maximum observed plasma concentration (Cmax), time to 
Cmax (tmax), area under the plasma concentration-time curve [AUC(0-3h) and AUC(0-
∞)], the last observed quantifiable concentration (Clast), time of the last quantifiable 
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
61
concentration (tlast), Cp10, Cp20, Cp30 (observed plasma concentrations at 10, 20 and 
30minutes post-dose, respectively), plasma clearance (CL; IV only), volume of 
distribution (V; IV only) and apparent terminal phase half-life (t1/2).  Other PK 
parameters may also be determined.
Pharmacokinetic data will be presented in graphical and/or tabular form and will be
summarized descriptively. All pharmacokinetic data will be stored in the Archives, 
GlaxoSmithKline Pharmaceuticals, R&D. 
If appropriate, a population PK analysis may also be conducted, in addition the oxytocin 
plasma concentration-time data may be merged with historical data and analysed as part 
of a population PK meta-analysis.
9.4.2.
Secondary Analyses
Statistical analyses of the PK parameter data will be performed by, or under direct 
auspices of Clinical Statistics, QSci.
9.4.2.1.
Pharmacokinetic Analysis
For evaluating pharmacokinetic treatment comparisons within Group 1 IH vs. IM, point 
estimates and corresponding two-sided 90% confidence intervals will be computed using 
a mixed effect model. Loge-transformed PK parameters will be analysed using the model 
with a fixed effect term for treatment and a random effect term for subject.
Further details of analysis and reporting of PK data will be given in the RAP.
9.4.3.
Exploratory Analyses
9.4.3.1.
Pharmacokinetic Analysis
For evaluating pharmacokinetic treatment comparisons between Group 1 and Group 2 
(IH oxytocin comparison in TSL vs. non-pregnant women on the combined oral 
contraceptive), and within Group 2 between Cohorts A and B (IH and IV oxytocin 
comparison in non-pregnant women in the presence and absence of oral contraceptive),
point estimates and corresponding two-sided 90% confidence intervals will be computed 
using a mixed effect model. Loge-transformed PK parameters will be analysed using the 
model with a fixed effect term for treatment and a random effect term for subject.
Further details of analysis and reporting of PK data will be given in the RAP.
9.4.3.2.
Device Acceptability Questionnaire
In Group 1, subject satisfaction with device, including instructions and ease of use, will 
be assessed. The questionnaire is located in Section 12.7
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
62
10.
STUDY GOVERNANCE CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and the guiding principles of the current 
version of the Declaration of Helsinki.  This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable

Obtaining signed informed consent

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol 
deviations to IRB/IEC)

GSK will provide full details of the above procedures, either verbally, in writing, 
or both.

Signed informed consent must be obtained for each subject prior to participation 
in the study

The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.  

Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.  

Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities.  In this situation,
written approval of the clinical protocol should state that approval of optional 
assessments is being deferred and the study, with the exception of the optional 
assessments, can be initiated.
10.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK monitors will contact the site prior to the start of the study to review with the 
site staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and GSK requirements.  
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
63

When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the CRF will 
serve as the source document.

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRFs <or> entered in the eCRFs that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study; also current medical 
records must be available.
GSK will monitor the study and site activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any 
other study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents.
10.4.
Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK 
may conduct a quality assurance assessment and/or audit of the site records, and 
the regulatory agencies may conduct a regulatory inspection at any time during or 
after completion of the study. 

In the event of an assessment, audit or inspection, the investigator (and institution) 
must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all 
relevant documents and to allocate their time and the time of their staff to discuss 
the conduct of the study, any findings/relevant issues and to implement any 
corrective and/or preventative actions to address any findings/issues identified.
10.5.
Study and Site Closure

Upon completion or premature discontinuation of the study, the GSK monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and GSK Standard 
Operating Procedures.

GSK reserves the right to temporarily suspend or prematurely discontinue this 
study at any time for reasons including, but not limited to, safety or ethical issues 
or severe non-compliance. For multicenter studies, this can occur at one or more 
or at all sites.  

If GSK determines such action is needed, GSK will discuss the reasons for taking 
such action with the investigator or the head of the medical institution (where 
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
64
applicable).  When feasible, GSK will provide advance notification to the 
investigator or the head of the medical institution, where applicable, of the 
impending action.

If the study is suspended or prematurely discontinued for safety reasons, GSK will 
promptly inform all investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study. GSK will also promptly 
inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action.  

If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation.
10.6.
Records Retention

Following closure of the study, the investigator or the head of the medical 
institution (where applicable) must maintain all site study records (except for 
those required by local regulations to be maintained elsewhere), in a safe and 
secure location.  

The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review 
in conjunction with assessment of the facility, supporting systems, and relevant 
site staff.  

Where permitted by local laws/regulations or institutional policy, some or all of 
these records can be maintained in a format other than hard copy (e.g., microfiche, 
scanned, electronic); however, caution needs to be exercised before such action is 
taken.  

The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, 
including re-generating a hard copy, if required.  Furthermore, the investigator 
must ensure there is an acceptable back-up of these reproductions and that an 
acceptable quality control process exists for making these reproductions.

GSK will inform the investigator of the time period for retaining these records to
comply with all applicable regulatory requirements.  The minimum retention time 
will meet the strictest standard applicable to that site for the study, as dictated by 
any institutional requirements or local laws or regulations, GSK 
standards/procedures, and/or institutional requirements. 

The investigator must notify GSK of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of 
ownership of the records in the event the investigator is no longer associated with 
the site.
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
65
10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publicly Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy.
A manuscript will be progressed for publication in the scientific literature if the results 
provide important scientific or medical knowledge.
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
66
11.
REFERENCES
Costantine MM. Physiologic and pharmacokinetic changes in pregnancy. Frontiers in
Pharmacology. 2014. Volume 5. Article 65: 1-5. 
GlaxoSmithKline Document Number 2015N234711_01. Study ID 201558. Clinical 
Pharmacology Study Protocol. A single centre, single blind study to investigate the 
safety, tolerability and pharmacokinetics of single doses of oxytocin (GR121619) 
administered via an inhaled route in healthy female volunteers. 16-NOV-2015.
GlaxoSmithKline Document Number 2015N239682_00. Study ID 201248 – Clinical
Pharmacology Study Report. An enabling study to compare the inhalation profiles of 
women in the third stage of labour to those of non-pregnant female volunteers and to 
explore whether there are any  differences which could impact the delivery of an inhaled 
medicinal product, 16-OCT-2016.
GlaxoSmithKline Document Number 2015N240749_01. GR121619 Investigator's 
Brochure, AUG-2015.  
GlaxoSmithKline Document Number 2016N277949_00. Study ID 201558 – Clinical 
Pharmacology Study Report. A single centre, single blind study to investigate the safety, 
tolerability and pharmacokinetics of single doses of oxytocin (GR121619) administered 
via an inhaled route in healthy female volunteers. 30-JUN-2016.
Khan KS, Wojdyla D, Say L, Gülmezoglu AM, Van Look PF. WHO analysis of causes 
of maternal death: a systematic review. Lancet. 2006;367(9516):1066-74.
Mousa HA, Blum J, Abou El Senoun G, Shakur H, Alfirevic Z. Treatment for primary 
postpartum haemorrhage. Cochrane Database of Systematic Reviews. 2014, Issue 2. Art. 
No.: CD003249. DOI: 10.1002/14651858.CD003249.pub3.
Prankerd RJ, Nguyen T, Ibrahim JP, et al. Pulmonary Delivery of an Ultra-Fine Oxytocin 
Dry Powder Formulation: Potential for Treatment of Postpartum Haemorrhage in 
Developing Countries. 2013; PLoS One. Vol 8: 12: Article e82965
Syntocinon Summary of Product Characteristics, Novartis, 2014
Thornton S, Davison JM, Baylis PH. Effect of human pregnancy on metabolic clearance 
rate of oxytocin. American Physiological Society. 1990. 0363-6119: R21-R24.
Thornton S, Davison JM, Baylis PH. Plasma oxytocin during third stage of labour: 
comparison of natural and active management.BMJ. 1988. Volume 297:167-169.
WHO Model List of Essential Medicines 18th list (April 2013). Available at: 
http://www.who.int/medicines/publications/essentialmedicines/en/. Accessed May 26, 
2015.
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
67
WHO Model List of Essential Medicines for Children 4th list (April 2013). Available at: 
http://www.who.int/medicines/publications/essentialmedicines/en/. Accessed May 26, 
2015.
WHO, UNICEF, UNFPA. The World Bank World Health Organization (WHO) Press. 
Trends in Maternal Mortality: 1990 to 2008: Estimates Developed by WHO, UNICEF, 
UNFPA and The World Bank. Geneva: WHO, 2010.
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
68
12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
ADAs
Anti drug antibodies
AE
Adverse Event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase (SGPT)
ANP
Atrial natriuretic peptide
AST
Aspartate aminotransferase (SGOT)
AUC
Area under concentration-time curve
AUC(0-3)
Area under the concentration-time curve from time zero 
(pre-dose) to three hours
AUC(0-∞)
Area under the concentration-time curve from time zero to 
infinity
BMI
Body mass index
BP
Blood pressure
BUN
Blood urea nitrogen
C
Centigrade
Ca2+
Intracellular calcium
CI
Confidence Interval
CL
Plasma clearance
Clast
last observed quantifiable concentration
Cmax
Maximum observed plasma concentration
COC
Combined oral contraceptive
CONSORT
Consolidated Standards of Reporting Trials
COPD
Chronic obstructive pulmonary disease
Cp10
Observed plasma concentrations at 10 minutes post-dose
Cp20
Observed plasma concentrations at 20 minutes post-dose
Cp30
Observed plasma concentrations at 30 minutes post-dose
CPK
Creatinine phosphokinase
CRF
Case report form
CVS
Cardiovascular system
DMPK
Drug Metabolism and Pharmacokinetics
DPI
Dry powder inhaler
ECG
Electrocardiogram
EDTA
Ethylenediaminetetraacetic acid
FDA
Food and Drug Administration
FEV1.0
Forced expiratory volume at 1 minute
FRP
Females of Reproductive Potential
FSH
Follicle Stimulating Hormone
FTIH
First time in human
g
Gram
GCP
Good Clinical Practice
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
69
GSK
GlaxoSmithKline
h/hr
Hour(s)
HBsAg
Hepatitis B surface antigen
hCG
Human chorionic gonadotropin
HCP
Health care professional
HIV
Human Immunodeficiency Virus
HPLC
High Performance Liquid Chromatography
HR
Heart rate
I.U.
International units
IB
Investigators Brochure
ICH
International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for 
Human Use
IDSL
Integrated Data Standards Library
IEC
Independent Ethics Committee
IgG
Immunoglobulin G
IgM
Immunoglobulin M
IH
Inhaled
IL
Interleukin
IM
Intramuscular
INR
International normalized ratio
IP
Investigational product
IRB
Institutional Review Board
IV
Intravenous
Kg
kilogram
LDH
Lactate dehydrogenase
m
Meter
mcg
Micrograms
MCH
Mean Corpuscular Hemoglobin
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
ml
Millilitre
mmHg
Millimeter of mercury
MSDS
Material Safety Data Sheet
Msec
Milliseconds
MW
Molecular weight
OTR
Oxytocin receptor
PGF
Prostaglandin F
PI
Principal Investigator
PK
Pharmacokinetics
PPH
Post-partum haemorrhage
QTc
Corrected QT interval
QTcF
QT duration corrected for heart rate by Fridericia’s formula
RAP
Reporting and Analysis plan
RBC
Red blood cells
SAE
Serious Adverse Event
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
70
SD
Standard deviation
SMC
Smooth muscle cells
SPC
Summary of product characteristics
SpO2
Peripheral capillary oxygen saturation
SRM
Study reference manual
T&E
Time and event
t1/2
Terminal phase half-life
TB
Tuberculosis
tmax
Time to Cmax
TSL
Third stage of labour
UK
United Kingdom
ULN
Upper Limit of Normal
V
Vassopresin
VOD
Volume of distribution
WBC
White blood cells
WHO
World Health Organization
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
ROTACAPS
Syntocinon
ROTAHALER
Uniject
WinNonlin
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
71
12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments
Phase I Liver chemistry stopping criteria have been designed to assure subject safety and 
to evaluate liver event etiology (in alignment with the Food and Drug Administration
[FDA] premarketing clinical liver safety guidance).
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Phase I liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria – Liver Stopping Event
ALT-absolute
ALT≥3xULN
If  ALT≥3xULN  AND bilirubin1,2 2xULN (>35% direct bilirubin) or  INR >1.5, 
Report as an SAE.
See additional Actions and Follow Up Assessments listed below
Required Actions and Follow up Assessments following Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue study treatment 

Report the event to GSK within 24 hours

Complete the liver event CRF, and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries 
resolve, stabilise, or return to within baseline 
(see MONITORING below)
MONITORING:
If ALT≥3xULN AND bilirubin 2xULN  or INR 
>1.5

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24 
hrs

Monitor subjects twice weekly until liver 
chemistries resolve, stabilise or return to 
within baseline

A specialist or hepatology consultation is 

Viral hepatitis serology3

Blood sample for pharmacokinetic (PK) 
analysis, obtained within 4h of the last 
dose4

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on 
the concomitant medications report form 
including acetaminophen, herbal remedies, 
other over the counter medications.

Record alcohol use on the liver event 
alcohol intake case report form
If ALT≥3xULN AND bilirubin 2xULN  or 
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
72
recommended
If ALT≥3xULN AND bilirubin < 2xULN  and 
INR ≤1.5:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24-
72 hrs

Monitor subjects weekly until liver 
chemistries resolve, stabilize or return to 
within baseline
INR >1.5:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG or gamma 
globulins).

Serum acetaminophen adduct High 
Performance Liquid Chromatography
(HPLC) assay (quantifies potential 
acetaminophen contribution to liver injury 
in subjects with definite or likely 
acetaminophen use in the preceding week 
[James, 2009]. NOTE: not required in 
China.

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured, which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); International normalized ratio (INR) measurement is not required 
and the threshold value stated will not apply to subjects receiving anticoagulants
3.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
4.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
73
12.3.
Appendix 3: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.3.1.
Definition of Adverse Events
Adverse Event Definition:

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.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae).

The signs and symptoms and/or clinical sequelae resulting from lack of efficacy will 
be reported if they fulfil the definition of an AE or SAE.  Also, "lack of efficacy" or 
"failure of expected pharmacological action" also constitutes an AE or SAE.
Events NOT meeting definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 
condition.
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
74

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
12.3.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
a.
Results in death
b.
Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c.
Requires hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting.  Complications that occur during hospitalization are 
AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d.
Results in disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
75
and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday 
life functions but do not constitute a substantial disruption
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition.  These should also be considered 
serious.

Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse
g.
Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** > 1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick.  If fractionation is unavailable and ALT 3xULN 
and total bilirubin 2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.
12.3.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
76

Deep venous thrombosis/pulmonary embolism

Revascularization
12.3.4.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the CRF

It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to GSK in lieu of completion of the GSK, AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK.  In this instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to 
submission of to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.
12.3.5.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort
and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. - an AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
77
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled 
out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of his/her assessment.

For each AE/SAE the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK.  However, it is very important 
that the investigator always make an assessment of causality for every event 
prior to the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.

The investigator is obligated to assist.  This may include additional laboratory tests 
or investigations, histopathological examinations or consultation with other health 
care professionals.

If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide GSK with a copy of any post-mortem findings, 
including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
78
12.3.6.
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data collection 
tool

If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and fax it to the Medical Monitor

Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.

The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of 
the SAE.

After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) will be taken off-line to prevent the entry of new data or changes to 
existing data

If a site receives a report of a new SAE from a study subject or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, the site can report this information on a paper SAE form or to the Medical 
Monitor or the SAE coordinator by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
79
12.4.
Appendix 4: Definition of and Procedures for Documenting 
Medical Device Incidents
12.4.1.
Definitions of a Medical Device Incident
The detection and documentation procedures described in this protocol apply to all GSK 
medical devices provided for use in the study (see Section 6.2 for the list of GSK medical 
devices).
Medical Device Incident Definition:

Incident – Any malfunction or deterioration in the characteristics and/or performance 
of a device, as well as any inadequacy in the labeling or the instructions for use 
which, directly or indirectly, might lead to or might have led to the death of a 
patient/user/other persons or to a serious deterioration in their state of health.

Not all incidents lead to death or serious deterioration in health.  The non-occurrence 
of such a result might have been due to other fortunate circumstances or to the 
intervention of health care personnel.
It is sufficient that:

an incident associated with a device happened and

the incident was such that, if it occurred again, might lead to death or a serious 
deterioration in health.
A serious deterioration in state of health can include:

life-threatening illness

permanent impairment of body function or permanent damage to a body structure

a condition necessitating medical or surgical intervention to prevent one of the above 

fetal distress, fetal death or any congenital abnormality or birth defects
Examples of incidents

a patient, user, care giver or professional is injured as a result of a medical device 
failure or its misuse

a patient’s treatment is interrupted or compromised by a medical device failure

misdiagnosis due to medical device failure leads to inappropriate treatment

a patient’s health deteriorates due to medical device failure
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
80
12.4.2.
Documenting Medical Device Incidents
Medical Device Incident Documenting:

Any medical device incident occurring during the study will be documented in the 
subject’s medical records, in accordance with the investigator’s normal clinical 
practice, and on the appropriate form.

For incidents fulfilling the definition of an AE or an SAE, the appropriate AE/SAE 
CRF page will be completed as described in Appendix 3.

The form will be completed as thoroughly as possible and signed by the investigator 
before transmittal to GSK.

It is very important that the investigator provides his/her assessment of causality to 
the medical device provided by GSK at the time of the initial report, and describes 
any corrective or remedial actions taken to prevent recurrence of the incident.

A remedial action is any action other than routine maintenance or servicing of a 
device where such action is necessary to prevent recurrence of an incident. This 
includes any amendment to the design to prevent recurrence.
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
81
12.5.
Appendix 5: List of Acceptable Methods for Avoiding 
Pregnancy in FRP and Collection of Pregnancy Information
12.5.1.
Group 2, Cohort B Only: List of Acceptable Non-hormonal
Methods for Avoiding Pregnancy in Females of Reproductive 
Potential (FRP)
The list does not apply to FRP with same sex partners or for subjects 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.
1.
Nonhormonal Intrauterine device or 
2.
Male condom combined with vaginal spermicide
3.
Male partner sterilization with documentation of azoospermia prior to the female 
subject's entry into the study, and this male is the sole partner for that subject 
[Hatcher, 2011]. The documentation on male sterility can come from the site 
personnel’s: review of subject’s medical records, medical examination and/or semen 
analysis, or medical history interview provided by her or her partner.
These allowed 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 these methods of contraception.
12.5.2.
Collection of Pregnancy Information
Group 2 Only

Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study

Information will be recorded on the appropriate form and submitted to GSK within 2 
weeks of learning of a subject's pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on mother and infant, which will be 
forwarded to GSK.  Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date. 

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
82

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK 
as described in Section 12.3. While the investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.
Any female subject who becomes pregnant while participating 

will discontinue study medication or be withdrawn from the study.
12.5.3.
References
Bolton TJ, Randall K, Yentis SM. Effect of the Confidential Enquiries into Maternal 
Deaths on the use of Syntocinon at Caesarean section in the UK. Anaesthesia 2003(58-
3):277-9.
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, Policar MS, 
editors. Contraceptive Technology. 20th edition. Atlanta, Georgia: Ardent Media, Inc., 
2011: 50. Table 3-2.
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
83
12.6.
Appendix 6: Country Specific Requirements
No country-specific requirements exist.
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
84
12.7.
Appendix 7: Device Acceptability Questionnaire
Device Acceptability Questionnaire
Please answer the following questions regarding your use of the ROTAHALER inhaler
for oxytocin.
1. Did you feel confident you had received the medicine?
Yes
No
Neutral
Decline to answer
2. Did you find the inhaler easy to use?
Yes
No
Neutral
Decline to answer
3. Did you prefer to have your medicine from an inhaler instead of an injection?
Yes
No
Neutral
Decline to answer
4. Do you feel using this inhaler is an acceptable way to administer the medicine?
Yes
No
Neutral
Decline to answer
Thank you for answering these questions.
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
85
12.8.
Appendix 8: Protocol Changes
12.8.1.
Protocol Amendment 01
As part of the Medical Device Notification assessment process, the Medicines and 
Healthcare products Regulatory Agency (MHRA) requested that the protocol 
prominently reflect that although the investigational device (the ROTAHALER) bears a 
CE mark, it has not been CE marked in accordance with the Medical Device Directive 
93/42/EEC as updated. This change applies to all sites.
Section 6.2 Medical Devices 
Change From:
The GSK manufactured medical device (or device manufactured for GSK by a third 
party) provided for use in this study is a high airflow resistance capsule-based inhaler 
(Modified Air Inlet ROTAHALER DPI device). 
Instructions for medical device use are provided in Section 6.7. Further details on use of 
the device are provided in the SRM.
GSK medical device incidents, including those resulting from malfunctions of the device, 
must be detected, documented, and reported by the investigator throughout the study –
see Section 12.4.
Change to:
The GSK manufactured medical device (or device manufactured for GSK by a third 
party) provided for use in this study is a high airflow resistance capsule-based inhaler 
(Modified Air Inlet ROTAHALER DPI device). Although this investigational device 
bears a CE mark, it has not been CE marked in accordance with the Medical 
Devices Directive 93/42/EEC.
Instructions for medical device use are provided in Section 6.7. Further details on use of 
the device are provided in the SRM.
GSK medical device incidents, including those resulting from malfunctions of the device, 
must be detected, documented, and reported by the investigator throughout the study –
see Section 12.4.
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
86
12.8.2.
Protocol Amendment 02
This amendment has been implemented to update the PK sample collection procedures in 
order to enhance ex-vivo PK stability, and to implement in-stream PK data analysis 
following the informal interim analysis of the first 10 subjects to complete Group 1. 
Location of name and contact information for Secondary Medical Monitor has also been 
updated.
Medical Monitor/Sponsor Information Page
Medical Monitor/SAE Contact Information
Change from:
Role
Name
Day Time Phone Number and 
email address
After-hours 
Phone/Cell/
Pager 
Number
Fax 
Number
Site 
Address
Secondary 
Medical 
Monitor
GSK
Gunnels 
Wood Road
Stevenage
SG1 2NY
UK
Change to
Role
Name
Day Time Phone 
Number and 
email address
After-hours 
Phone/Cell/
Pager 
Number
Fax 
Number
Site 
Address
Secondary 
Medical 
Monitor
Name and contact 
details available in 
Study Reference 
Manual
Section 1 Type and number of subjects
Change of typographical error from 45 to 50 subjects.
Change from:
In the event of this, sufficient subjects will be screened such that a maximum of 45 
subjects complete Group 1.
 
2019N402257_00
PPD


2016N281575_03
CONFIDENTIAL
205920
87
Change to:
In the event of this, sufficient subjects will be screened such that a maximum of 50 
subjects complete Group 1.
Section 2.2.2 PK Specimen Stability as Observed in 205920
Addition of this section to describe results from first informal interim analysis:
Prior to the initiation of the current trial, a sample-handling process was developed using 
blood from pregnant subjects of at least 37 weeks gestation to ensure ex-vivo oxytocin 
stability in specimens collected from Group 1 TSL subjects. 
Per protocol, after 10 subjects had completed all procedures in Group 1, an informal 
interim PK analysis was conducted. It was observed that in the majority of the plasma 
samples collected from TSL subjects, oxytocin concentrations were below the limit of 
quantification (BLQ) or at very low concentrations (approximately 3pg/mL) approaching 
the lower limit of quantification (LLQ) of the assay (2pg/mL). This was seen across both 
IM and IH routes of administration. This was an unexpected finding which has been 
confirmed by re-analysis of selected samples. As such, it is considered that it may be due 
to ex-vivo oxytocin instability related to uninhibited oxytocinase and peptidases, which 
are believed to be at increased concentrations in the plasma of postpartum women 
compared with non-pregnant women, and women at 37 weeks gestation. This finding 
resulted in a temporary halt to the trial.
Section 3.1 Group 1: Women in TSL
Typographical error correction.
Change from:
To characterize the pharmacokinetics of single doses of IH oxytocin and 10 I.U. IM 
oxytocinin women in TSL.
Change to:
To characterize the pharmacokinetics of single doses of IH oxytocin and 10 I.U. IM 
oxytocin in women in TSL.
Section 4.3 Type and Number of Subjects
Change of typographical error from 45 to 50 subjects.
Change from:
In the event of this, sufficient subjects will be screened such that a maximum of 45
subjects complete Group 1.
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
88
Change to:
In the event of this, sufficient subjects will be screened such that a maximum of 50
subjects complete Group 1.
Section 5.4.6 Plasma oxytocin concentration stopping criteria
Addition of this section and following text:
Per Section 9.3.2.1, the plasma oxytocin concentrations in up to 5 subjects in Group 1 
will be analysed in real time. If the plasma oxytocin concentration is BLQ or sufficiently 
low to prohibit interpretation in these 5 subjects irrespective of treatment, the study will 
be halted and reviewed.
Section 6.3 Treatment Assignment
Addition of following text:
If deemed necessary or if there is a new site identified for conducting and/or continuing 
the clinical trial, then a new randomization schedule may be generated by Clinical
Statistics, prior to the start of the study at the new site, using validated internal software.
Section 6.4 Planned Dose Adjustments
Typographical error correction
Change from: 
For Group 2, if an exaggerated physicological response is seen with the IV dose, such as 
increased heart rate and decreased blood pressure, then consideration will be given to 
changing to a 5-minute infusion.
Change to:
For Group 2, if an exaggerated physiological response is seen with the IV dose, such as 
increased heart rate and decreased blood pressure, then consideration will be given to 
changing to a 5-minute infusion.
Section 7.4.1 Blood Sample Collection 
Change from:
At each time point, 4 mL of blood will be collected into K2 or K3 
Ethylenediaminetetraacetic acid (EDTA) tubes and stored on ice for up to 2 hours prior to 
centrifugation in a refrigerated centrifuge. Further details regarding collection/shipping 
procedures are provided in the SRM.
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
89
Change to:
At each time point, 4 mL of blood will be collected into study-specific tubes formulated 
to further inhibit peptidase activity. Additional details regarding collection/shipping 
procedures are provided in the SRM.
Section 7.4.2 Sample Analysis 
Addition of the following text:
Once the plasma has been analyzed for oxytocin any remaining plasma may be analysed 
for metabolites of oxytocin and the results reported separately.
Section 9.3.2 Interim Analyses 
Change from:
No formal interim analysis is planned. However, PK samples will be analysed and 
preliminary PK parameters derived following completion of 5 women on each of the 
following treatments: 400 mcg IH and 10 I.U. IM to women in TSL (Group 1) and 
400 mcg IH to non-pregnant women on the combined  oral contraceptive (Group 2 
Cohort A).  Based on the PK profiles the dose of IH oxytocin to be administered to 
women in TSL will either remain at 400 mcg or be increased (to 600 mcg) (See Section
6.4.1). This decision will be made by the study team in collaboration with the Principal 
Investigator. 
Change to:
No formal interim analyses are planned. PK data will be reviewed per Section 9.3.2.1 and 
Section 9.3.2.2.
9.3.2.1 Informal Interim Reviews
PK samples will be analysed and preliminary PK parameters derived following 
completion of 5 women on each of the following treatments: 400 mcg IH and 10 I.U. IM 
to women in TSL (Group 1) and 400 mcg IH to non-pregnant women on the combined 
oral contraceptive (Group 2 Cohort A).  Based on the PK profiles the dose of IH oxytocin 
to be administered to women in TSL will either remain at 400 mcg or be increased (to 
600 mcg) (See Section 6.4.1). This decision will be made by the study team in 
collaboration with the Principal Investigator. 
This will be repeated after restart from the temporary halt for Group 1.
9.3.2.2 In-Stream Analysis of Group 1
Following restart from temporary halt, PK specimens from each of up to 5 subjects in 
Group 1 will be analysed as soon as possible after collection. This will allow for 
confirmation that the revised specimen collection procedures allow for detection of 
adequate oxytocin PK profile. 
 
2019N402257_00


2016N281575_03
CONFIDENTIAL
205920
90
12.8.3.
Protocol Amendment 03
This protocol amendment updates the analysis plans to permit sharing of informal interim 
data with key partners, and to complete the analysis of Group 2 before Group 1 is 
complete.
Section 1 Protocol Synopsis (Objectives/Endpoints), Section 3.2, Section 3.3
Correction of typographical error: “AUC(0-3h)” listed twice in various endpoints.
Section 9.3.2
Addition of the following italic text:
No formal interim analyses are planned. PK data will be reviewed per Section 9.3.2.1,
Section 9.3.2.2, and Section 9.3.2.3, and may be shared with any relevant third party to 
allow for discussion around future partnering opportunities for IH oxytocin.
Addition of the following section:
Section 9.3.2.3 Analysis of Group 2
An analysis of Group 2 (non-pregnant volunteers) will be performed once Group 2 has 
completed to allow for full reporting of non-pregnant volunteer data prior to completion 
of Group 1.
There will be no changes to the study design or Group 1 of the study as a result of this 
analysis. The RAP will describe the planned analysis in greater detail.
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
The GlaxoSmithKline group of companies
205920
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
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.
Compound Number:
GR121619
Development Phase
I
Effective Date:
04-JAN-2018
Protocol Amendment Number:  02
Author (s):
 
Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2016N281575_00
2016-AUG-22
Original
2016N281575_01
2016-OCT-10
Amendment No. 1
Section 6.2: Inclusion of information on CE marking.
2016N281575_02
2018-JAN-04
Amendment No. 2
Update to PK collection procedures and implementation of in-stream PK data analysis.
Update to location of Secondary Medical Monitor contact information.
Copyright 2018 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
2019N402257_00
PPD


 
2019N402257_00
PPD
PPD


2016N281575_02
CONFIDENTIAL
205920
3
MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information: 
Role
Name
Day Time Phone Number 
and email address
After-hours 
Phone/Cell/
Pager 
Number
Fax 
Number
Site 
Address
Primary 
Medical 
Monitor 
GSK
Gunnels 
Wood 
Road
Stevenage
SG1 2NY
UK
Secondary 
Medical 
Monitor
Name and 
contact 
details 
available in 
Study 
Reference 
Manual
SAE contact  
information 
Medical 
monitor as 
above 
Sponsor Legal Registered Address:
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline (GSK)
Affiliate Company (or designee). If applicable, the details of the alternative Sponsor and 
contact person in the territory will be provided to the relevant regulatory authority as part 
of the clinical trial application.   
Regulatory Agency Identifying Number(s): EudraCT 2016-002672-27
 
2019N402257_00
PPD


2016N281575_02
CONFIDENTIAL
205920
4
INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol 205920
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
5
TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 205920........................................................9
2.
INTRODUCTION....................................................................................................13
2.1.
Study Rationale ..........................................................................................14
2.2.
Brief Background ........................................................................................14
2.2.1.
IH Oxytocin FTIH Study 201558 ..................................................16
2.2.2.
PK Specimen Stability as Observed in 205920 ............................16
3.
OBJECTIVES AND ENDPOINTS...........................................................................17
3.1.
Group 1: Women in TSL .............................................................................17
3.2.
Group 2: Non-pregnant, non-lactating females of child bearing 
potential......................................................................................................18
3.3.
Groups 1 and 2: Women in TSL and Non-pregnant, non-lactating 
females of child bearing potential................................................................19
4.
STUDY DESIGN ....................................................................................................19
4.1.
Overall Design ............................................................................................19
4.1.1.
Study Schematic Group 1: Women in TSL...................................19
4.1.2.
Study Schematic Group 2: Non-pregnant, non-lactating 
females of child bearing potential.................................................19
4.1.3.
Study Design Detail .....................................................................19
4.1.3.1.
Pregnant Females (Group 1)......................................20
4.1.3.2.
Non-pregnant Females (Group 2)...............................20
4.1.4.
ROTAHALER Inhaler Training .....................................................21
4.1.5.
Length of Stay for All Subjects.....................................................21
4.2.
Treatment Arms and Duration.....................................................................22
4.3.
Type and Number of Subjects.....................................................................23
4.4.
Design Justification.....................................................................................23
4.5.
Dose Justification........................................................................................23
4.6.
Benefit:Risk Assessment ............................................................................26
4.6.1.
Risk Assessment .........................................................................26
4.6.2.
Immunogenicity Risk....................................................................29
4.6.3.
Benefit Assessment and Overall Benefit:Risk Conclusion............29
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............30
5.1.
Inclusion Criteria.........................................................................................30
5.2.
Exclusion Criteria........................................................................................33
5.3.
Screening/Baseline/Run-in Failures............................................................35
5.3.1.
Re-screening ...............................................................................35
5.4.
Withdrawal/Stopping Criteria.......................................................................35
5.4.1.
Pregnancy Complication Stopping Criteria (Group 1 Only) ..........35
5.4.2.
Anaphylaxis Stopping Criteria......................................................36
5.4.3.
QTc Stopping Criteria (Group 2 Only)..........................................36
5.4.4.
Blood Pressure Stopping Criteria (Group 2 Only).........................36
5.4.5.
Liver Chemistry Stopping Criteria ................................................36
5.4.6.
Plasma oxytocin concentration stopping criteria...........................37
5.5.
Subject and Study Completion....................................................................37
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
6
6.
STUDY TREATMENT ............................................................................................37
6.1.
Investigational Product and Other Study Treatment....................................37
6.2.
Medical Devices..........................................................................................38
6.3.
Treatment Assignment................................................................................38
6.4.
Planned Dose Adjustments.........................................................................39
6.4.1.
Dose Adjustment .........................................................................39
6.5.
Blinding.......................................................................................................40
6.6.
Packaging and Labeling..............................................................................40
6.7.
Preparation/Handling/Storage/Accountability..............................................40
6.8.
Compliance with Study Treatment Administration.......................................41
6.9.
Treatment of Study Treatment Overdose....................................................42
6.10.
Treatment after the End of the Study ..........................................................43
6.11.
Lifestyle and/or Dietary Restrictions............................................................43
6.11.1.
Meals and Dietary Restrictions ....................................................43
6.11.2.
Caffeine and Alcohol....................................................................43
6.11.3.
Activity .........................................................................................44
6.12.
Concomitant Medications and Non-Drug Therapies....................................44
6.12.1.
Permitted Medications and Non-Drug Therapies..........................44
6.12.2.
Prohibited Medications and Non-Drug Therapies.........................44
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................44
7.1.
Time and Events Table...............................................................................46
7.1.1.
Time and Events Table – General Overview................................46
7.1.2.
Time and Events – Main Phase Procedures ................................48
7.2.
Screening and Critical Baseline Assessments ............................................50
7.3.
Safety .........................................................................................................50
7.3.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........50
7.3.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................50
7.3.1.2.
Method of Detecting AEs and SAEs ...........................51
7.3.1.3.
Follow-up of AEs and SAEs........................................51
7.3.1.4.
Regulatory Reporting Requirements for SAEs............51
7.3.2.
Adverse Events of Special Interest (AESI)...................................52
7.3.3.
Pregnancy ...................................................................................52
7.3.4.
Medical Device Incidents (Including Malfunctions).......................52
7.3.4.1.
Time Period for Detecting Medical Device 
Incidents.....................................................................52
7.3.4.2.
Follow-up of Medical Device Incidents........................52
7.3.4.3.
Prompt Reporting of Medical Device Incidents 
to GSK........................................................................53
7.3.4.4.
Regulatory Reporting Requirements for 
Medical Device Incidents............................................53
7.3.5.
Physical Exams ...........................................................................53
7.3.6.
Vital Signs....................................................................................53
7.3.7.
Documentation of Labour Events.................................................53
7.3.8.
Electrocardiogram (ECG) (Group 2 Only) ....................................54
7.3.9.
Continuous Cardiac Telemetry (Group 2 Only) ............................54
7.3.10.
Device Acceptability Questionnaire (Group 1 Only) .....................54
7.3.11.
Clinical Safety Laboratory Assessments ......................................54
7.4.
Pharmacokinetics .......................................................................................56
7.4.1.
Blood Sample Collection..............................................................56
7.4.2.
Sample Analysis ..........................................................................56
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
7
7.5.
Biomarkers .................................................................................................56
7.5.1.
Pharmacodynamic Markers .........................................................56
7.5.2.
Immunogenicity............................................................................56
8.
DATA MANAGEMENT ...........................................................................................57
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................57
9.1.
Hypotheses.................................................................................................57
9.2.
Sample Size Considerations.......................................................................58
9.2.1.
Sample Size Sensitivity................................................................58
9.2.2.
Sample Size Re-estimation or Adjustment...................................59
9.3.
Data Analysis Considerations .....................................................................59
9.3.1.
Analysis Populations....................................................................59
9.3.2.
Interim Analyses ..........................................................................59
9.3.2.1.
Informal Interim Reviews ............................................60
9.3.2.2.
In-Stream Analysis of Group 1....................................60
9.4.
Key Elements of Analysis Plan ...................................................................60
9.4.1.
Primary Analyses.........................................................................60
9.4.1.1.
Safety Analysis...........................................................60
9.4.1.2.
Pharmacokinetic Analysis...........................................60
9.4.2.
Secondary Analyses ....................................................................61
9.4.2.1.
Pharmacokinetic Analysis...........................................61
9.4.3.
Exploratory Analyses ...................................................................61
9.4.3.1.
Pharmacokinetic Analysis...........................................61
9.4.3.2.
Device Acceptability Questionnaire ............................61
10. STUDY GOVERNANCE CONSIDERATIONS........................................................61
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............61
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................62
10.3.
Quality Control (Study Monitoring) ..............................................................62
10.4.
Quality Assurance.......................................................................................63
10.5.
Study and Site Closure ...............................................................................63
10.6.
Records Retention......................................................................................64
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................64
11. REFERENCES.......................................................................................................66
12. APPENDICES........................................................................................................68
12.1.
Appendix 1 Abbreviations and Trademarks.................................................68
12.2.
Appendix 2 Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................71
12.3.
Appendix 3 Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................73
12.3.1.
Definition of Adverse Events........................................................73
12.3.2.
Definition of Serious Adverse Events...........................................74
12.3.3.
Definition of Cardiovascular Events .............................................75
12.3.4.
Recording of AEs and SAEs ........................................................76
12.3.5.
Evaluating AEs and SAEs............................................................76
12.3.6.
Reporting of SAEs to GSK...........................................................78
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
8
12.4.
Appendix 4  Definition of and Procedures for Documenting Medical 
Device Incidents .........................................................................................79
12.4.1.
Definitions of a Medical Device Incident.......................................79
12.4.2.
Documenting Medical Device Incidents .......................................80
12.5.
Appendix 5 List of Acceptable Methods for Avoiding Pregnancy in 
FRP and Collection of Pregnancy Information ............................................81
12.5.1.
Group 2, Cohort B Only:  List of Acceptable Non-hormonal 
Methods for Avoiding Pregnancy in Females of 
Reproductive Potential (FRP) ......................................................81
12.5.2.
Collection of Pregnancy Information ............................................81
12.5.3.
References ..................................................................................82
12.6.
Appendix 6 Country Specific Requirements................................................83
12.7.
Appendix 7 Device Acceptability Questionnaire ..........................................84
12.8.
Appendix 8 Protocol Changes.....................................................................85
12.8.1.
Protocol Amendment 01 ..............................................................85
12.8.2.
Protocol Amendment 02 ..............................................................85
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
9
1.
PROTOCOL SYNOPSIS FOR STUDY 205920
Rationale
Post-partum hemorrhage is one of the main causes of maternal mortality in the 
developing world. The World Health Organization (WHO) lists oxytocin on its list of 
‘Essential Medicines’ for Humanity as a preventative treatment for post-partum 
hemorrhage; however, because of its cold-chain storage requirement and parenteral 
administration route, high-quality oxytocin is not always available in resource-poor 
settings. GlaxoSmithKline (GSK) has developed a stable, dry-powder formulation of 
oxytocin to address this unmet need, with the goal of reducing post-partum hemorrhage 
morbidity and mortality in these settings.
This study is being conducted to further assess safety and tolerability of inhaled oxytocin, 
and to characterize the pharmacokinetic (PK) profile of inhaled oxytocin 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 inhaled 
(IH) or intramuscular (IM) oxytocin as active management of the third stage of labour. 
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.
Objectives/Endpoints
Group 1 – Women in Third Stage of Labour (TSL)
Objectives
Endpoints
Primary

To characterize the pharmacokinetics of 
single doses of IH oxytocin and 
10 International Units (I.U.) IM oxytocin in 
women in TSL.

Plasma concentration time profile for IH 
oxytocin and 10 I.U. IM oxytocin.

PK parameters: Maximum observed plasma 
concentration (Cmax), Observed plasma 
concentrations at 10 minutes (min) post-
dose (Cp10), Observed plasma 
concentrations at 20 min post-dose (Cp20), 
Observed plasma concentrations at 30 min 
post-dose (Cp30), Time to Cmax (tmax), 
Area under concentration-time curve (AUC), 
and Terminal phase half-life (t1/2) will be 
calculated as data permit.
Secondary

To evaluate the safety and tolerability of 
inhaled oxytocin.

General safety parameters: adverse events
(AE); absolute values and changes over 
time of vital signs (blood pressure, heart 
rate, respiratory rate, temperature).

To compare pharmacokinetics of IH 
oxytocin to 10 I.U. IM oxytocin in women in 
TSL.

Cmax, Cp10, Cp20, Cp30, Area under the 
concentration-time curve from time zero 
(pre-dose) to three hours (h) (AUC[0-3h]) 
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
10
Objectives
Endpoints
will be compared as data permit.
Exploratory 

Pharmacodynamic effect of IH oxytocin 
and 10 I.U. IM oxytocin in women in TSL.

Pre and post-delivery haemoglobin. 

Participant feedback regarding ease of 
use, instructions, and perceived ability of 
patients to use the ROTAHALER.

Questionnaire results from participants.
Group 2 – Non-pregnant, non-lactating females of child bearing potential
Objectives
Endpoints
Primary

To evaluate the safety and tolerability of IH 
and IV oxytocin.

General safety parameters: adverse events; 
absolute values and changes over time of 
vital signs (blood pressure, heart rate) and 
12-lead electrocardiogram (ECG) 
parameters (PR, QRS, QT, Corrected QT 
interval [QTc] intervals) from pre-dose 
values. 

Specific respiratory safety parameters: 
adverse respiratory events as monitored by 
spirometry including Forced expiratory 
volume at 1 minute (FEV1.0), respiratory 
rate, and pulse oximetry.

To characterize the pharmacokinetics of 
single doses of IH oxytocin and 5 I.U. IV 
oxytocin.

Plasma concentration time profile for IH 
oxytocin and 5 I.U. IV oxytocin.

PK parameters: Cmax, Cp10, Cp20, Cp30, 
tmax, AUC, Plasma clearance (CL), volume 
of distribution and t1/2 will be calculated as 
data permit.
Exploratory 

To evaluate endogenous plasma oxytocin 
concentrations in non-pregnant females in 
the presence and absence of the combined 
oral contraceptive.

Pre-dose plasma concentrations of 
oxytocin.

To compare the IH pharmacokinetics of 
oxytocin between Cohort A (subjects on 
combined oral contraceptive) and Cohort B 
(subjects using a non-hormonal form of 
contraception).

Cp10, Cp20, Cp30, AUC(0-3h) Cmax, 
AUC(0-3h), Area under the concentration-
time curve from time zero to infinity
(AUC[0-∞]) and t1/2, will be compared as 
data permit.

To compare the IV pharmacokinetics of 
oxytocin between Cohort A and Cohort B.

Cmax, AUC, t1/2, CL and Volume of 
distribution (VOD) will be compared as 
data permit.
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
11
Groups 1 and 2 – Women in TSL and Non-pregnant, non-lactating females of child bearing 
potential
Objectives
Endpoints
Exploratory 

To compare pharmacokinetics of IH 
oxytocin between Group 1 and Group 2

Cp10, Cp20, Cp30, AUC(0-3h) Cmax, 
AUC(0-3h) AUC(0-∞), and t1/2 will be 
compared as data permit.
Overall Design
Group 1 – Women in TSL
Group 2 – Non-pregnant, non-lactating females of child bearing potential
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
12
Treatment Arms and Duration
Screening
Group 1: All screening assessments to be completed after the 18th
week of pregnancy (based on estimated date of delivery).
Group 2: All screening assessments to be completed within 28 days
prior to the first dose.
Treatment Session
Group 1: Each subject will take part in 1 dosing session.
Group 2: Each subject will take part in 2 dosing sessions.
Treatment Arms1
Group 1: Subjects will be randomised to receive one of the following 
study treatments:

400 micrograms (mcg) IH oxytocin

10 I.U. IM oxytocin
Group 2: Subjects will receive both of the following study treatments 
over the course of two dosing sessions:

400 mcg IH oxytocin

5 I.U. IV oxytocin
Follow-up
Group 1: Follow Up 1 – Within approximately 24 h post dose.
Group 1: Follow Up 2 –  At least 7 days and no greater than 14 days 
after study drug administration.
Both visits may be conducted in-person or via telephone.
Group 2: At least 7 days and no greater than 21 days after last study 
drug administration.
This visit will be conducted in-person.
If warranted, additional follow-up visits may be scheduled for both 
Groups.
Total Duration
Group 1: Screening after 18th week of pregnancy (i.e. within 168 days of 
1 dosing session) + follow up of 7 - 14 days = approximately 183 days
Group 2: Screening within 28 days of dosing session 1 + 2 dosing 
sessions with a maximum of 14 days between dosing + follow-up of 7 –
21 days = 64 days
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
13
Type and Number of Subjects
Sufficient subjects will be screened such that approximately 20 subjects complete all 
study procedures in Group 1, and approximately 10 subjects complete all study 
procedures in Group 2 (approximately 5 in each cohort of Group 2). 
If subjects prematurely discontinue the study, additional replacement subjects may be 
recruited and assigned to the same treatment sequence at the discretion of the Sponsor. 
Replacement subjects will complete all study procedures.
If the PK variability between subjects in Group 1 is higher than expected, it may be 
required to increase the sample size up to a maximum of 10 additional subjects per 
treatment group for inhaled and intramuscular oxytocin. In the event of this, sufficient 
subjects will be screened such that a maximum of 50 subjects complete Group 1.
If a dose adjustment is required in either group, additional subjects may be recruited such 
that a full 10 subjects receive the final IH or IV dose.
Analysis
The primary objective of this study is to characterize pharmacokinetics of IH oxytocin 
and IM oxytocin in women in the third stage of labour.
No formal hypotheses will be tested, however, comparisons of interest, within Group 1,
and between Group 1 and Group 2 and between Cohorts A and B in Group 2 will be 
made and the point estimates and corresponding two-sided 90% confidence intervals (CI)
will be presented to provide the range of plausible values for the comparisons. 
2.
INTRODUCTION
Maternal mortality associated with postpartum hemorrhage (PPH) is one of the major 
public health problems in the developing world. Approximately half a million women 
worldwide die annually from causes directly related to pregnancy and childbirth, and up 
to one third of these deaths in Africa and Asia are caused by complications as a result of 
PPH [Khan, 2006;WHO, 2010]. A Cochrane Review meta-analysis of the data from 
multiple preventative trials with oxytocin at 10 international units (I.U.) given via the 
intramuscular (IM) route has confirmed this specific uterotonic, and this particular route 
of administration, to be the gold standard prophylactic therapy for PPH [Mousa, 2014]. 
For this reason, the World Health Organization (WHO) has designated oxytocin as one of 
its ‘Essential Medicines’ for humanity [WHO Model List of Essential Medicines 18th list, 
April 2013; WHO Model List of Essential Medicines for Children 4th list, April 2013].
However, in resource-poor settings within the developing world, the 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 
[Mousa, 2014]. Although single-use, oxytocin prefilled, syringes for IM injection are 
available in many developing countries (e.g. UNIJECT device), the development of a 
needle-free and self-administered inhaled (IH) oxytocin product, which delivers 
comparable systemic exposure to 10 I.U. IM, would be a major step-change in the 
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
14
administration of this life-saving medicine to pregnant women in resource-poor regions 
of the developing world. This would be particularly relevant in rural areas where the 
mother has no routine access to a trained HCP and/or where there is no reliable electricity 
supply to permit refrigerated storage of oxytocin injection vials. 
We have developed a stable, dry-powder formulation of oxytocin to be administered via 
the oral inhaled pulmonary route (compared to 10 I.U. of IM oxytocin) using a 
GlaxoSmithKline (GSK)-manufactured medical device (or device manufactured for GSK 
by a third party) which is a capsule-based inhaler (Modified Air Inlet ROTAHALERTM
Dry Powder Inhaler (DPI) device, hereafter referred to as ROTAHALER). This 
formulation and delivery method has the potential to be used in settings where effective 
oxytocin is currently unavailable to women in the third stage of labour (TSL).
2.1.
Study Rationale
This study will be the second investigation of oxytocin in humans via the IH route, which 
follows the first time in human (FTIH) study, 201558 [GlaxoSmithKline Document 
Number 2015N234711_01, 2015; see Section 2.2.1 for more information on the FTIH 
trial)]. Published literature on the pharmacokinetics (PK) of oxytocin in non-pregnant and 
pregnant women is limited.  There is some evidence to suggest that the metabolic 
clearance of oxytocin may increase during pregnancy; potentially related to degradation 
by the circulating aminopeptidase, oxytocinase, and/or pregnancy related changes in 
hepatic and renal function [Syntocinon Summary of Product Characteristics, Novartis, 
2014; Thornton, 1990].  In addition, endogenous oxytocin plasma concentrations have 
been reported to either increase or remain constant after the delivery of the fetal anterior 
shoulder [Thornton, 1988]. As a result of these pregnancy related changes, systemic 
exposure to oxytocin may differ between healthy non-pregnant women and women in the 
TSL for a given dose and route of administration of oxytocin. To further understand the 
effect of pregnancy on the PK of oxytocin, this study will investigate the PK of oxytocin 
in pregnant women in TSL following either IH (400 micrograms [mcg]) or 10 I.U. IM 
(17 mcg) administration. A greater understanding of the PK of oxytocin in TSL will help 
facilitate extrapolation of data obtained in healthy non-pregnant women to women in 
TSL. An additional group of  non-pregnant non-lactating female volunteers will also be 
included as a control group and will receive 400 mcg IH oxytocin and 5 I.U. intravenous 
(IV) oxytocin. This second group will enrol one cohort of subjects taking the combined 
oral contraceptive (COC), and another cohort using a non-hormonal form of 
contraception. This will assess if women need to be on an oral contraceptive vs. other 
methods of birth control in future clinical studies, since although the COC is believed to 
suppress endogenous oxytocin levels the literature is not consistent about this 
observation. As the requirement to be taking the COC makes recruitment more of a 
challenge it will be helpful to know if this inclusion is essential, or if women using non-
hormonal forms of birth control might also have sufficiently low systemic oxytocin levels 
suitable for PK studies.
2.2.
Brief Background
Oxytocin is a nonapeptide which is produced by the hypothalamus and released into the 
systemic circulation by the posterior pituitary gland. Within the brain, oxytocin, like most 
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
15
hypothalamic synthesized hormones, acts as a neurotransmitter. In human pregnancy,
during the later phases of the third trimester, increasing circulating levels of oxytocin act 
as a potent endogenous uterotonic which facilitates the initiation of labour. Furthermore, 
a neurohormonal positive feedback loop exists between dilatation of the cervico-vaginal 
canal by fetal passage and the hypothalamus (i.e. Fergusson reflex) which augments 
oxytocin production, thus increasing uterine contraction intensity and frequency which 
facilitates vaginal delivery. However, once the fetus is delivered, plasma oxytocin levels 
rapidly diminish probably due to a combination of increased circulating levels of 
oxytocinase (the principal oxytocin deactivating enzyme), in the plasma, an overall 
reduction in hypothalamic oxytocin synthesis (Figure 1), and a reduction in uterine 
oxytocin receptor (OTR) density. This oxytocin-depleted, relatively auterotonic, 
physiological environment puts the mother at risk of PPH during the subsequent placental 
delivery phase (i.e. TSL). 
Figure 1
Oxytocin During Physiological Fetal Delivery
Oxytocin receptors are constitutively expressed in smooth muscle cells (SMCs) in the 
uterine myometrium, muscular walls of the bronchi and upper digestive tract, 
myoepithelial cells of the breast duct which are essential for the oxytocin-dependent 
postpartum breast milk let-down reflex, and in different regions of the brain.  Although 
uterine OTR expression increases during the later stages of pregnancy, it is not known 
whether pregnancy increases OTR expression at non-uterine sites, such as the maternal 
brain, where neuronal oxytocin signalling has been implicated in postpartum bonding 
behaviour with the baby. Within the kidney, oxytocin is known to bind to vasopressin 
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
16
(V2) receptors, rather than OTR, in the medullary renal collecting duct which triggers an 
antidiuretic effect.
Binding of oxytocin to OTR triggers an increase in intracellular calcium (Ca2+), which is 
partly mediated through oxytocin-dependent up-regulation of prostaglandin F (PGF)2α 
synthesis, which in the uterine myometrium leads to physiological uterine contractions 
during 3rd-stage labour.
More recent research has shown oxytocin to be present in broncho-alveloar lavage fluid 
collected from the respiratory tract of adult humans of both sexes, but oxytocinase 
expression was not assessed. In an in vivo pharmacology study [Prankerd , 2013] in
pregnant ewes intratracheal insufflation of a dry-powder formulation of oxytocin was 
associated with poor absolute bioavailability (ca 5%), but despite low systemic exposure, 
this still caused a pharmacodynamic response that was manifested by increased electrical 
uterine activity measured by electromyography, probably as a result of increased OTR 
stimulation in the pregnant uterus.
2.2.1.
IH Oxytocin FTIH Study 201558
Study 201558 [GlaxoSmithKline Document Number 2016N277949_00] was the FTIH 
study to evaluate safety, tolerability, and characterize the PK profile of 4 dose strengths 
of IH oxytocin compared to oxytocin 10 I.U. IM. The study enrolled 16 healthy, non-
pregnant, premenopausal female subjects. One subject was withdrawn prior to IH 
oxytocin dosing due to inability to cannulate. Subjects were administered 10 I.U. IM 
oxytocin, IH placebo containing (only) the excipients found in the IH oxytocin 
formulation, and IH oxytocin. A minimum washout period of 48 hours (h) was required 
between each dose of active drug. This dose escalation study evaluated 4 doses of IH 
oxytocin: 50 mcg, 200 mcg, 400 mcg, and 600 mcg. The most frequently reported 
Adverse Event (AE) was headache, and occurred in at least one subject in each treatment 
arm. In general, IH oxytocin was well-tolerated, no safety concerns with IH dosing were 
identified, no clinically significant effect on respiratory parameters were observed, and 
no Serious Adverse Events (SAEs) were reported. The PK profile of the 400 mcg IH 
oxytocin dose was similar to that of 10 I.U. IM, and has been selected for further 
evaluation. See Section 4.5 for further information on PK characteristics.
2.2.2.
PK Specimen Stability as Observed in 205920
Prior to the initiation of the current trial, a sample-handling process was developed using 
blood from pregnant subjects of at least 37 weeks gestation to ensure ex-vivo oxytocin 
stability in specimens collected from Group 1 TSL subjects. 
Per protocol, after 10 subjects had completed all procedures in Group 1, an informal 
interim PK analysis was conducted. It was observed that in the majority of the plasma 
samples collected from TSL subjects, oxytocin concentrations were below the limit of 
quantification (BLQ) or at very low concentrations (approximately 3pg/mL) approaching 
the lower limit of quantification (LLQ) of the assay (2pg/mL). This was seen across both 
IM and IH routes of administration. This was an unexpected finding which has been 
confirmed by re-analysis of selected samples. As such, it is considered that it may be due 
to ex-vivo oxytocin instability related to uninhibited oxytocinase and peptidases, which 
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
17
are believed to be at increased concentrations in the plasma of postpartum women 
compared with non-pregnant women, and women at 37 weeks gestation. This finding
resulted in a temporary halt to the trial.
3.
OBJECTIVES AND ENDPOINTS
3.1.
Group 1: Women in TSL
Objectives
Endpoints
Primary

To characterize the pharmacokinetics of 
single doses of IH oxytocin and 10 I.U. IM 
oxytocin in women in TSL.

Plasma concentration time profile for IH 
oxytocin and 10 I.U. IM oxytocin.

PK parameters: Maximum observed plasma 
concentration (Cmax), Observed plasma 
concentrations at 10 minutes (min) post-
dose (Cp10), Observed plasma 
concentrations at 20 min post-dose (Cp20), 
Observed plasma concentrations at 30 min 
post-dose (Cp30), Time to Cmax (tmax), 
Area under concentration-time curve (AUC), 
and Terminal phase half-life (t1/2) will be 
calculated as data permit.
Secondary

To evaluate the safety and tolerability of 
inhaled oxytocin.

General safety parameters: adverse events; 
absolute values and changes over time of 
vital signs (blood pressure, heart rate, 
respiratory rate, temperature).

To compare pharmacokinetics of IH 
oxytocin to 10 I.U. IM oxytocin in women in 
TSL.

Cmax ,Cp10, Cp20, Cp30, Area under the 
concentration-time curve from time zero 
(pre-dose) to three hours (h) (AUC[0-3h])
will be compared as data permit.
Exploratory 

Pharmacodynamic effect of IH oxytocin 
and 10 I.U. IM in women in TSL.

Pre and post-delivery haemoglobin. 

Participant feedback regarding ease of 
use, instructions, and perceived ability of 
patients to use the ROTAHALER.

Questionnaire results from participants.
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
18
3.2.
Group 2: Non-pregnant, non-lactating females of child 
bearing potential
Objectives
Endpoints
Primary

To evaluate the safety and tolerability of IH 
and IV oxytocin.

General safety parameters: adverse events; 
absolute values and changes over time of 
vital signs (blood pressure, heart rate) and 
12-lead electrocardiogram (ECG) 
parameters (PR, QRS, QT, Corrected QT 
interval [QTc] intervals) from pre-dose 
values. 

Specific respiratory safety parameters: 
adverse respiratory events as monitored by 
spirometry including Forced expiratory 
volume at 1 minute (FEV1.0), respiratory 
rate, and pulse oximetry.

To characterize the pharmacokinetics of 
single doses of IH oxytocin and 5 I.U. IV 
oxytocin.

Plasma concentration time profile for IH 
oxytocin and 5 I.U. IV oxytocin.

PK parameters: Cmax, Cp10, Cp20, Cp30, 
tmax, AUC, Plasma clearance (CL), volume 
of distribution and t1/2 will be calculated as 
data permit.
Exploratory 

To evaluate endogenous plasma oxytocin 
concentrations in non-pregnant females in 
the presence and absence of the combined 
oral contraceptive.

Pre-dose plasma concentrations of 
oxytocin.

To compare the IH pharmacokinetics of 
oxytocin between Cohort A (subjects on 
combined oral contraceptive) and Cohort B 
(subjects using a non-hormonal form of 
contraception).

Cp10, Cp20, Cp30, AUC(0-3h) Cmax, 
AUC(0-3h), Area under the concentration-
time curve from time zero to infinity 
(AUC[0-∞]) and t1/2, will be compared as 
data permit.

To compare the IV pharmacokinetics of 
oxytocin between Cohort A and Cohort B.

Cmax, AUC, t1/2, CL and Volume of 
distribution (VOD) will be compared as 
data permit.
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
19
3.3.
Groups 1 and 2: Women in TSL and Non-pregnant, non-
lactating females of child bearing potential
Objectives
Endpoints
Exploratory 

To compare pharmacokinetics of IH 
oxytocin between Group 1 and Group 2.

Cp10, Cp20, Cp30, AUC(0-3h) Cmax, 
AUC(0-3h) AUC(0-∞), and t1/2 will be 
compared as data permit.
4.
STUDY DESIGN
4.1.
Overall Design
4.1.1.
Study Schematic Group 1: Women in TSL
4.1.2.
Study Schematic Group 2: Non-pregnant, non-lactating females 
of child bearing potential
4.1.3.
Study Design Detail
This study will enrol two groups. 
Group 1 - Women in TSL
Group 1 will enrol women with an uncomplicated pregnancy, and main phase procedures 
will occur during TSL. Subjects will be randomized to receive either IH or IM oxytocin 
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
20
as active management of TSL.  The specific timing of this dose will be as per local 
standard of care.1
Group 2 - Non-pregnant, non-lactating females of child bearing potential
Group 2 will enrol healthy, non-pregnant, non-lactating female subjects of childbearing 
potential, and each subject will participate in 2 dosing sessions. Group 2 will be divided
into two cohorts: Cohort A will enrol women on a combined oral contraceptive, and 
Cohort B will enrol women who are not using a hormonal form of contraceptive. Group 2 
subjects will receive IH oxytocin at one dosing session, and IV oxytocin at the other 
dosing session; the order of IH versus IV oxytocin administration will be randomly 
assigned.
PK samples will be analysed periodically throughout the study duration to enable 
development of the population PK model and derivation of PK parameters via non-
compartmental methods, as data permits.
No formal interim analysis is planned, however, PK samples will be analysed and 
preliminary PK parameters derived following completion of approximately 5 women on 
each treatment group: IH, IM in Group 1 and IH in Group 2 Cohort A in order to assess if 
dose escalation is required.  
4.1.3.1.
Pregnant Females (Group 1)
Subjects will review the study information and if they agree to participate, sign the
informed consent form. For most subjects this is expected to take place at an outpatient
antenatal visit, or additional study-specific screening visit. If a subject meets all 
inclusion/exclusion criteria for the study, she will be eligible for enrolment in the study.
To facilitate recruitment, and provide subjects ample time to consider participation, 
screening may occur any time after 18 weeks gestation (based on estimated date of 
delivery). See time and events (T&E) table in Section 7.1 for details.
4.1.3.2.
Non-pregnant Females (Group 2)
Subjects will review the study information and if they agree to participate, sign the 
informed consent form. If a subject meets all inclusion/exclusion criteria for the study, 
she will be enrolled in the study.
Screening may occur within 28 days prior to randomization for non-pregnant volunteers. 
If a subject falls outside this window prior to randomization and enrolment, she must be 
re-screened. Certain screening procedures may not be required to be repeated; see T&E 
(Section 7.1) for details.
                                                
1 For information only: Standard of care at proposed clinical site is to administer the oxytocic drug by IM 
injection with the birth of the anterior shoulder, or immediately after the birth of the baby and before the 
cord is clamped and cut.
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
21
Group 2 subjects will take part in 2 dosing sessions, which must be conducted a 
minimum of 48 hours apart. It is recommended that subjects complete Session 2 within 
14 days of Session 1. Subjects will be randomized to receive either IH or IV oxytocin 
during Session 1, and to receive the other treatment during Session 2, such that all 
subjects in Group 2 receive both treatments over the course of the 2 sessions.
4.1.4.
ROTAHALER Inhaler Training
The investigator/designee will be trained to load the ROTACAPS powder capsule into 
the device, prime the dose and instruct the subjects to inhale from the ROTAHALER 
inhaler in the appropriate manner (refer to Section 6.7). Subjects will be instructed by the 
investigator/designee to use an inspiration technique (2 inhalations) that enables maximal 
inhalation of the ROTACAPS powder capsule contents (refer to Section 6.7 for full 
details). This will ensure optimal and consistent drug delivery (full instructions available 
in the Study Reference Manual [SRM]). 
4.1.5.
Length of Stay for All Subjects
Group 1 - Women in TSL
Subjects in Group 1 will be admitted to hospital during labour as part of their routine 
care, and will be required to remain inpatient for a minimum of 4 hours after receiving 
any study-related dose of oxytocin. After final PK collection, subjects will be finished 
with study procedures and the main phase of the study will be considered complete. 
Discharge from hospital will be determined by the subject’s medical provider. 
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
22
Group 2 - Non-pregnant, non-lactating females of child bearing potential
Subjects in Group 2 will be admitted to the clinical unit prior to dosing on Day 1 and are 
to remain inpatient until at least 4 hours after dosing. Discharge will occur at the 
discretion of the investigator.
4.2.
Treatment Arms and Duration
Screening
Group 1: All screening assessments to be completed after the 18th
week of pregnancy (based on estimated date of delivery)
Group 2: All screening assessments to be completed within 28 days
prior to the first dose
Treatment Session
Group 1: Each subject will take part in 1 dosing session.
Group 2: Each subject will take part in 2 dosing sessions
Treatment Arms1
Group 1: Subjects will be randomised to receive one of the following 
study treatments:

400 mcg IH oxytocin

10 I.U. IM oxytocin
Group 2: Subjects will receive both of the following study treatments 
over the course of two dosing sessions:

400 mcg IH oxytocin

5 I.U. IV oxytocin
Follow-up
Group 1: Follow Up 1 – Within approximately 24 hours post dose.
Group 1: Follow Up 2 –  At least 7 days and no greater than 14 days 
after study drug administration.
Both visits may be conducted in-person or via telephone. Group 2: At 
least 7 days and no greater than 21 days after last study drug 
administration.
This visit will be conducted in-person.
If warranted, additional follow-up visits may be scheduled for both 
Groups.
Total Duration
Group 1: Screening after 18th week of pregnancy (i.e. within 168 days of 
1 dosing session) + follow up of 7 - 14 days = approximately 183 days
Group 2: Screening within 28 days of dosing session 1 + 2 dosing 
sessions with a maximum of 14 days between dosing + follow-up of 7 –
21 days = 64 days
1 See Section 6.4 for possible dose adjustment to IH oxytocin.
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
23
4.3.
Type and Number of Subjects
Sufficient subjects will be screened such that approximately 20 subjects complete all 
study procedures in Group 1, and approximately 10 subjects complete all study 
procedures in Group 2 (approximately 5 in each cohort of Group 2). Refer to Section 6.3
for treatment assignment information.
If subjects prematurely discontinue the study, additional replacement subjects may be 
recruited and assigned to the same treatment at the discretion of the Sponsor. 
Replacement subjects will complete all study procedures as outlined in Section 7.1.
If the PK variability between subjects in Group 1 is higher than expected, it may be 
required to increase the sample size up to a maximum of 10 additional subjects per 
treatment group for IH and IM. In the event of this, sufficient subjects will be screened 
such that a maximum of 50 subjects complete Group 1.
If a dose adjustment is required in either group, additional subjects may be recruited such 
that a full 10 subjects receive the final IH or IV dose. See Section 6.4.1 for more details.
4.4.
Design Justification
Group 1 - Women in TSL
This trial uses a randomized, single-dose approach to assign women in TSL to receive 
oxytocin by one of two routes: IM or IH. No placebo is being used, as the current 
standard of care is to administer oxytocin as active management of TSL to prevent PPH.
Group 2 - Non-pregnant, non-lactating females of child bearing potential
A group of non-pregnant, non-lactating women of childbearing potential will receive IH 
and IV oxytocin. This group will be divided into two cohorts: Cohort A will enrol women 
on the combined oral contraceptive. This cohort will serve as a control group, as they 
most closely resemble the population enrolled in the FTIH study. Cohort B will enrol 
women using a non-hormonal form of contraception. This comparison group will help 
characterize the effect of oral contraceptives on endogenous oxytocin production and the 
PK profile of oxytocin.
Blinding
This study uses an open-label design. 
4.5.
Dose Justification
Single inhaled doses of oxytocin (50-600 mcg) have been generally well tolerated in the 
FTIH study, with no emerging safety signals, in healthy, non-pregnant, premenopausal 
female subjects (Study 201558) [GlaxoSmithKline Document Number 
2016N277949_00; see also Section 2.2.1].  Following inhaled administration oxytocin 
was rapidly absorbed into the systemic circulation (tmax ranging from 0.05 to 0.50 h) 
with systemic exposure (Cmax and AUC) increasing with inhaled dose in an 
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
24
approximately proportional manner between 200 and 600 mcg.  In general, the shape of 
the observed oxytocin concentration-time profile following inhaled administration was 
consistent with that following IM administration.
Based on the data from the FTIH study, and assuming that the PK characteristics of IH 
and IM oxytocin are similar in TSL compared with non-pregnant women, the 400 mcg 
inhaled dose is predicted to be an effective dose in women in TSL by ensuring that the 
systemic exposure (Cp10, Cp30 and AUC(0-3 h) following IH dosing is at least that 
following IM administration at the approved dose of 10 I.U. This would be based on the
adjusted geometric mean ratio (90% Confidence Interval [CI]) treatment comparisons for
Cp10, Cp30 and AUC (0-3 h) following 400 mcg IH compared with 10 I.U. IM, namely 
1.10 (0.85,1.43), 1.65 (1.30, 2.09) and 1.27 (1.07, 1.50) respectively in study 201558. 
The PK parameters (Cp10, Cp30 and AUC(0-3 h)) have been selected to ensure onset and 
duration of action of the IH product is at least comparable to IM.
The clinical safety and reported AEs with oxytocin correlates to Cmax, with the Cmax of 
10 I.U. IV representing the upper bounds of what could be considered safe in current 
clinical practice (AEs include flushing, which can cause a transient decrease in blood 
pressure and reflex tachycardia; see the Oxytocin Summary of Product Characteristics for 
more information). The recommendation in the United Kingdom (UK) in clinical practice 
has been to reduce the IV dose to 5 I.U. IV or administer by a controlled IV infusion 
[Bolton, 2003].
Minimising the risk of high Cmax levels of oxytocin following the IH administration is 
therefore important.  Based on a comparison of  model predicted systemic exposure 
following IV administration to non-pregnant, premenopausal female subjects with 
observed PK profiles following 400 mcg IH oxytocin, it is anticipated that Cmax 
following administration of the 400 mcg dose will not markedly exceed values following 
5 I.U. IV bolus oxytocin (Figure 2). The inclusion of the 5 I.U. IV dose will allow an 
assessment of the potential safety and PK of the inhaled formulation compared to IV 
route of administration.
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
25
Figure 2
Model predicted profiles (median (95%PI)) following IM (10 I.U. and 
IV bolus (5 I.U. administration of oxytocin overlaid with observed 
plasma concentrations of oxytocin following 400 mcg IH oxytocin to 
healthy non-pregnant females
Whilst published literature on the PK of oxytocin in non-pregnant and pregnant women is 
limited there is some evidence to suggest that the metabolic clearance of oxytocin may 
increase during pregnancy. This may be related to degradation by the circulating 
aminopeptidase, oxytocinase, and/or pregnancy-related changes in hepatic and renal 
function [Syntocinon, 2014;Thornton, 1990]. In addition, there may be circulating levels 
of endogenous oxytocin in the plasma in women in TSL [Thornton, 1988] and increases 
in blood volume (40-50%) and total body water [Costantine, 2014]. As a result of these 
pregnancy related changes, systemic exposure to oxytocin may differ between healthy 
non-pregnant women and women in TSL for a given dose and route of administration of 
oxytocin. However, given that any pregnancy-related changes in systemic clearance, 
and/or distribution and baseline oxytocin levels, are considered to equally impact on each 
route of administration (IV, IM and IH), it is considered that the relative ratio of IV to IM 
and IH exposure observed in non-pregnant women is likely to be maintained in 
pregnancy. The only exception may be if pregnancy results in marked changes in 
absorption profiles.  However, in a study of inhalation profiles of non-pregnant and 
women in the third stage of labour, the inhalation endpoints appeared to be broadly 
similar across the two cohorts and any small changes are not considered to markedly 
impact the delivery of an inhaled product in the third stage of labour [GlaxoSmithKline 

= Observed 400 mcg IH oxytocin plasma concentration in study 
5  I.U. IV oxytocin
10 I.U. IM oxytocin
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
26
Document Number 2015N239682_00]. In addition, in a pre-clinical sheep model the ratio 
IH:IV was generally similar in non-pregnant and post-partum ewes (Data on file 
Monash). In the event of enhanced pulmonary absorption in pregnancy, the selected 
400 mcg inhaled dose is predicted to have an approximate 2-fold safe cover for Cmax 
compared with an 10 I.U. IV bolus oxytocin (assumes linearity from 5 -10 I.U. IV). 
4.6.
Benefit:Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
GR121619 can be found in the Investigator’s Brochure [GlaxoSmithKline Document 
Number 2015N240749_01] and oxytocin for parenteral administration [Syntocinon, 
2014]. The following section outlines the risk assessment and mitigation strategy for this 
protocol:  
4.6.1.
Risk Assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
Investigational Product (IP) – Inhaled Oxytocin – GR121619 
Bronchospasm, cough and 
dyspnoea, with increased 
theoretical risk in asthmatic 
subjects.
Oxytocin receptors are known 
to be expressed in human 
bronchial smooth muscle and 
up regulated by interleukin 
(IL)-13. Therefore, there is a 
hypothetical risk of 
bronchospasm, cough and 
dyspnoea. 
See Section 5.2 for exclusion 
criteria.
The oxytocin summary of 
product characteristics (SPC) 
does not list asthma as a 
contraindication to 
administration. 
Symptomatic wheezing may 
be treated with bronchodilator 
at the discretion of the 
investigator.
Forced expiratory volume at 1 
minute (FEV1) monitoring for 
both paradoxical and oxytocin 
induced bronchospasm
Subjects with asthma or 
known pulmonary disease are 
excluded.
Hypotension, tachycardia and 
prolongation of QTc interval
Transient flushing, 
hypotension and tachycardia 
could be observed if the IH PK 
profile is comparable to an IM
or IV oxytocin profile. 
Effects of oxytocin on the 
Ongoing assessments of study 
subjects’ cardiovascular 
function including blood 
pressure (BP), heart rate (HR) 
and ECG.
Only single-dose IH, IM, or 
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
27
Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
Cardiovascular system (CVS) 
is unclear and contradictory in 
the literature but IV 
administered oxytocin can 
have a vasodilatory and 
negative inotropic effect in 
humans. Hypotension is 
thought to arise as a result of 
vascular smooth muscle 
relaxation and oxytocin 
binding to cardiac atrial OTR 
which leads to atrial natriuetic 
peptide (ANP) being 
transiently released into the 
systemic circulation. 
Prolongation of the QTc 
interval has been reported at 
the time of caesarean delivery  
with 10 IU IV oxytocin 
administration, rather than IM 
injection, in susceptible 
individuals
5 IU IV bolus injection routes 
of administration will be used 
as study treatment. Telemetry 
and frequent 12-lead ECGs 
will be used to monitor the 
healthy subject cohorts
The 5 IU IV dose of oxytocin is 
the standard dose 
administered at the Rosie 
Maternity hospital post 
Caesarean Section.
IV bolus will be given as a 
slow IV injection over 30 
seconds with the option to 
change to a 5 minute infusion 
if frequent CV adverse effects 
are observed
Exclusion of subjects with long 
QT syndrome, congenital 
cardiac abnormalities, and 
subjects taking anti-arrhythmic 
drugs.
12-lead ECG and telemetry 
covering Cmax in healthy 
subjects administered IH, IM 
and IV oxytocin
Insufficient uterotonic effect
The altered physiology and 
pharmacokinetics of women in 
the TSL my lead to a sub-
optimal dose of inhaled 
oxytocin, resulting in a 
reduced or absent uterotonic 
effect.
In this setting, women in TSL 
and post-delivery are 
intensively observed. 
Therefore, any adverse 
events, including excessive 
blood loss due to unenhanced 
uterine contraction, will be 
managed in accordance with 
current local practice 
guidelines. This will usually 
include administration of 
additional uterotonic agents in 
the first instance.
A follow-up within 24 h of 
discharge by the study team 
will be performed to 
specifically enquire if any late 
bleeding problems had 
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
28
Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
occurred.
An interim analysis of IH and 
IM PK in the TSL group will be 
performed to ensure that the 
PK is in the acceptable range 
for efficacy to be anticipated.
Reference Intervention - IM Oxytocin / IV Oxytocin
Hypotension, tachycardia and 
prolongation of QTc interval
See above section.
See above section.
Subjects receiving the IV 
Oxytocin are required to have 
a systolic BP ≥ 90 Millimeter of 
mercury (mmHg) prior to 
dosing.
Myocardial Ischaemia and ST 
change on ECG
ECG changes consistent with 
myocardial ischaemia have 
been observed with 10 IU 
oxytocin IV bolus in healthy 
women associated with 
hypotension and tachycardia.
Oxytocic cardiovascular effects 
appear to be transient
and persistent myocardial 
damage very rare and 
associated with 10 IU IV.
Study is only using 5 IU IV as a 
slow IV bolus which is 
associated with a short lived 
increase in heart rate and 
reduction in BP but not ST 
changes on ECG in women 
undergoing Caesarean 
Section.
Telemetry and 12-lead ECG 
monitoring in healthy subjects.
Abdominal pain
There is a hypothetical risk 
that IM oxytocin may trigger 
abdominal pain through 
contractions of the non-
pregnant uterus in healthy 
women. 
Given the short half-life of 
oxytocin (approximately 30 
minutes), the duration of a 
single abdominal pain episode 
This is a theoretical possibility 
and not expected to occur. 
Ongoing assessments of study 
subjects’ well-being along with 
vital signs and laboratory
evaluations will be completed 
throughout the duration of the 
study.  
Abdominal pain which is 
clinically uncomfortable to the 
subject may be treated with 
paracetamol at the local 
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
29
Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
would be expected to be brief, 
not sustained and not 
recurrent in the absence of 
further oxytocin administration.
Furthermore, no abdominal 
pain was observed in the FTiH 
study.
investigator’s discretion.  
4.6.2.
Immunogenicity Risk
The oxytocin material used in the inhaled product is produced synthetically and so does 
not include any other protein/cell impuritites which might be intrinsically immunogenic.
A review of the risk of immunogenicity of oxytocin and/or excipients was considered as 
part of the non-clinical safety studies but as the lymphoid tissues were not deemed to be 
pathologically affected and there were difficulties in generating a suitable assay, anti-
drug antibodies (ADAs) were not measured. The FTIH study involved repeat dosing, and 
did not reveal any unexpected differences in PK which may have signalled the 
development of ADAs.
Oxytocin is an endogenous human peptide with a short systemic half-life and there are no 
reports of immunogenicity with oxytocin via parenteral administration. Thus it is 
considered unlikely that inhaled delivery of a small molecular weight (MW) peptide 
molecule like oxytocin would invoke an immunogenic response.
However, blood samples will be retained for anti-oxytocin antibody analysis if required 
in the event of an anaphylactic / allergic reaction (refer to Section 5.4.2) or other 
observation which would suggest an immunogenic effect.
4.6.3.
Benefit Assessment and Overall Benefit:Risk Conclusion
Oxytocin has been administered to postpartum women for over 40 years via both the IM 
and IV routes, and has an established safety profile for each of these routes of 
administration. The FTIH study into IH oxytocin revealed no safety concerns for any of 
the subjects who received this new formulation. There are no direct clinical benefits to 
the volunteers within this study. The main contribution to their participation will be in the 
further development of a therapy (i.e. inhaled oxytocin) which may be ultimately used as 
a preventative therapy for postpartum haemorrhage in women during TSL in resource 
poor settings. It is fundamental to the project to clearly understand the PK of oxytocin 
following IH and IM administration to women in TSL in order to confirm the dose level 
that delivers a PK profile comparable to that of 10 I.U. IM (i.e. current standard of care in 
the developed world setting). Taking into account the measures taken to minimize risk to 
subjects participating in this study, the potential risks identified in association with 
oxytocin (IH IM, and IV) are justified by the supporting data and overall benefit 
anticipated for women’s health worldwide.
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
30
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the investigator brochure for 
GR121619 [GlaxoSmithKline Document Number 2015N240749_01] and SPC for 
oxytocin administered IM or IV.
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
5.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
AGE
All Groups: 
1. Between 18 and 40 years of age inclusive, at the time of signing the informed 
consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
All Groups: 
2. 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.
Note: At time of randomisation, investigator or designee should confirm the subject 
feels fit and well, and is safely able to participate in the study.
3. Subject clinical chemistry and haematology values within an acceptable range for the 
population recruited and not of abnormal clinical significance.
Note: Additional laboratory tests beyond those which are done as part of routine care 
(e.g. 28-week visit) are not required for subjects in Group 1. The 
investigator/designee may use his/her judgment in deciding whether to perform 
additional laboratory assessments to determine eligibility.
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. 
4. Adequate peripheral venous access for cannulation.
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
31
Group 1 Only: 
5. Currently pregnant, with an uncomplicated pregnancy as determined by the 
investigator or designee.
6. Estimated date of delivery within 24 weeks of screening.
7. Planned spontaneous vaginal birth and considered by investigator at low risk for PPH.
8. Planned birth in between the 37th and 42nd week of pregnancy.
Note: Subjects can only receive study treatment if the onset of labour is between 
approximately 37 and 42 weeks estimated gestation. If a subject goes into labour 
before or after this timeframe, she should not receive study treatment.
9. Women who qualify for oxytocin as appropriate for active management of TSL and 
who agree to have active management.
Group 2 Only:
10. ECG normal, or abnormal and not clinically significant.
11. FEV1 >80% of predicted.
12. Systolic blood pressure ≥90 mmHg.
WEIGHT
Group 2 Only:
13. Body mass index (BMI) within the range 18 – 32 Kilogram (kg)/ meter (m)2
(inclusive).
SEX
14. 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:
a.
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.
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
32
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:
a.
Is of reproductive potential and has been using the same non-hormonal 
contraceptive method (see List of Acceptable Nonhormonal Methods for Avoiding 
Pregnancy in Females of Reproductive Potential [see Appendix 5] from 3 months
prior to the first dose of study medication and until the follow-up contact.
b.
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.
c.
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.  
INFORMED CONSENT
All Groups: 
15. Capable of giving signed informed consent as described in Section 10.2 which 
includes compliance with the requirements and restrictions listed in the consent form 
and in this protocol.
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
33
5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL) 
All Groups: 
1. Postmenopausal as defined by gynaecological history.
2. Chronic lung condition of any etiology including asthma, Chronic obstructive 
pulmonary disease (COPD), emphysema, interstitial lung disease or active 
Tuberculosis (TB).
      Note: Childhood asthma (resolved) is not exclusionary.
3. Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones).
4. Blood pressure >140 systolic or >90 diastolic.
Group 1 Only:
5. Females with planned Caesarean Section.
6. Females with significant medical complications as determined by investigator.
Group 2 Only:
7. Currently breastfeeding or lactating.
8. QT duration corrected for heart rate by Fridericia’s formula (QTcF) 
>450 milliseconds (msec).
9. 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%).
10. Subjects with highly-active or symptomatic gynaecological disorders (such as large 
symptomatic fibroids).
CONCOMITANT MEDICATIONS
All Groups: 
11. Prescription or non-prescription drugs not approved by the investigator (refer to 
Section 6.12.1 for approved medications).
12. Oxytocin for any reason (including, but not limited to, induction or augmentation of 
labour) prior to administration of study-related oxytocin.
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
34
RELEVANT HABITS
All Groups: 
13. 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 (~240 milliliter [ml]) of beer, 1 glass (125 ml) of 
wine or 1 (25 ml) measure of spirits. 
14. 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.
a.
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.
CONTRAINDICATIONS 
All Groups: 
15. 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).
16. Participation in another clinical trial, which in the opinion of the investigator, 
jeopardizes the subject’s safety or study outcomes.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
All Groups: 
17. Where participation in the study would result in donation of blood or blood products 
in excess of 500 mL within 56 days.
18. 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).
19. Exposure to more than four new chemical entities within 12 months prior to the first 
dosing day.
Group 2 Only: 
20. Presence of hepatitis B surface antigen or positive hepatitis C antibody test result.
21. A positive Human Immunodeficiency Virus (HIV) antibody test.
22. A positive pre-study drugs of abuse test (not explained by diet or approved 
concomitant medications).
23. A positive alcohol breath test.
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
35
5.3.
Screening/Baseline/Run-in Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomized. In order to ensure transparent reporting of screen 
failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and respond to queries from Regulatory authorities, a minimal 
set of screen failure information is required including Demography, Screen Failure 
details, Eligibility Criteria, and Serious Adverse Events (see Section 7.3.1.4).
5.3.1.
Re-screening
If a subject fails screening, she may be rescreened one additional time.
5.4.
Withdrawal/Stopping Criteria
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as 
soon as possible. 

The site must counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or should 
continue in the study. 

In cases where the subject is deemed ‘lost to follow up’, the investigator or 
designee must make every effort to regain contact with the subject (where 
possible, 3 telephone calls and if necessary a certified letter to the subject’s last 
known mailing address or local equivalent methods). These contact attempts 
should be documented in the subject’s medical record. 

Should the subject continue to be unreachable, only then will she be considered to 
have withdrawn from the study with a primary reason of “Lost to Follow-up”. 
A subject may withdraw from study treatment at any time at her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioural or 
administrative reasons. If a subject withdraws from the study, she may request 
destruction of any samples taken, and the investigator must document this in the site 
study records. 
5.4.1.
Pregnancy Complication Stopping Criteria (Group 1 Only)
Any complication requiring clinical intervention which no longer allows for a vaginal 
delivery or safe completion of study procedures will be cause for immediate withdrawal 
from the study. Investigators should continue to manage any pregnancy complication per 
local guidelines, and record any associated AE/SAE or concomitant medication. This 
includes the need for additional uterotonic administration.
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
36
5.4.2.
Anaphylaxis Stopping Criteria
Clinical signs or symptoms of anaphylaxis / allergic reaction to IH oxytocin will be an 
automatic stopping criterion. Stored serum samples will be analysed for anti-oxytocin 
antibody analysis for affected subjects as detailed in Section 7.5.2. The samples will be 
analysed for Immunoglobulin E (IgE)/ Immunoglobulin G (IgG) anti-oxytocin titres 
biochemical markers of mast cell degranulation (e.g. tryptase) in the event of an 
anaphylactic / allergic reaction occurring.  
5.4.3.
QTc Stopping Criteria (Group 2 Only)

The same QT correction formula must be used for each individual subject to 
determine eligibility for and discontinuation from the study.  This formula may 
not be changed or substituted once the subject has been enrolled.

For example, if a subject is eligible for the protocol based on QTcF, then QTcF
must be used for discontinuation of this individual subject as well.

Once the QT correction formula has been chosen for a subject’s eligibility, the 
same formula must continue to be used for that subject for all QTc data being 
collected for data analysis.  Safety ECGs and other non-protocol specified 
ECGs are an exception.  

The QTc should be based on single or averaged QTc values of triplicate 
electrocardiograms obtained over a brief (e.g., 5-10 minute) recording period.  
QTcF is proposed to be used for this study. If a subject meets either of the following 
bulleted criterion below, she will be withdrawn from the study.  

QTcF > 500 msec,

Change from baseline: Increase in QTcF >60 msec.
Withdrawal of subjects is to be based on an average QTcF value of triplicate ECGs.  If an 
ECG demonstrates a prolonged QT interval, then obtain 2 more ECGs over a brief period 
of time and then use the averaged QTcF values of the 3 ECGs to determine whether the 
subject should be withdrawn from the study.
5.4.4.
Blood Pressure Stopping Criteria (Group 2 Only)
Subjects with a pre-dose systolic blood pressure of <90 mm Hg should not be dosed until 
systolic blood pressure is ≥90 mm Hg.
5.4.5.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
37
Study treatment will be discontinued for a subject if liver chemistry stopping criteria are 
met:
Phase I Liver Chemistry Stopping Criteria – Liver Stopping Event Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
*INR value not applicable to subjects on anticoagulants 
ALT ≥3xULN 
No
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments  section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in
Appendix 2.
5.4.6.
Plasma oxytocin concentration stopping criteria
Per Section 9.3.2.2, the plasma oxytocin concentrations in up to 5 subjects in Group 1 
will be analysed in real time. If the plasma oxytocin concentration is BLQ or sufficiently 
low to prohibit interpretation in these 5 subjects irrespective of treatment, the study will 
be halted and reviewed.
5.5.
Subject and Study Completion
A completed subject is one who has completed all phases of the study including the 
follow-up visit(s).
6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design. Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments.
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
38
Table 1
Study Treatment Information
Study Treatment
Product name:
Oxytocin  (GR121619 
capsule for inhalation)
Oxytocin
Oxytocin
Formulation 
description:
Powder Blend for Inhalation
Solution for Infusion
Solution for Infusion
Dosage form:
Inhalation powder, hard 
capsule
1ml ampoule
1ml ampoule
Unit dose 
strengths:
400 mcg
200 mcg
5 I.U./mL, or 10 
I.U./mL
5 I.U./mL, or 10 
I.U./mL
Route of 
Administration
For oral inhalation
Intramuscular (thigh)
Intravenous
Dosing 
instructions:
Capsule unit dose 
dispensed by ROTAHALER 
inhaler 
Standard 
intramuscular injection
Adminster as a 30-
second bolus
Physical 
description:
Colourless and clear 
HPMC capsules 
containing a white 
powder
Colourless and clear 
sterile solution
Colourless and clear 
sterile solution
Device:
ROTAHALER inhaler
Needle/Syringe 
Intravenous Infusion 
Device
6.2.
Medical Devices
The GSK manufactured medical device (or device manufactured for GSK by a third 
party) provided for use in this study is a high airflow resistance capsule-based inhaler 
(Modified Air Inlet ROTAHALER DPI device). Although this investigational device 
bears a CE mark, it has not been CE marked in accordance with the Medical 
Devices Directive 93/42/EEC.
Instructions for medical device use are provided in Section 6.7. Further details on use of 
the device are provided in the SRM.
GSK medical device incidents, including those resulting from malfunctions of the device, 
must be detected, documented, and reported by the investigator throughout the study –
see Section 12.4.
6.3.
Treatment Assignment
Subjects in Group 1 will be assigned to one of two treatments (IH oxytocin or IM 
oxytocin). Subjects in Group 2 will receive both IH and IV oxytocin in separate dosing 
sessions in a cross over design. Treatment assignment in Group 1, and order of dosing in 
Group 2, will be done in accordance with the randomization schedule generated by 
Clinical Statistics, prior to the start of the study, using validated internal software.
A description of each regimen is provided in Table 2:
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
39
Table 2
Treatment Assignment
Group
Session
Treatment 1
Number of Subjects2
Group 1
1
400 mcg IH oxytocin
10
10 I.U. IM Oxytocin
10
Group 2, Cohort A
1
400 mcg IH oxytocin or 
5 I.U. IV oxytocin
5
2
400 mcg IH oxytocin or 
5 I.U. IV oxytocin
Group 2, Cohort B
1
400mcg IH oxytocin or 
5 I.U. IV oxytocin
5
2
400 mcg IH oxytocin or 
5 I.U. IV oxytocin
1 See Section 6.4 for possible dose adjustment.
2 See Section 9.2.2 for possible adjustment to subject numbers to Group 1
If deemed necessary or if there is a new site identified for conducting and/or continuing 
the clinical trial, then a new randomization schedule may be generated by Clinical
Statistics, prior to the start of the study at the new site, using validated internal software.
6.4.
Planned Dose Adjustments
There is no plan to adjust the dose of IH oxytocin in this study. However, if systemic 
exposure seen in 400 mcg IH oxytocin in TSL subjects is less than expected and not 
comparable to the 10 I.U. IM profile, a consideration to escalate the dose to 600 mcg may 
be made as detailed in Section 6.4.1.
For Group 2, if an exaggerated physiological response is seen with the IV dose, such as 
increased heart rate and decreased blood pressure, then consideration will be given to 
changing to a 5-minute infusion.
6.4.1.
Dose Adjustment
The decision to adjust the IH dose in women in TSL will be determined by the GSK 
study team based on Group 1 PK data in TSL and Group 2, Cohort A PK data.  After a 
minimum of n=5 women in TSL have received 400 mcg IH and 10 I.U. IM and a 
minimum of n=5 non-pregnant women on the combined oral contraceptive (Group 2, 
Cohort A) have received 400 mcg IH oxytocin, PK samples will be analysed and PK 
parameters derived (including but not limited to Cp10, Cp30 and AUC(0-3h)).  
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
40
The median Cp10 will be estimated for women in TSL for each dose group (IH or IM) 
and the median ratio (IH/IM; n=5) derived.  Based on the estimated ratio, the dose of IH 
oxytocin to be administered to women in TSL will either remain at 400 mcg or be 
increased per the criteria described in Table 3:
Table 3
Dose Adjustment Decision Criteria
Median Ratio IH/IM
Decision
< 0.5
Consider study halt and review data.
≥ 0.5 to <0.7
Consider dose adjust to 600 mcg IH in women in TSL.
≥ 0.7
Continue with 400 mcg IH dose.
If a decision to increase the dose is made, additional subjects will be enrolled into Group 
1 such that 10 subjects receive the 600 mcg IH oxytocin dose.
6.5.
Blinding
This will be an open-label study.
6.6.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
6.7.
Preparation/Handling/Storage/Accountability

The investigator/designee will be trained to load the ROTACAPS powder capsule 
into the device, prime the dose and instruct the subjects to inhale from the 
ROTAHALER inhaler in the appropriate manner. The investigator/designee will 
always load and prime the ROTACAPS powder capsule in the device before the 
subject self-administers an IH oxytocin dose

All subjects will be taught by the investigator/designee to use the device in the 
“full-tilt” position and to use a “fast and deep” inspiration technique per 
inhalation, to achieve two rapidly consecutive maximal inhalations for IH 
oxytocin administration. This will ensure optimal and consistent treatment 
delivery. For subjects, the training session will be at any time during the 28-day 
Screening Period, as deemed appropriate by the investigator/designee. 

ROTACAPS powder capsules should be kept in their sealed packaging at room 
temperature (15-25°Centigrade [C]). The packaging should only be opened 
immediately prior to use.

ROTAHALER inhaler devices will be supplied in bulk and unlabelled to the site.
After dosing all ROTAHALER inhaler devices will be uniquely labelled and 
retained after each dosing session. The devices (which should not be opened up at 
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
41
the clinical study site) will be stored until further instruction from the sponsor is 
received.

The investigator or designee must confirm appropriate temperature conditions 
have been maintained during transit for all study treatment received and any 
discrepancies are reported and resolved before use of the study treatment.

Only subjects enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment.  All study 
treatments must be stored in a secure environmentally controlled and monitored 
(manual or automated) area in accordance with the labelled storage conditions 
with access limited to the investigator and authorized site staff. 

The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (i.e. receipt, reconciliation and final disposition records).  

Further guidance and information for final disposition of unused study treatment 
are provided in the SRM. 

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff. Take adequate precautions to 
avoid direct eye or skin contact and the generation of aerosols or mists. In the case 
of unintentional occupational exposure notify the monitor, Medical Monitor 
and/or GSK study contact.

A Material Safety Data Sheet (MSDS)/equivalent document describing 
occupational hazards and recommended handling precautions either will be 
provided to the investigator, where this is required by local laws, or is available 
upon request from GSK.
6.8.
Compliance with Study Treatment Administration
Per ROTACAPS powder capsule dose, each subject will be asked to inhale twice from 
the ROTAHALER inhaler to reduce the possibility of inadequate administration due to a 
single poor inhalation manoeuvre. If failure of the ROTACAPS powder capsule 
actuation is suspected by the investigator (i.e. due to failure to open the capsule during 
device priming), the investigator is permitted to rechallenge the individual with a 
maximum of two further administrations at the same dose using the same capsule. 
When subjects are dosed at the site, they will receive study treatment directly from the 
investigator or designee, under medical supervision.  The date and time of each dose 
administered in the clinic will be recorded in the source documents.  The dose of study 
treatment and study subject identification will be confirmed at the time of dosing by a 
member of the study site staff other than the person administering the study treatment.  
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
42
Group 1 – Women in TSL
Following randomisation and any pre-dose procedures, subjects will receive a single 
study treatment as active management of TSL. The specific timing of this dose will be as 
per local standard of care.2
Administration will be documented in the source documents and reported in the Case 
report form (CRF).
Group 2 – Non-pregnant, non-lactating females of child bearing potential
Following randomisation and all pre-dose procedures, subjects will receive two doses of 
oxytocin, separated by at least 48 hours. Randomisation will determine the order in which 
the IH and IV formulation is administered. 
Administration will be documented in the source documents and reported in the Case 
report form (CRF).
6.9.
Treatment of Study Treatment Overdose
For this study, any dose of the following compounds will be considered an overdose 
when administered as part of study procedures: 

IH oxytocin > 400 mcg 
o
If study dose is increased to 600 mcg, then an overdose will be considered 
any dose > 600 mcg.

Oxytocin > 10 I.U. IM 

Oxytocin > 5 I.U. IV
Note: Group 1 subjects may receive additional doses of oxytocin (IM or IV) when 
required as part of their general care and as clinically indicated. Additional doses of 
oxytocin will be recorded as concomitant medications, as will any related AEs.
General medical management consists of supportive care. 
GSK does not recommend specific treatment for an overdose.
In the event of a study drug overdose the investigator or treating physician should:
1.
Contact the Medical Monitor immediately.
                                                
2 For information only: Standard of care at proposed clinical site is to administer the oxytocic drug by IM 
injection with the birth of the anterior shoulder, or immediately after the birth of the baby and before the 
cord is clamped and cut.
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
43
2. Closely monitor the subject for adverse events (AEs)/serious adverse events (SAEs) 
and laboratory abnormalities until oxytocin can no longer be detected systemically (at 
least 4 hours).
3. Obtain an additional plasma sample for pharmacokinetic (PK) analysis if requested 
by the Medical Monitor (determined on a case-by-case basis).
4. Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the subject.
6.10.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study because either only healthy volunteers are eligible for study participation, or there 
are other treatment options are available.
The investigator is responsible for ensuring that consideration has been given to the post-
study care of postpartum subjects’ medical conditions, whether or not GSK is providing 
specific post-study treatment.
6.11.
Lifestyle and/or Dietary Restrictions
6.11.1.
Meals and Dietary Restrictions
There are no dietary restrictions for subjects in either cohort.
6.11.2.
Caffeine and Alcohol
Group 1 – Women in TSL

There are no restrictions for Group 1.
Group 2 – Non-pregnant, non-lactating females of child bearing potential

During each dosing session, subjects will abstain from ingesting caffeine- or 
xanthine-containing products (e.g., coffee, tea, cola drinks and chocolate) for 
12 hours prior to the start of dosing until collection of the final pharmacokinetic 
sample during each session. 

During each dosing session, subjects will abstain from alcohol for 12 hours prior to 
the start of dosing until collection of the final pharmacokinetic sample during each 
session. 
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
44
6.11.3.
Activity
Group 1 – Women in TSL
There are no activity restrictions.
Group 2 – Non-pregnant, non-lactating females of child bearing potential
Subjects will abstain from strenuous exercise for 48 hours prior to each blood collection 
for clinical laboratory tests.  Subjects may participate in light recreational activities 
during studies (e.g., watch television, read).
6.12.
Concomitant Medications and Non-Drug Therapies
6.12.1.
Permitted Medications and Non-Drug Therapies
Paracetamol, at doses equal to or below the maximum recommended daily dose, is 
permitted for use during the screening period or at any time deemed necessary by the 
investigator or subject. All concomitant medication related to routine care during 
pregnancy and delivery is allowed (including pain relief [e.g. gas/air mixture] and 
epidural), and other medication may be considered on a case by case basis by the 
investigator or designee (in consultation with the Medical Monitor if required). 
The start and stop time of any concomitant medications administered at any time during 
labour (including nitrous oxide gas/air mixtures) should be documented on the CRF.
6.12.2.
Prohibited Medications and Non-Drug Therapies
Use of the following medications will result in immediate withdrawal of subject:

Oxytocin for any reason (including, but not limited to, induction or augmentation 
of labour) before or after administration of study-related oxytocin.
7.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct.
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Table in Section 7.1.
The following points must be noted: 

If assessments are scheduled for the same nominal time, THEN the assessments 
are recommended to occur in the following order:
1. 12-lead ECG
2. vital signs
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
45
3. blood draws
Note: The timing of the assessments should allow the blood draw to occur at the 
exact nominal time.

The timing and number of planned study assessments, including safety, 
pharmacokinetic, pharmacodynamic, immunogenic or other assessments may be 
altered during the course of the study based on newly available data (e.g., to 
obtain data closer to the time of peak plasma concentrations) to ensure 
appropriate monitoring. 

The change in timing or addition of time points for any planned study 
assessments must be documented in a Note to File which is approved by the
relevant GSK study team member and then archived in the study sponsor and 
site study files, but this will not constitute a protocol amendment. 

The Institutional Review Board (IRB)/ Independent Ethics Committee (IEC)
will be informed of any safety issues that require alteration of the safety 
monitoring scheme or amendment of the Informed Consent Form. 

No more than 500 mL of blood will be collected over the duration of the study, 
including any extra assessments that may be required.
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
46
7.1.
Time and Events Table
7.1.1.
Time and Events Table – General Overview
Group 1
Study Day
Procedure
Screening4
Main Phase 
Follow – Up 1 (approx. 24 
hours post dose)
Follow – Up 2 (7-14 days post dose)
Informed Consent and Demography
X
Brief Physical Examination
X
Medical history (incl. substance abuse)
X
Inhaler device training / education session
X
Laboratory assessments1
X
Vital signs2
X
X
Pharmacokinetic blood sample
X
Oxytocin Administration (IM/IH)
X
Full blood count
X
Labour Events Documentation
X
Device acceptability questionnaire3
X
Prior / concomitant medication review
X
X
X
X
AE review
------------------------------ continuous review ------------------------------------------------------
SAE review
 ---------------------------------------------------------------- continuous review  -------------------------------------------------
1.
Only required if done as part of routine care. Additional study-specific laboratory assessments not required.
2.
Includes blood pressure, heart rate, temperature, respiratory rate
3.
Only to be used when randomized to IH oxytocin
4.
To be completed after 18th week of pregnancy (based on estimated date of delivery).
 
 
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
47
Group 2
Study Day
Procedure
Screening5
Main Phase
Follow - Up (7-21
days post 
dose)
Informed Consent and Demography
X
Brief Physical Examination
X
X
Medical history
X
Pregnancy test 
X
X
Alcohol Breath Test, Smokerlyzer, Urine Drug Screen1 
X
X
HIV, Hep B and Hep C screen2
X
Inhaler device training / education session
X
Laboratory assessments (including liver chemistries)
X
X
Immunogenicity sample
X
X
12-lead ECG
X4
X
CardiacTelemetry
X
Vital signs3
X
X
Spirometry (FEV-1)4
X
X
Admission to unit
X
Pharmacokinetic blood sample
X
X
Oxytocin Administration (IH or IV)
X
Prior / concomitant medication review
X
X
X
AE review
------ continuous review -----------------------------------
SAE review
 ----------------------------------- continuous review  --------------------------------
Discharge from unit
X
1.
Smokerlyzer at PI/designee discretion if smoking history in question.
2.
If test otherwise performed within 3 months prior to first dose of study treatment, repeat testing at screening is not required.
3.
Includes blood pressure, heart rate, temperature, respiratory rate, and SpO2.
4.
Performed in triplicate.
5.
To be completed within 28 days of randomization.
 
 
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
48
7.1.2.
Time and Events – Main Phase Procedures
Group 1 
Time post dose
Procedure
Pre-
dose
3 min
5 min
10 
min
15 min
20 
min
30 
min
1 hr
2 hr
2.5 hr
3 hr
4 hr
Vital signs1
X
X
Pharmacokinetic blood sample
X2
X
X
X
X
X
X
X
X
X
X
X
Prior  medication review
X
Concomitant  medication review
---------------------------------------------------------- continuous review  ---------------------------------------------------
AE review
--------------------------------------------------------- continuous review  ---------------------------------------------------
SAE Review
------------------------------------------------------------------------ continuous review  -----------------------------------------------------
Device Acceptability Questionnaire3
X
Full Blood Count
X
X
1.
Includes blood pressure, heart rate, temperature, respiratory rate
2.
Predose PK sample to be taken immediately prior to administration of study treatment 
3.
Only to be administered when randomized to IH oxytocin
 
 
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
49
Group 2 – Sessions 1 and 2
Time Post Dose
Procedure
Pre-
dose
2 
min
3 
min
5 
min
8 
min
10 
min
15 
min
20 
min
30 
min
45 
min
1 hr
1.5 hr
2 hr
2.5 hr
3 hr
4 hr
Brief Physical Exam
X
Pregnancy Test
X
Alcohol Breath Test, Smokerlyzer, Urine 
Drug Screen1
X
Vital signs2
X
X
X
X
X
X
12-lead ECG
X
X
X
X
X
X
X
CardiacTelemetry
---------------------------------------------Continuous-----------------------------------------------
Spirometry3
X
X
Pharmacokinetic blood sample
X5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Immunogenicity Sample
X
Laboratory assessments (including liver 
chemistries)
X
X
Prior medication review
X
Concomitant medication review
------------------------------------------------------------ continuous review  ----------------------------------------------------
AE review
----------------------------------------------------------- continuous review  ----------------------------------------------------
SAE Review
------------------------------------------------------------------------- continuous review  ----------------------------------------------------
Discharge from unit4
X
1.
Smokerlyzer at Principal Investigator (PI)/designee discretion if smoking history in question.
2.
Includes blood pressure, heart rate, temperature, respiratory rate, and SpO2
3.
FEV 1.0 will be performed in triplicate at each time point. Record all three values on source document, and record best effort in eCRF.
4.
Discharge at PI discretion, no sooner than 4-hours post-dose.
5.
3 pre-dose samples: approximately 1 hr pre-dose, 30 minutes pre-dose, and 15 minutes pre-dose
 
 
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
50
7.2.
Screening and Critical Baseline Assessments
Cardiovascular medical history/risk factors (as detailed in the CRF) will be assessed at 
screening.
The following demographic parameters will be captured: year of birth, sex, race and 
ethnicity.
Medical/medication/family history will be assessed as related to the inclusion/exclusion 
criteria listed in Section 5.  
Procedures conducted as part of the subject’s routine clinical management [e.g. brief 
physical exam, laboratory assessments] and obtained prior to signing of informed consent 
may be utilized for Screening or baseline purposes provided the procedure meets the 
protocol-defined criteria and has been performed within the timeframe defined in the 
Time and Events Schedule.
7.3.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1).  Additional time points for safety tests (such as vital signs, physical exams 
and laboratory safety tests) may be added during the course of the study based on newly 
available data to ensure appropriate safety monitoring.
7.3.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 3 (see Section 12.3).
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 
7.3.1.1.
Time period and Frequency for collecting AE and SAE information

Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK 
product will be recorded from the time a subject consents to participate in the 
study up to and including any follow-up contact. 

AEs will be collected from the start of Study Treatment until the follow-up 
contact (see Section 7.3.1.3), at the timepoints specified in the Time and Events 
Table (Section 7.1).

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the CRF or appropriate source document.

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in
Appendix 3.

Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects. However, if the investigator learns of any SAE, including a death, at any 
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
51
time after a subject has been discharged from the study, and she considers the 
event reasonably related to the study treatment or study participation, the 
investigator must promptly notify GSK.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Appendix 3.
7.3.1.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:

“How are you feeling?” 

“Have you had any (other) medical problems since your last visit/contact?”

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?” 
7.3.1.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All SAEs, and non-serious AEs of special interest 
(as defined in Section 4.6.1) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up 
(as defined in Section 5.4). Further information on follow-up procedures is given in
Appendix 3.
7.3.1.4.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK of SAEs related to study treatment (even 
for non- interventional post-marketing studies) is essential so that legal obligations and 
ethical responsibilities towards the safety of subjects and the safety of a product under 
clinical investigation are met. 
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, IRB/ IEC and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the Investigators Brochure (IB) and will notify the IRB/IEC, if appropriate according to 
local requirements.
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
52
7.3.2.
Adverse Events of Special Interest (AESI)
Any problem related to the delivery of the placenta or postpartum haemorrhage should be 
documented as an AESI using the appropriate case report form (CRF). 
7.3.3.
Pregnancy
Group 2 Only:

Details of all pregnancies will be collected after the start of dosing and until 
follow-up.

If a pregnancy is reported then the investigator should inform GSK within 2 
weeks of learning of the pregnancy and should follow the procedures outlined in
Appendix 5.
7.3.4.
Medical Device Incidents (Including Malfunctions)
GSK medical devices are being provided for use in this study.  In order to fulfil 
regulatory reporting obligations worldwide the investigator is responsible for the 
detection and documentation of events meeting the definitions of incident or malfunction 
that occur during the study with such devices. 
The definition of a Medical Device Incident can be found in Section 12.4.
NOTE: Incidents fulfilling the definition of an AE/SAE will also follow the processes 
outlined in Section 12.3.6 and Appendix 3 of the Protocol. 
7.3.4.1.
Time Period for Detecting Medical Device Incidents

Medical device incidents or malfunctions of the device that result in an incident will 
be detected, documented and reported during all periods of the study in which the 
GSK medical devices are available for use. 

If the investigator learns of any incident at any time after a subject has been 
discharged from the study, and such incident is reasonably related to a GSK medical 
device provided for the study, the investigator will promptly notify GSK.
NOTE: The method of documenting Medical Device Incidents is provided in 
Appendix 4.
7.3.4.2.
Follow-up of Medical Device Incidents

All medical device incidents involving an AE will be followed until resolution of the 
event, until the condition stabilizes, until the condition is otherwise explained, or 
until the subject is lost to follow-up (as defined in Section 5.4). This applies to all 
subjects, including those withdrawn prematurely. 

The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as may be indicated to elucidate as completely as practical the nature 
and/or causality of the incident.
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
53

New or updated information will be recorded on the originally completed form with 
all changes signed and dated by the investigator.
7.3.4.3.
Prompt Reporting of Medical Device Incidents to GSK

Medical device incidents will be reported to GSK within 24 hours once the 
investigator determines that the event meets the protocol definition of a medical 
device incident.

Facsimile transmission of the "Medical Device Incident Report Form" is the 
preferred method to transmit this information to the Medical Monitor or SAE 
coordinator.

The same individual will be the contact for receipt of medical device reports and 
SAEs.

In the absence of facsimile equipment, notification by telephone is acceptable for 
incidents, with a copy of the "Medical Device Incident Report Form" sent by 
overnight mail. 
7.3.4.4.
Regulatory Reporting Requirements for Medical Device Incidents

The investigator will promptly report all incidents occurring with any GSK medical 
device provided for use in the study in order for GSK to fulfil the legal responsibility 
to notify appropriate regulatory bodies and other entities about certain safety 
information relating to medical devices being used in clinical studies.

The investigator, or responsible person according to local requirements (e.g., the 
head of the medical institution in Japan), will comply with the applicable local 
regulatory requirements relating to the reporting of incidents to the IRB/IEC.
7.3.5.
Physical Exams

A brief physical examination will include, at a minimum assessments of the lungs, 
cardiovascular system, and abdomen (liver and spleen if palpable).

Investigators should pay special attention to clinical signs related to previous 
serious illnesses
7.3.6.
Vital Signs
Vital signs will be measured in semi-supine position after 5 minutes rest and will 
include temperature, systolic and diastolic blood pressure, pulse rate and respiratory 
rate (unless otherwise specified in T&E). 
7.3.7.
Documentation of Labour Events
The time that the following labour events occurred will be collected:

Time of crowning

Time of birth

Time of delivery of placenta
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
54
7.3.8.
Electrocardiogram (ECG) (Group 2 Only)

Triplicate 12-lead ECGs will be obtained at screening as listed in Section 7.1.1.

Single 12-lead ECGs will be obtained at each timepoint as listed in Section 7.1.2
using an ECG machine that automatically calculates the heart rate and measures 
PR, QRS, QT, and QTc intervals.  Refer to Section 5.4.3 for QTc withdrawal 
criteria and additional QTc readings that may be necessary.

At all single 12-lead ECG time-points if QTc >450, repeat twice and take average 
reading.
7.3.9.
Continuous Cardiac Telemetry (Group 2 Only)
Continuous cardiac telemetry will be started at least 10 minutes pre-dose (to obtain a 
stable reading) and continue until at least the first hour after IV and IH placebo / 
oxytocin administration and then as deemed necessary by the investigator.  Full 
disclosures will be reviewed in detail and the review maintained as part of the 
subject’s source documents.
7.3.10.
Device Acceptability Questionnaire (Group 1 Only)
A device acceptability questionnaire will be administered to subjects in Group 1 
following use of the ROTAHALER (Appendix 7). 
7.3.11.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as required by Section 7.1 and defined in 
Table 4, must be conducted in accordance with the Laboratory Manual, and Protocol 
Time and Events Schedule. Laboratory requisition forms must be completed and samples 
must be clearly labelled with the subject number, protocol number, site/centre number, 
and visit date. Details for the preparation and shipment of samples will be provided by 
the laboratory and are detailed in the SRM. Reference ranges for all safety parameters 
will be provided to the site by the laboratory responsible for the assessments.
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the CRF.
Refer to the SRM for appropriate processing and handling of samples to avoid duplicate 
and/or additional blood draws.
All study-required laboratory assessments will be performed by a central laboratory, apart 
from:

Tests performed as part of routine care in Group 1.
NOTE:  Local laboratory results are only required in the event that the central laboratory
results are not available in time for either a treatment and/or response evaluation to be 
performed. Additionally if the local laboratory results are used to make either a treatment 
or response evaluation, the results must be entered into the CRF.
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
55
Subjects in Group 1 are not required to undergo additional laboratory assessments beyond 
those done as part of their routine care. However, the investigator/designee may conduct 
any of the tests listed in Table 4 in order to confirm eligibility. Haematology, clinical 
chemistry, and additional parameters to be tested in all Group 2 subjects are listed in 
Table 4.
Table 4
Protocol Required Safety Laboratory Assessments
Laboratory
Assessments
Parameters
Haematology
Platelet Count
RBC Indices:
White Blood Cell (WBC) count 
with Differential:
Red Blood Cell (RBC)
Count
Mean 
Corpuscular 
Volume 
(MCV)
Neutrophils
Hemoglobin
Mean 
Corpuscular 
Hemoglobin 
(MCH)
Lymphocytes
Hematocrit
Monocytes
Eosinophils
Basophils
Clinical 
Chemistry 1
Blood Urea 
Nitrogen 
(BUN)
Potassium
Aspartate 
aminotransferase 
(AST) (SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
Alanine 
aminotransferase 
(ALT) (SGPT)
Total Protein
Glucose 
Calcium
Alkaline phosphatise
Albumin
Other 
Screening 
Tests
HIV
Hepatitis B (HBsAg)
Hepatitis C (Hep C antibody)
Follicle Stimulating Hormone (FSH) and estradiol (as needed in women 
of suspected non-child bearing potential only)
Alcohol and drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines)
Serum or urine hCG Pregnancy test (Group 2 only) 2
NOTES :
1.
Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up 
Assessments after liver stopping or monitoring event are given in Section 12.2 and
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
56
Appendix 2
2.
Local urine testing will be standard for the protocol unless serum testing is required 
by local regulation or ethics committee.
All laboratory tests with values that are considered clinically significantly abnormal 
during participation in the study should be repeated until the values return to normal or 
baseline.  If such values do not return to normal within a period judged reasonable by the 
investigator, the etiology should be identified and the sponsor notified.
7.4.
Pharmacokinetics
7.4.1.
Blood Sample Collection
Blood samples for pharmacokinetic (PK) analysis of oxytocin will be collected at the 
time points indicated in Section 7.1, Time and Events Table.  The actual date and time of 
each blood sample collection will be recorded.  The timing of PK samples may be altered 
and/or PK samples may be obtained at additional time points to ensure thorough PK 
monitoring.  
At each time point, 4 mL of blood will be collected into study-specific tubes formulated 
to further inhibit peptidase activity. Additional details regarding collection/shipping 
procedures are provided in the SRM.
7.4.2.
Sample Analysis
Plasma analysis will be performed under the control of PTS-DMPK, GlaxoSmithKline, 
the details of which will be included in the SRM. Concentrations of oxytocin will be 
determined in plasma samples using the currently approved bioanalytical methodology.
Raw data will be archived at the bioanalytical site (detailed in the SRM). Once the 
plasma has been analyzed for oxytocin any remaining plasma may be analysed for 
metabolites of oxytocin and the results reported separately.
7.5.
Biomarkers
7.5.1.
Pharmacodynamic Markers
Pre and post-delivery full blood counts will be collected from Group 1 subjects to assess 
for a change in haemoglobin levels.
7.5.2.
Immunogenicity
Blood samples will be taken at the time points specified in the Time and Events Table 
(Section 7.1) to assess the immunogenicity of oxytocin.
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
57
Pre- and post-dose samples will be retained in the event that further immunologic tests 
are deemed necessary to support observations of unexpected anaphylaxis/
hypersensitivity, and / or a PK profile for IH oxytocin in any Dosing Session which is 
regarded by the GSK Study Team to be reasonably attributable to circulating anti-
oxytocin antibodies.
Details of the collection / shipping procedures are provided in the SRM.
8.
DATA MANAGEMENT

For this study subject data will be entered into GSK defined CRFs, transmitted 
electronically to GSK or designee and combined with data provided from other 
sources in a validated data system.  

Management of clinical data will be performed in accordance with applicable 
GSK standards and data cleaning procedures to ensure the integrity of the data, 
e.g., removing errors and inconsistencies in the data.

Adverse events and concomitant medications terms will be coded using MedDRA 
(Medical Dictionary for Regulatory Activities) and an internal validated 
medication dictionary, GSKDrug.  

CRFs (including queries and audit trails) will be retained by GSK, and copies will 
be sent to the investigator to maintain as the investigator copy.  Subject initials 
will not be collected or transmitted to GSK according to GSK policy.
9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
9.1.
Hypotheses
The primary objective of this study is to characterize the pharmacokinetics of 400 mcg IH 
oxytocin and 10 I.U. IM oxytocin in women in TSL. 
No formal hypotheses will be tested, however, the following comparisons are of interest,
within Group 1, (IH vs. IM) and between Group 1 and Group 2 (IH oxytocin comparison 
in TSL vs. non-pregnant women on oral contraception) and between Cohorts A and B in 
Group 2 (IH and IV oxytocin comparison in non-pregnant women in the presence and 
absence of oral contraceptive). For each PK endpoint of interest, point estimates and 
corresponding two-sided 90% confidence intervals will be constructed for the ratio of the 
geometric mean of the test treatment to the geometric mean of the reference treatment, 
μ(test)/μ(reference) to provide the range of plausible values for the comparisons of 
interest. 
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
58
9.2.
Sample Size Considerations
A sufficient number of subjects will be enrolled to ensure approximately 20 evaluable 
subjects (10 in each of the IM and IH groups) complete all dosing and critical 
assessments in Group 1, as well as 5 subjects in each cohort in Group 2. Whilst sample 
size is based on feasibility, precision calculation was also done to approximate the 
estimate of the expected half width of 90% CI around point estimate for the main 
comparison of interest (IH oxytocin to 10 I.U. IM oxytocin in women in TSL) using a t-
test. 
Table 5 illustrates the associated 90% CIs for the mean treatment ratios, assuming 
between subject SDs of 0.424 and 0.601 (SDs are based on log transformed data) for 
AUC (0-3h) and CP10 respectively, for the comparisons of interest detailed in Section 
9.1. Calculations are based on a symmetric two-tailed procedure on the loge scale and a 
type I error rate of 10%. These values represent estimates of the between-subject 
variability observed in the FTIH study 201558 [GlaxoSmithKline Document Number 
2016N277949_00].
Table 5
Estimated 90% Confidence Intervals for Treatment Ratios
N
Parameter
Between
Subject 
Standard 
Deviation 
(SD)
Estimated 
Treatment 
Ratio
Precision
Expected 
90% CI
10
AUC(0-3h)
0.424 
(CVb=44.35%)
1
38.30%
(0.72, 1.38)
10
Cp10
0.601 
(Cvb=65.96%)
1
58.20%
(0.63,1.58)
The precision estimates are deemed acceptable to assess the study objectives at this stage
of development.
9.2.1.
Sample Size Sensitivity
Considering the variability of AUC(0-3h) and Cp10, Table 6 shows the scenarios for 
different sample size and the precision estimates for IH vs. IM in Group 1.
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
59
Table 6
Estimated 90% Confidence Intervals for Treatment Ratios for Sample 
Size Sensitivity
%CVb
N
Precision
Assuming ratio 1, the 
confidence interval
44.35%
5
61.90%
(0.61, 1.61)
15
29.80%
(0.77,1.29)
65.96%
5
98.00%
(0.50, 1.98)
15
44.80%
(0.69, 1.44)
20
37.40%
(0.72,1.37)
85.35%*
5
131.90%
(0.43, 2.31)
10
75.90%
(0.56, 1.75)
15
57.60%
(0.63, 1.57)
20
48.00%
(0.67, 1.48)
* 85.35%  was the largest between subject CV for AUC(0-10) observed for FTIH study 201558 
[GlaxoSmithKline Document Number:2016N277949_00]
9.2.2.
Sample Size Re-estimation or Adjustment
No formal sample size re-estimation is planned for this study. However, if the variability 
is high (for example approaching 85%) then the sample size for Group 1 may be 
increased to a maximum of 10 additional subjects per treatment arm (IH and IM only).
9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations
Enrolled Population

Defined as all subjects who were enrolled for the trial 
irrespective of whether they were randomized or not and 
for whom a record exist on the study database. This 
population will be used for summarizing screening failure 
reasons.
All Subjects Population

Comprise of subjects who receive at least one dose of 
study medication. This population will be used for the 
study population and safety displays.
Pharmacokinetic 
Population

Subjects in the ‘All Subjects’ population for whom a 
pharmacokinetic sample was obtained and analysed.  PK 
population will be the population for reporting PK data.
9.3.2.
Interim Analyses
No formal interim analyses are planned. PK data will be reviewed per Section 9.3.2.1 and
Section 9.3.2.2
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
60
9.3.2.1.
Informal Interim Reviews
PK samples will be analysed and preliminary PK parameters derived following 
completion of 5 women on each of the following treatments: 400 mcg IH and 10 I.U. IM 
to women in TSL (Group 1) and 400 mcg IH to non-pregnant women on the combined  
oral contraceptive (Group 2 Cohort A).  Based on the PK profiles the dose of IH oxytocin 
to be administered to women in TSL will either remain at 400 mcg or be increased (to 
600 mcg) (See Section 6.4.1). This decision will be made by the study team in 
collaboration with the Principal Investigator. 
This will be repeated after restart from the temporary halt for Group 1.
9.3.2.2.
In-Stream Analysis of Group 1
Following restart from temporary halt, PK specimens from each of up to 5 subjects in 
Group 1 will be analysed as soon as possible after collection. This will allow for 
confirmation that the revised specimen collection procedures allow for detection of
adequate oxytocin PK profile. 
9.4.
Key Elements of Analysis Plan
9.4.1.
Primary Analyses
9.4.1.1.
Safety Analysis
Safety data will be presented in tabular and/or graphical format and summarized 
descriptively according to GSK’s Integrated Data Standards Library (IDSL) standards.
9.4.1.2.
Pharmacokinetic Analysis
Pharmacokinetics analysis will be the responsibility of the Clinical Pharmacokinetics 
Modeling & Simulation department within GlaxoSmithKline.  Plasma oxytocin
concentration-time data will be analyzed by non-compartmental methods with 
WinNonlin V6.3 or greater.  Calculations will be based on the actual sampling times 
recorded during the study. 
From the plasma concentration-time data, the following pharmacokinetic parameters will 
be determined, as data permit: maximum observed plasma concentration (Cmax), time to 
Cmax (tmax), area under the plasma concentration-time curve [AUC(0-3h) and AUC(0-
∞)], the last observed quantifiable concentration (Clast), time of the last quantifiable 
concentration (tlast), Cp10, Cp20, Cp30 (observed plasma concentrations at 10, 20 and 
30minutes post-dose, respectively), plasma clearance (CL; IV only), volume of 
distribution (V; IV only) and apparent terminal phase half-life (t1/2).  Other PK 
parameters may also be determined.
Pharmacokinetic data will be presented in graphical and/or tabular form and will be
summarized descriptively. All pharmacokinetic data will be stored in the Archives, 
GlaxoSmithKline Pharmaceuticals, R&D. 
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
61
If appropriate, a population PK analysis may also be conducted, in addition the oxytocin 
plasma concentration-time data may be merged with historical data and analysed as part 
of a population PK meta-analysis.
9.4.2.
Secondary Analyses
Statistical analyses of the PK parameter data will be performed by, or under direct 
auspices of Clinical Statistics, QSci.
9.4.2.1.
Pharmacokinetic Analysis
For evaluating pharmacokinetic treatment comparisons within Group 1 IH vs. IM, point 
estimates and corresponding two-sided 90% confidence intervals will be computed using 
a mixed effect model. Loge-transformed PK parameters will be analysed using the model 
with a fixed effect term for treatment and a random effect term for subject.
Further details of analysis and reporting of PK data will be given in the Reporting 
Analysis Plan (RAP).
9.4.3.
Exploratory Analyses
9.4.3.1.
Pharmacokinetic Analysis
For evaluating pharmacokinetic treatment comparisons between Group 1 and Group 2 
(IH oxytocin comparison in TSL vs. non-pregnant women on the combined oral 
contraceptive), and within Group 2 between Cohorts A and B (IH and IV oxytocin 
comparison in non-pregnant women in the presence and absence of oral contraceptive),
point estimates and corresponding two-sided 90% confidence intervals will be computed 
using a mixed effect model. Loge-transformed PK parameters will be analysed using the 
model with a fixed effect term for treatment and a random effect term for subject.
Further details of analysis and reporting of PK data will be given in the Reporting 
Analysis Plan (RAP).
9.4.3.2.
Device Acceptability Questionnaire
In Group 1, subject satisfaction with device, including instructions and ease of use, will 
be assessed. The questionnaire is located in Section 12.7
10.
STUDY GOVERNANCE CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
62
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and the guiding principles of the current 
version of the Declaration of Helsinki.  This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable

Obtaining signed informed consent

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol 
deviations to IRB/IEC)

GSK will provide full details of the above procedures, either verbally, in writing, 
or both.

Signed informed consent must be obtained for each subject prior to participation 
in the study

The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.  

Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.  

Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities.  In this situation, 
written approval of the clinical protocol should state that approval of optional 
assessments is being deferred and the study, with the exception of the optional 
assessments, can be initiated.
10.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK monitors will contact the site prior to the start of the study to review with the 
site staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and GSK requirements.  

When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the CRF will 
serve as the source document.

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRFs <or> entered in the eCRFs that are transcribed from 
source documents must be consistent with the source documents or the 
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
63
discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study; also current medical 
records must be available.
GSK will monitor the study and site activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any 
other study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents.
10.4.
Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK 
may conduct a quality assurance assessment and/or audit of the site records, and 
the regulatory agencies may conduct a regulatory inspection at any time during or 
after completion of the study. 

In the event of an assessment, audit or inspection, the investigator (and institution) 
must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all 
relevant documents and to allocate their time and the time of their staff to discuss 
the conduct of the study, any findings/relevant issues and to implement any 
corrective and/or preventative actions to address any findings/issues identified.
10.5.
Study and Site Closure

Upon completion or premature discontinuation of the study, the GSK monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and GSK Standard 
Operating Procedures.

GSK reserves the right to temporarily suspend or prematurely discontinue this 
study at any time for reasons including, but not limited to, safety or ethical issues 
or severe non-compliance. For multicenter studies, this can occur at one or more 
or at all sites.  

If GSK determines such action is needed, GSK will discuss the reasons for taking 
such action with the investigator or the head of the medical institution (where 
applicable).  When feasible, GSK will provide advance notification to the 
investigator or the head of the medical institution, where applicable, of the 
impending action.

If the study is suspended or prematurely discontinued for safety reasons, GSK will 
promptly inform all investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study. GSK will also promptly 
inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action.  
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
64

If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation.
10.6.
Records Retention

Following closure of the study, the investigator or the head of the medical 
institution (where applicable) must maintain all site study records (except for 
those required by local regulations to be maintained elsewhere), in a safe and 
secure location.  

The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review 
in conjunction with assessment of the facility, supporting systems, and relevant 
site staff.  

Where permitted by local laws/regulations or institutional policy, some or all of 
these records can be maintained in a format other than hard copy (e.g., microfiche, 
scanned, electronic); however, caution needs to be exercised before such action is 
taken.  

The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, 
including re-generating a hard copy, if required.  Furthermore, the investigator 
must ensure there is an acceptable back-up of these reproductions and that an 
acceptable quality control process exists for making these reproductions.

GSK will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements.  The minimum retention time 
will meet the strictest standard applicable to that site for the study, as dictated by 
any institutional requirements or local laws or regulations, GSK 
standards/procedures, and/or institutional requirements. 

The investigator must notify GSK of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of 
ownership of the records in the event the investigator is no longer associated with 
the site.
10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
65
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy.
A manuscript will be progressed for publication in the scientific literature if the results 
provide important scientific or medical knowledge.
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
66
11.
REFERENCES
Costantine MM. Physiologic and pharmacokinetic changes in pregnancy. Frontiers in
Pharmacology. 2014. Volume 5. Article 65: 1-5. 
GlaxoSmithKline Document Number 2015N234711_01. Study ID 201558. Clinical 
Pharmacology Study Protocol. A single centre, single blind study to investigate the 
safety, tolerability and pharmacokinetics of single doses of oxytocin (GR121619) 
administered via an inhaled route in healthy female volunteers. 16-NOV-2015.
GlaxoSmithKline Document Number 2015N239682_00. Study ID 201248 – Clinical
Pharmacology Study Report. An enabling study to compare the inhalation profiles of 
women in the third stage of labour to those of non-pregnant female volunteers and to 
explore whether there are any  differences which could impact the delivery of an inhaled 
medicinal product, 16-OCT-2016.
GlaxoSmithKline Document Number 2015N240749_01. GR121619 Investigator's 
Brochure, AUG-2015.  
GlaxoSmithKline Document Number 2016N277949_00. Study ID 201558 – Clinical 
Study Report.. 30-JUN-2016.
Khan KS, Wojdyla D, Say L, Gülmezoglu AM, Van Look PF. WHO analysis of causes 
of maternal death: a systematic review. Lancet. 2006;367(9516):1066-74.
Mousa HA, Blum J, Abou El Senoun G, Shakur H, Alfirevic Z. Treatment for primary 
postpartum haemorrhage. Cochrane Database of Systematic Reviews. 2014, Issue 2. Art. 
No.: CD003249. DOI: 10.1002/14651858.CD003249.pub3.
Prankerd RJ, Nguyen T, Ibrahim JP, et al. Pulmonary Delivery of an Ultra-Fine Oxytocin 
Dry Powder Formulation: Potential for Treatment of Postpartum Haemorrhage in 
Developing Countries. 2013; PLoS One. Vol 8: 12: Article e82965
Syntocinon Summary of Product Characteristics, Novartis, 2014
Thornton S, Davison JM, Baylis PH. Effect of human pregnancy on metabolic clearance 
rate of oxytocin. American Physiological Society. 1990. 0363-6119: R21-R24.
Thornton S, Davison JM, Baylis PH. Plasma oxytocin during third stage of labour: 
comparison of natural and active management.BMJ. 1988. Volume 297:167-169.
WHO Model List of Essential Medicines 18th list (April 2013). Available at: 
http://www.who.int/medicines/publications/essentialmedicines/en/. Accessed May 26, 
2015.
WHO Model List of Essential Medicines for Children 4th list (April 2013). Available at: 
http://www.who.int/medicines/publications/essentialmedicines/en/. Accessed May 26, 
2015.
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
67
WHO, UNICEF, UNFPA. The World Bank World Health Organization (WHO) Press. 
Trends in Maternal Mortality: 1990 to 2008: Estimates Developed by WHO, UNICEF, 
UNFPA and The World Bank. Geneva: WHO, 2010.
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
68
12.
APPENDICES
12.1.
Appendix 1
Abbreviations and Trademarks
Abbreviations
ADAs
Anti drug antibodies
AE
Adverse Event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase (SGPT)
ANP
Atrial natriuretic peptide
AST
Aspartate aminotransferase (SGOT)
AUC
Area under concentration-time curve
AUC(0-3)
Area under the concentration-time curve from time zero 
(pre-dose) to three hours
AUC(0-∞)
Area under the concentration-time curve from time zero to 
infinity
BMI
Body mass index
BP
Blood pressure
BUN
Blood urea nitrogen
C
Centigrade
Ca2+
Intracellular calcium
CI
Confidence Interval
CL
Plasma clearance
Clast
last observed quantifiable concentration
Cmax
Maximum observed plasma concentration
COC
Combined oral contraceptive
CONSORT
Consolidated Standards of Reporting Trials
COPD
Chronic obstructive pulmonary disease
Cp10
Observed plasma concentrations at 10 minutes post-dose
Cp20
Observed plasma concentrations at 20 minutes post-dose
Cp30
Observed plasma concentrations at 30 minutes post-dose
CPK
Creatinine phosphokinase
CRF
Case report form
CVS
Cardiovascular system
DMPK
Drug Metabolism and Pharmacokinetics
DPI
Dry powder inhaler
ECG
Electrocardiogram
EDTA
Ethylenediaminetetraacetic acid
FDA
Food and Drug Administration
FEV1.0
Forced expiratory volume at 1 minute
FRP
Females of Reproductive Potential
FSH
Follicle Stimulating Hormone
FTIH
First time in human
g
Gram
GCP
Good Clinical Practice
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
69
GSK
GlaxoSmithKline
h/hr
Hour(s)
HBsAg
Hepatitis B surface antigen
hCG
Human chorionic gonadotropin
HCP
Health care professional
HIV
Human Immunodeficiency Virus
HPLC
High Performance Liquid Chromatography
HR
Heart rate
I.U.
International units
IB
Investigators Brochure
ICH
International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for 
Human Use
IDSL
Integrated Data Standards Library
IEC
Independent Ethics Committee
IgG
Immunoglobulin G
IgM
Immunoglobulin M
IH
Inhaled
IL
Interleukin
IM
Intramuscular
INR
International normalized ratio
IP
Investigational product
IRB
Institutional Review Board
IV
Intravenous
Kg
kilogram
LDH
Lactate dehydrogenase
m
Meter
mcg
Micrograms
MCH
Mean Corpuscular Hemoglobin
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
ml
Millilitre
mmHg
Millimeter of mercury
MSDS
Material Safety Data Sheet
Msec
Milliseconds
MW
Molecular weight
OTR
Oxytocin receptor
PGF
Prostaglandin F
PI
Principal Investigator
PK
Pharmacokinetics
PPH
Post-partum haemorrhage
QTc
Corrected QT interval
QTcF
QT duration corrected for heart rate by Fridericia’s formula
RAP
Reporting and Analysis plan
RBC
Red blood cells
SAE
Serious Adverse Event
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
70
SD
Standard deviation
SMC
Smooth muscle cells
SPC
Summary of product characteristics
SpO2
Peripheral capillary oxygen saturation
SRM
Study reference manual
T&E
Time and event
t1/2
Terminal phase half-life
TB
Tuberculosis
tmax
Time to Cmax
TSL
Third stage of labour
UK
United Kingdom
ULN
Upper Limit of Normal
V
Vassopresin
VOD
Volume of distribution
WBC
White blood cells
WHO
World Health Organization
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
ROTACAPS
Syntocinon
ROTAHALER
Uniject
WinNonlin
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
71
12.2.
Appendix 2
Liver Safety Required Actions and Follow up 
Assessments
Phase I Liver chemistry stopping criteria have been designed to assure subject safety and 
to evaluate liver event etiology (in alignment with the Food and Drug Administration
[FDA] premarketing clinical liver safety guidance).
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Phase I liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria – Liver Stopping Event
ALT-absolute
ALT≥3xULN
If  ALT≥3xULN  AND bilirubin1,2 2xULN (>35% direct bilirubin) or  INR >1.5, 
Report as an SAE.
See additional Actions and Follow Up Assessments listed below
Required Actions and Follow up Assessments following Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue study treatment 

Report the event to GSK within 24 hours

Complete the liver event CRF, and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries 
resolve, stabilise, or return to within baseline 
(see MONITORING below)
MONITORING:
If ALT≥3xULN AND bilirubin 2xULN  or INR 
>1.5

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24 
hrs

Monitor subjects twice weekly until liver 
chemistries resolve, stabilise or return to 
within baseline

A specialist or hepatology consultation is 

Viral hepatitis serology3

Blood sample for pharmacokinetic (PK) 
analysis, obtained within 4h of the last 
dose4

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on 
the concomitant medications report form 
including acetaminophen, herbal remedies, 
other over the counter medications.

Record alcohol use on the liver event 
alcohol intake case report form
If ALT≥3xULN AND bilirubin 2xULN  or 
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
72
recommended
If ALT≥3xULN AND bilirubin < 2xULN  and 
INR ≤1.5:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24-
72 hrs

Monitor subjects weekly until liver 
chemistries resolve, stabilize or return to 
within baseline
INR >1.5:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG or gamma 
globulins).

Serum acetaminophen adduct High 
Performance Liquid Chromatography
(HPLC) assay (quantifies potential 
acetaminophen contribution to liver injury 
in subjects with definite or likely 
acetaminophen use in the preceding week 
[James, 2009]. NOTE: not required in 
China.

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured, which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); International normalized ratio (INR) measurement is not required 
and the threshold value stated will not apply to subjects receiving anticoagulants
3.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody
4.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
73
12.3.
Appendix 3
Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.3.1.
Definition of Adverse Events
Adverse Event Definition:

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.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae).

The signs and symptoms and/or clinical sequelae resulting from lack of efficacy will 
be reported if they fulfil the definition of an AE or SAE.  Also, "lack of efficacy" or 
"failure of expected pharmacological action" also constitutes an AE or SAE.
Events NOT meeting definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 
condition.
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
74

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
12.3.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
a.
Results in death
b.
Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c.
Requires hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting.  Complications that occur during hospitalization are 
AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d.
Results in disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
75
and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday 
life functions but do not constitute a substantial disruption
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition.  These should also be considered 
serious.

Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse
g.
Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** > 1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick.  If fractionation is unavailable and ALT 3xULN 
and total bilirubin 2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.
12.3.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
76

Deep venous thrombosis/pulmonary embolism

Revascularization
12.3.4.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the CRF

It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to GSK in lieu of completion of the GSK, AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK.  In this instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to 
submission of to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.
12.3.5.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. - an AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
77
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled 
out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of his/her assessment.

For each AE/SAE the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK.  However, it is very important 
that the investigator always make an assessment of causality for every event 
prior to the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.

The investigator is obligated to assist.  This may include additional laboratory tests 
or investigations, histopathological examinations or consultation with other health 
care professionals.

If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide GSK with a copy of any post-mortem findings, 
including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
78
12.3.6.
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data collection 
tool

If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and fax it to the Medical Monitor

Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.

The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of 
the SAE.

After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) will be taken off-line to prevent the entry of new data or changes to 
existing data

If a site receives a report of a new SAE from a study subject or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, the site can report this information on a paper SAE form or to the Medical 
Monitor or the SAE coordinator by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
79
12.4.
Appendix 4
Definition of and Procedures for 
Documenting Medical Device Incidents
12.4.1.
Definitions of a Medical Device Incident
The detection and documentation procedures described in this protocol apply to all GSK 
medical devices provided for use in the study (see Section 6.2 for the list of GSK medical 
devices).
Medical Device Incident Definition:

Incident – Any malfunction or deterioration in the characteristics and/or performance 
of a device, as well as any inadequacy in the labeling or the instructions for use 
which, directly or indirectly, might lead to or might have led to the death of a 
patient/user/other persons or to a serious deterioration in their state of health.

Not all incidents lead to death or serious deterioration in health.  The non-occurrence 
of such a result might have been due to other fortunate circumstances or to the 
intervention of health care personnel.
It is sufficient that:

an incident associated with a device happened and

the incident was such that, if it occurred again, might lead to death or a serious 
deterioration in health.
A serious deterioration in state of health can include:

life-threatening illness

permanent impairment of body function or permanent damage to a body structure

a condition necessitating medical or surgical intervention to prevent one of the above 

fetal distress, fetal death or any congenital abnormality or birth defects
Examples of incidents

a patient, user, care giver or professional is injured as a result of a medical device 
failure or its misuse

a patient’s treatment is interrupted or compromised by a medical device failure

misdiagnosis due to medical device failure leads to inappropriate treatment

a patient’s health deteriorates due to medical device failure
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
80
12.4.2.
Documenting Medical Device Incidents
Medical Device Incident Documenting:

Any medical device incident occurring during the study will be documented in the 
subject’s medical records, in accordance with the investigator’s normal clinical 
practice, and on the appropriate form.

For incidents fulfilling the definition of an AE or an SAE, the appropriate AE/SAE 
CRF page will be completed as described in Appendix 3.

The form will be completed as thoroughly as possible and signed by the investigator 
before transmittal to GSK.

It is very important that the investigator provides his/her assessment of causality to 
the medical device provided by GSK at the time of the initial report, and describes 
any corrective or remedial actions taken to prevent recurrence of the incident.

A remedial action is any action other than routine maintenance or servicing of a 
device where such action is necessary to prevent recurrence of an incident. This 
includes any amendment to the design to prevent recurrence.
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
81
12.5.
Appendix 5
List of Acceptable Methods for Avoiding 
Pregnancy in FRP and Collection of Pregnancy Information
12.5.1.
Group 2, Cohort B Only: List of Acceptable Non-hormonal
Methods for Avoiding Pregnancy in Females of Reproductive 
Potential (FRP)
The list does not apply to FRP with same sex partners or for subjects 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.
1.
Nonhormonal Intrauterine device or 
2.
Male condom combined with vaginal spermicide
3.
Male partner sterilization with documentation of azoospermia prior to the female 
subject's entry into the study, and this male is the sole partner for that subject 
[Hatcher, 2011]. The documentation on male sterility can come from the site 
personnel’s: review of subject’s medical records, medical examination and/or semen 
analysis, or medical history interview provided by her or her partner.
These allowed 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 these methods of contraception.
12.5.2.
Collection of Pregnancy Information
Group 2 Only

Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study

Information will be recorded on the appropriate form and submitted to GSK within 2 
weeks of learning of a subject's pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on mother and infant, which will be 
forwarded to GSK.  Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date. 

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
82

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK 
as described in Section 12.3. While the investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.
Any female subject who becomes pregnant while participating 

will discontinue study medication or be withdrawn from the study.
12.5.3.
References
Bolton TJ, Randall K, Yentis SM. Effect of the Confidential Enquiries into Maternal 
Deaths on the use of Syntocinon at Caesarean section in the UK. Anaesthesia 2003(58-
3):277-9.
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, Policar MS, 
editors. Contraceptive Technology. 20th edition. Atlanta, Georgia: Ardent Media, Inc., 
2011: 50. Table 3-2.
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
83
12.6.
Appendix 6
Country Specific Requirements
No country-specific requirements exist.
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
84
12.7.
Appendix 7
Device Acceptability Questionnaire
Device Acceptability Questionnaire
Please answer the following questions regarding your use of the ROTAHALER inhaler
for oxytocin.
1. Did you feel confident you had received the medicine?
Yes
No
Neutral
Decline to answer
2. Did you find the inhaler easy to use?
Yes
No
Neutral
Decline to answer
3. Did you prefer to have your medicine from an inhaler instead of an injection?
Yes
No
Neutral
Decline to answer
4. Do you feel using this inhaler is an acceptable way to administer the medicine?
Yes
No
Neutral
Decline to answer
Thank you for answering these questions.
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
85
12.8.
Appendix 8
Protocol Changes
12.8.1.
Protocol Amendment 01
As part of the Medical Device Notification assessment process, the Medicines and 
Healthcare products Regulatory Agency (MHRA) requested that the protocol 
prominently reflect that although the investigational device (the ROTAHALER) bears a 
CE mark, it has not been CE marked in accordance with the Medical Device Directive 
93/42/EEC as updated. This change applies to all sites.
Section 6.2 Medical Devices 
Change From:
The GSK manufactured medical device (or device manufactured for GSK by a third 
party) provided for use in this study is a high airflow resistance capsule-based inhaler 
(Modified Air Inlet ROTAHALER DPI device). 
Instructions for medical device use are provided in Section 6.7. Further details on use of 
the device are provided in the SRM.
GSK medical device incidents, including those resulting from malfunctions of the device, 
must be detected, documented, and reported by the investigator throughout the study –
see Section 12.4.
Change to:
The GSK manufactured medical device (or device manufactured for GSK by a third 
party) provided for use in this study is a high airflow resistance capsule-based inhaler 
(Modified Air Inlet ROTAHALER DPI device). Although this investigational device 
bears a CE mark, it has not been CE marked in accordance with the Medical 
Devices Directive 93/42/EEC.
Instructions for medical device use are provided in Section 6.7. Further details on use of 
the device are provided in the SRM.
GSK medical device incidents, including those resulting from malfunctions of the device, 
must be detected, documented, and reported by the investigator throughout the study –
see Section 12.4.
12.8.2.
Protocol Amendment 02
This amendment has been implemented to update the PK sample collection procedures in 
order to enhance ex-vivo PK stability, and to implement in-stream PK data analysis 
following the informal interim analysis of the first 10 subjects to complete Group 1. 
Location of name and contact information for Secondary Medical Monitor has also been 
updated.
Medical Monitor/Sponsor Information Page
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
86
Medical Monitor/SAE Contact Information
Change from:
Role
Name
Day Time Phone Number and 
email address
After-hours 
Phone/Cell/
Pager 
Number
Fax 
Number
Site 
Address
Secondary 
Medical 
Monitor
GSK
Gunnels 
Wood Road
Stevenage
SG1 2NY
UK
Change to
Role
Name
Day Time Phone 
Number and 
email address
After-hours 
Phone/Cell/
Pager 
Number
Fax 
Number
Site 
Address
Secondary 
Medical 
Monitor
Name and contact 
details available in 
Study Reference 
Manual
Section 1 Type and number of subjects
Change of typographical error from 45 to 50 subjects.
Change from:
In the event of this, sufficient subjects will be screened such that a maximum of 45 
subjects complete Group 1.
Change to:
In the event of this, sufficient subjects will be screened such that a maximum of 50 
subjects complete Group 1.
Section 2.2.2 PK Specimen Stability as Observed in 205920
Addition of this section to describe results from first informal interim analysis:
Prior to the initiation of the current trial, a sample-handling process was developed using 
blood from pregnant subjects of at least 37 weeks gestation to ensure ex-vivo oxytocin 
stability in specimens collected from Group 1 TSL subjects. 
 
2019N402257_00
PPD


2016N281575_02
CONFIDENTIAL
205920
87
Per protocol, after 10 subjects had completed all procedures in Group 1, an informal 
interim PK analysis was conducted. It was observed that in the majority of the plasma 
samples collected from TSL subjects, oxytocin concentrations were below the limit of 
quantification (BLQ) or at very low concentrations (approximately 3pg/mL) approaching 
the lower limit of quantification (LLQ) of the assay (2pg/mL). This was seen across both 
IM and IH routes of administration. This was an unexpected finding which has been 
confirmed by re-analysis of selected samples. As such, it is considered that it may be due 
to ex-vivo oxytocin instability related to uninhibited oxytocinase and peptidases, which 
are believed to be at increased concentrations in the plasma of postpartum women 
compared with non-pregnant women, and women at 37 weeks gestation. This finding 
resulted in a temporary halt to the trial.
Section 3.1 Group 1: Women in TSL
Typographical error correction.
Change from:
To characterize the pharmacokinetics of single doses of IH oxytocin and 10 I.U. IM 
oxytocinin women in TSL.
Change to:
To characterize the pharmacokinetics of single doses of IH oxytocin and 10 I.U. IM 
oxytocin in women in TSL.
Section 4.3 Type and Number of Subjects
Change of typographical error from 45 to 50 subjects.
Change from:
In the event of this, sufficient subjects will be screened such that a maximum of 45
subjects complete Group 1.
Change to:
In the event of this, sufficient subjects will be screened such that a maximum of 50
subjects complete Group 1.
Section 5.4.6 Plasma oxytocin concentration stopping criteria
Addition of this section and following text:
Per Section 9.3.2.1, the plasma oxytocin concentrations in up to 5 subjects in Group 1 
will be analysed in real time. If the plasma oxytocin concentration is BLQ or sufficiently 
low to prohibit interpretation in these 5 subjects irrespective of treatment, the study will 
be halted and reviewed.
Section 6.3 Treatment Assignment
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
88
Addition of following text:
If deemed necessary or if there is a new site identified for conducting and/or continuing 
the clinical trial, then a new randomization schedule may be generated by Clinical
Statistics, prior to the start of the study at the new site, using validated internal software.
Section 6.4 Planned Dose Adjustments
Typographical error correction
Change from: 
For Group 2, if an exaggerated physicological response is seen with the IV dose, such as 
increased heart rate and decreased blood pressure, then consideration will be given to 
changing to a 5-minute infusion.
Change to:
For Group 2, if an exaggerated physiological response is seen with the IV dose, such as 
increased heart rate and decreased blood pressure, then consideration will be given to 
changing to a 5-minute infusion.
Section 7.4.1 Blood Sample Collection
Change from:
At each time point, 4 mL of blood will be collected into K2 or K3 
Ethylenediaminetetraacetic acid (EDTA) tubes and stored on ice for up to 2 hours prior to 
centrifugation in a refrigerated centrifuge. Further details regarding collection/shipping 
procedures are provided in the SRM.
Change to:
At each time point, 4 mL of blood will be collected into study-specific tubes formulated 
to further inhibit peptidase activity. Additional details regarding collection/shipping 
procedures are provided in the SRM.
Section 7.4.2 Sample Analysis
Addition of the following text:
Once the plasma has been analyzed for oxytocin any remaining plasma may be analysed 
for metabolites of oxytocin and the results reported separately.
Section 9.3.2 Interim Analyses
Change from:
No formal interim analysis is planned. However, PK samples will be analysed and 
preliminary PK parameters derived following completion of 5 women on each of the 
 
2019N402257_00


2016N281575_02
CONFIDENTIAL
205920
89
following treatments: 400 mcg IH and 10 I.U. IM to women in TSL (Group 1) and 
400 mcg IH to non-pregnant women on the combined  oral contraceptive (Group 2 
Cohort A).  Based on the PK profiles the dose of IH oxytocin to be administered to 
women in TSL will either remain at 400 mcg or be increased (to 600 mcg) (See Section
6.4.1). This decision will be made by the study team in collaboration with the Principal 
Investigator. 
Change to:
No formal interim analyses are planned. PK data will be reviewed per Sections 9.3.2.1
and 9.3.2.2.
9.3.2.1 Informal Interim Reviews
PK samples will be analysed and preliminary PK parameters derived following 
completion of 5 women on each of the following treatments: 400 mcg IH and 10 I.U. IM 
to women in TSL (Group 1) and 400 mcg IH to non-pregnant women on the combined 
oral contraceptive (Group 2 Cohort A).  Based on the PK profiles the dose of IH oxytocin 
to be administered to women in TSL will either remain at 400 mcg or be increased (to 
600 mcg) (See Section 6.4.1). This decision will be made by the study team in 
collaboration with the Principal Investigator. 
This will be repeated after restart from the temporary halt for Group 1.
9.3.2.2 In-Stream Analysis of Group 1
Following restart from temporary halt, PK specimens from each of up to 5 subjects in 
Group 1 will be analysed as soon as possible after collection. This will allow for 
confirmation that the revised specimen collection procedures allow for detection of 
adequate oxytocin PK profile. 
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
The GlaxoSmithKline group of companies
205920
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
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.
Compound Number:
GR121619
Development Phase:
I
Effective Date:
10-OCT-2016
Protocol Amendment Number: 01
Author (s):
 (Respiratory TAU); 
(GCSP); 
 
(MNHU), 
(Clinical Statistics); 
 
(GCSP); 
(QSci CPMS); 
(CPSSO)
Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2016N281575_00
2016-AUG-22
Original
2016N281575_01
2016-OCT-10
Amendment No. 1
Section 6.2: Inclusion of information on CE marking.
Copyright 2016 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
2019N402257_00
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


 
2019N402257_00
PPD
PPD


2016N281575_01
CONFIDENTIAL
205920
3
MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information: 
Role
Name
Day Time Phone Number and 
email address
After-hours 
Phone/Cell/
Pager 
Number
Fax 
Number
Site 
Address
Primary 
Medical 
Monitor 
GSK
Gunnels 
Wood 
Road
Stevenage
SG1 2NY
UK
Secondary 
Medical 
Monitor
GSK
Gunnels 
Wood 
Road
Stevenage
SG1 2NY
UK
SAE 
contact  
information 
Medical 
monitor as 
above 
Sponsor Legal Registered Address:
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline (GSK)
Affiliate Company (or designee). If applicable, the details of the alternative Sponsor and 
contact person in the territory will be provided to the relevant regulatory authority as part 
of the clinical trial application.   
Regulatory Agency Identifying Number(s): EudraCT 2016-002672-27
 
2019N402257_00
PPD


2016N281575_01
CONFIDENTIAL
205920
4
INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number 205920
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
5
TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 205920........................................................9
2.
INTRODUCTION....................................................................................................13
2.1.
Study Rationale ..........................................................................................14
2.2.
Brief Background ........................................................................................14
2.2.1.
IH Oxytocin FTIH Study 201558 ..................................................16
3.
OBJECTIVES AND ENDPOINTS...........................................................................16
3.1.
Group 1: Women in TSL .............................................................................16
3.2.
Group 2: Non-pregnant, non-lactating females of child bearing 
potential......................................................................................................17
3.3.
Groups 1 and 2: Women in TSL and Non-pregnant, non-lactating 
females of child bearing potential................................................................18
4.
STUDY DESIGN ....................................................................................................18
4.1.
Overall Design ............................................................................................18
4.1.1.
Study Schematic Group 1: Women in TSL...................................18
4.1.2.
Study Schematic Group 2: Non-pregnant, non-lactating 
females of child bearing potential.................................................19
4.1.3.
Study Design Detail .....................................................................19
4.1.3.1.
Pregnant Females (Group 1)......................................20
4.1.3.2.
Non-pregnant Females (Group 2)...............................20
4.1.4.
ROTAHALER Inhaler Training .....................................................20
4.1.5.
Length of Stay for All Subjects.....................................................20
4.2.
Treatment Arms and Duration.....................................................................21
4.3.
Type and Number of Subjects.....................................................................22
4.4.
Design Justification.....................................................................................22
4.5.
Dose Justification........................................................................................22
4.6.
Benefit:Risk Assessment ............................................................................25
4.6.1.
Risk Assessment .........................................................................25
4.6.2.
Immunogenicity Risk....................................................................28
4.6.3.
Benefit Assessment and Overall Benefit:Risk Conclusion............28
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............29
5.1.
Inclusion Criteria.........................................................................................29
5.2.
Exclusion Criteria........................................................................................32
5.3.
Screening/Baseline/Run-in Failures............................................................34
5.3.1.
Re-screening ...............................................................................34
5.4.
Withdrawal/Stopping Criteria.......................................................................34
5.4.1.
Pregnancy Complication Stopping Criteria (Group 1 Only) ..........34
5.4.2.
Anaphylaxis Stopping Criteria......................................................35
5.4.3.
QTc Stopping Criteria (Group 2 Only)..........................................35
5.4.4.
Blood Pressure Stopping Criteria (Group 2 Only).........................35
5.4.5.
Liver Chemistry Stopping Criteria ................................................35
5.5.
Subject and Study Completion....................................................................36
6.
STUDY TREATMENT ............................................................................................36
6.1.
Investigational Product and Other Study Treatment....................................36
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
6
6.2.
Medical Devices..........................................................................................37
6.3.
Treatment Assignment................................................................................37
6.4.
Planned Dose Adjustments.........................................................................38
6.4.1.
Dose Adjustment .........................................................................38
6.5.
Blinding.......................................................................................................39
6.6.
Packaging and Labeling..............................................................................39
6.7.
Preparation/Handling/Storage/Accountability..............................................39
6.8.
Compliance with Study Treatment Administration.......................................40
6.9.
Treatment of Study Treatment Overdose....................................................41
6.10.
Treatment after the End of the Study ..........................................................42
6.11.
Lifestyle and/or Dietary Restrictions............................................................42
6.11.1.
Meals and Dietary Restrictions ....................................................42
6.11.2.
Caffeine and Alcohol....................................................................42
6.11.3.
Activity .........................................................................................43
6.12.
Concomitant Medications and Non-Drug Therapies....................................43
6.12.1.
Permitted Medications and Non-Drug Therapies..........................43
6.12.2.
Prohibited Medications and Non-Drug Therapies.........................43
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................43
7.1.
Time and Events Table...............................................................................45
7.1.1.
Time and Events Table – General Overview................................45
7.1.2.
Time and Events – Main Phase Procedures ................................47
7.2.
Screening and Critical Baseline Assessments ............................................49
7.3.
Safety .........................................................................................................49
7.3.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........49
7.3.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................49
7.3.1.2.
Method of Detecting AEs and SAEs ...........................50
7.3.1.3.
Follow-up of AEs and SAEs........................................50
7.3.1.4.
Regulatory Reporting Requirements for SAEs............50
7.3.2.
Adverse Events of Special Interest (AESI)...................................51
7.3.3.
Pregnancy ...................................................................................51
7.3.4.
Medical Device Incidents (Including Malfunctions).......................51
7.3.4.1.
Time Period for Detecting Medical Device 
Incidents.....................................................................51
7.3.4.2.
Follow-up of Medical Device Incidents........................51
7.3.4.3.
Prompt Reporting of Medical Device Incidents 
to GSK........................................................................52
7.3.4.4.
Regulatory Reporting Requirements for 
Medical Device Incidents............................................52
7.3.5.
Physical Exams ...........................................................................52
7.3.6.
Vital Signs....................................................................................52
7.3.7.
Documentation of Labour Events.................................................53
7.3.8.
Electrocardiogram (ECG) (Group 2 Only) ....................................53
7.3.9.
Continuous Cardiac Telemetry (Group 2 Only) ............................53
7.3.10.
Device Acceptability Questionnaire (Group 1 Only) .....................53
7.3.11.
Clinical Safety Laboratory Assessments ......................................53
7.4.
Pharmacokinetics .......................................................................................55
7.4.1.
Blood Sample Collection..............................................................55
7.4.2.
Sample Analysis ..........................................................................55
7.5.
Biomarkers .................................................................................................56
7.5.1.
Pharmacodynamic Markers .........................................................56
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
7
7.5.2.
Immunogenicity............................................................................56
8.
DATA MANAGEMENT ...........................................................................................56
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................56
9.1.
Hypotheses.................................................................................................56
9.2.
Sample Size Considerations.......................................................................57
9.2.1.
Sample Size Sensitivity................................................................58
9.2.2.
Sample Size Re-estimation or Adjustment...................................58
9.3.
Data Analysis Considerations .....................................................................58
9.3.1.
Analysis Populations....................................................................58
9.3.2.
Interim Analysis ...........................................................................59
9.4.
Key Elements of Analysis Plan ...................................................................59
9.4.1.
Primary Analyses.........................................................................59
9.4.1.1.
Safety Analysis...........................................................59
9.4.1.2.
Pharmacokinetic Analysis...........................................59
9.4.2.
Secondary Analyses ....................................................................59
9.4.2.1.
Pharmacokinetic Analysis...........................................60
9.4.3.
Exploratory Analyses ...................................................................60
9.4.3.1.
Pharmacokinetic Analysis...........................................60
9.4.3.2.
Device Acceptability Questionnaire ............................60
10. STUDY GOVERNANCE CONSIDERATIONS........................................................60
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............60
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................60
10.3.
Quality Control (Study Monitoring) ..............................................................61
10.4.
Quality Assurance.......................................................................................62
10.5.
Study and Site Closure ...............................................................................62
10.6.
Records Retention......................................................................................62
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................63
11. REFERENCES.......................................................................................................64
12. APPENDICES........................................................................................................66
12.1.
Appendix 1 Abbreviations and Trademarks.................................................66
12.2.
Appendix 2 Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................69
12.3.
Appendix 3 Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................71
12.3.1.
Definition of Adverse Events........................................................71
12.3.2.
Definition of Serious Adverse Events...........................................72
12.3.3.
Definition of Cardiovascular Events .............................................73
12.3.4.
Recording of AEs and SAEs ........................................................74
12.3.5.
Evaluating AEs and SAEs............................................................74
12.3.6.
Reporting of SAEs to GSK...........................................................76
12.4.
Appendix 4  Definition of and Procedures for Documenting Medical 
Device Incidents .........................................................................................77
12.4.1.
Definitions of a Medical Device Incident.......................................77
12.4.2.
Documenting Medical Device Incidents .......................................78
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
8
12.5.
Appendix 5 List of Acceptable Methods for Avoiding Pregnancy in 
FRP and Collection of Pregnancy Information ............................................79
12.5.1.
Group 2, Cohort B Only:  List of Acceptable Non-hormonal 
Methods for Avoiding Pregnancy in Females of 
Reproductive Potential (FRP) ......................................................79
12.5.2.
Collection of Pregnancy Information ............................................79
12.5.3.
References ..................................................................................80
12.6.
Appendix 6 Country Specific Requirements................................................81
12.7.
Appendix 7 Device Acceptability Questionnaire ..........................................82
12.8.
Appendix 8 Protocol Changes....................................................................83
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
9
1.
PROTOCOL SYNOPSIS FOR STUDY 205920
Rationale
Post-partum hemorrhage is one of the main causes of maternal mortality in the 
developing world. The World Health Organization (WHO) lists oxytocin on its list of 
‘Essential Medicines’ for Humanity as a preventative treatment for post-partum 
hemorrhage; however, because of its cold-chain storage requirement and parenteral 
administration route, high-quality oxytocin is not always available in resource-poor 
settings. GlaxoSmithKline (GSK) has developed a stable, dry-powder formulation of 
oxytocin to address this unmet need, with the goal of reducing post-partum hemorrhage 
morbidity and mortality in these settings.
This study is being conducted to further assess safety and tolerability of inhaled oxytocin, 
and to characterize the pharmacokinetic (PK) profile of inhaled oxytocin 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 inhaled 
(IH) or intramuscular (IM) oxytocin as active management of the third stage of labour. 
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.
Objectives/Endpoints
Group 1 – Women in Third Stage of Labour (TSL)
Objectives
Endpoints
Primary

To characterize the pharmacokinetics of 
single doses of IH oxytocin and 
10 International Units (I.U.) IM oxytocin in 
women in TSL.

Plasma concentration time profile for IH 
oxytocin and 10 I.U. IM oxytocin.

PK parameters: Maximum observed plasma 
concentration (Cmax), Observed plasma 
concentrations at 10 minutes (min) post-
dose (Cp10), Observed plasma 
concentrations at 20 min post-dose (Cp20), 
Observed plasma concentrations at 30 min 
post-dose (Cp30), Time to Cmax (tmax), 
Area under concentration-time curve (AUC),
and Terminal phase half-life (t1/2) will be 
calculated as data permit.
Secondary

To evaluate the safety and tolerability of 
inhaled oxytocin.

General safety parameters: adverse events
(AE); absolute values and changes over 
time of vital signs (blood pressure, heart 
rate, respiratory rate, temperature).

To compare pharmacokinetics of IH 
oxytocin to 10 I.U. IM oxytocin in women in 
TSL.

Cmax ,Cp10, Cp20, Cp30, Area under the 
concentration-time curve from time zero 
(pre-dose) to three hours (h) (AUC[0-3h])
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
10
Objectives
Endpoints
will be compared as data permit.
Exploratory 

Pharmacodynamic effect of IH oxytocin 
and 10 I.U. IM oxytocin in women in TSL.

Pre and post-delivery haemoglobin. 

Participant feedback regarding ease of 
use, instructions, and perceived ability of 
patients to use the ROTAHALER.

Questionnaire results from participants.
Group 2 – Non-pregnant, non-lactating females of child bearing potential
Objectives
Endpoints
Primary

To evaluate the safety and tolerability of IH 
and IV oxytocin.

General safety parameters: adverse events; 
absolute values and changes over time of 
vital signs (blood pressure, heart rate) and 
12-lead electrocardiogram (ECG) 
parameters (PR, QRS, QT, Corrected QT 
interval [QTc] intervals) from pre-dose 
values. 

Specific respiratory safety parameters: 
adverse respiratory events as monitored by 
spirometry including Forced expiratory 
volume at 1 minute (FEV1.0), respiratory 
rate, and pulse oximetry.

To characterize the pharmacokinetics of 
single doses of IH oxytocin and 5 I.U. IV 
oxytocin.

Plasma concentration time profile for IH 
oxytocin and 5 I.U. IV oxytocin.

PK parameters: Cmax, Cp10, Cp20, Cp30, 
tmax, AUC, Plasma clearance (CL), volume 
of distribution and t1/2 will be calculated as 
data permit.
Exploratory 

To evaluate endogenous plasma oxytocin 
concentrations in non-pregnant females in 
the presence and absence of the combined 
oral contraceptive.

Pre-dose plasma concentrations of 
oxytocin.

To compare the IH pharmacokinetics of 
oxytocin between Cohort A (subjects on 
combined oral contraceptive) and Cohort B 
(subjects using a non-hormonal form of 
contraception).

Cp10, Cp20, Cp30, AUC(0-3h) Cmax, 
AUC(0-3h), Area under the concentration-
time curve from time zero to infinity
(AUC[0-∞]) and t1/2, will be compared as 
data permit.

To compare the IV pharmacokinetics of 
oxytocin between Cohort A and Cohort B.

Cmax, AUC, t1/2, CL and Volume of 
distribution (VOD) will be compared as 
data permit.
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
11
Groups 1 and 2 – Women in TSL and Non-pregnant, non-lactating females of child bearing 
potential
Objectives
Endpoints
Exploratory 

To compare pharmacokinetics of IH 
oxytocin between Group 1 and Group 2

Cp10, Cp20, Cp30, AUC(0-3h) Cmax, 
AUC(0-3h) AUC(0-∞), and t1/2 will be 
compared as data permit.
Overall Design
Group 1 – Women in TSL
Group 2 – Non-pregnant, non-lactating females of child bearing potential
Treatment Arms and Duration
Screening
Group 1: All screening assessments to be completed after the 18th
week of pregnancy (based on estimated date of delivery).
Group 2: All screening assessments to be completed within 28 days
prior to the first dose.
Treatment Session
Group 1: Each subject will take part in 1 dosing session.
Group 2: Each subject will take part in 2 dosing sessions.
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
12
Treatment Arms1
Group 1: Subjects will be randomised to receive one of the following 
study treatments:

400 micrograms (mcg) IH oxytocin

10 I.U. IM oxytocin
Group 2: Subjects will receive both of the following study treatments 
over the course of two dosing sessions:

400 mcg IH oxytocin

5 I.U. IV oxytocin
Follow-up
Group 1: Follow Up 1 – Within approximately 24 h post dose.
Group 1: Follow Up 2 –  At least 7 days and no greater than 14 days 
after study drug administration.
Both visits may be conducted in-person or via telephone.
Group 2: At least 7 days and no greater than 21 days after last study 
drug administration.
This visit will be conducted in-person.
If warranted, additional follow-up visits may be scheduled for both 
Groups.
Total Duration
Group 1: Screening after 18th week of pregnancy (i.e. within 168 days of 
1 dosing session) + follow up of 7 - 14 days = approximately 183 days
Group 2: Screening within 28 days of dosing session 1 + 2 dosing 
sessions with a maximum of 14 days between dosing + follow-up of 7 –
21 days = 64 days
Type and Number of Subjects
Sufficient subjects will be screened such that approximately 20 subjects complete all 
study procedures in Group 1, and approximately 10 subjects complete all study 
procedures in Group 2 (approximately 5 in each cohort of Group 2). 
If subjects prematurely discontinue the study, additional replacement subjects may be 
recruited and assigned to the same treatment sequence at the discretion of the Sponsor. 
Replacement subjects will complete all study procedures.
If the PK variability between subjects in Group 1 is higher than expected, it may be 
required to increase the sample size up to a maximum of 10 additional subjects per 
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
13
treatment group for inhaled and intramuscular oxytocin. In the event of this, sufficient 
subjects will be screened such that a maximum of 45 subjects complete Group 1.
If a dose adjustment is required in either group, additional subjects may be recruited such 
that a full 10 subjects receive the final IH or IV dose.
Analysis
The primary objective of this study is to characterize pharmacokinetics of IH oxytocin 
and IM oxytocin in women in the third stage of labour.
No formal hypotheses will be tested, however, comparisons of interest, within Group 1,
and between Group 1 and Group 2 and between Cohorts A and B in Group 2 will be 
made and the point estimates and corresponding two-sided 90% confidence intervals (CI)
will be presented to provide the range of plausible values for the comparisons. 
2.
INTRODUCTION
Maternal mortality associated with postpartum hemorrhage (PPH) is one of the major 
public health problems in the developing world. Approximately half a million women 
worldwide die annually from causes directly related to pregnancy and childbirth, and up 
to one third of these deaths in Africa and Asia are caused by complications as a result of 
PPH [Khan, 2006;WHO, 2010]. A Cochrane Review meta-analysis of the data from 
multiple preventative trials with oxytocin at 10 international units (I.U.) given via the 
intramuscular (IM) route has confirmed this specific uterotonic, and this particular route 
of administration, to be the gold standard prophylactic therapy for PPH [Mousa, 2014]. 
For this reason, the World Health Organization (WHO) has designated oxytocin as one of 
its ‘Essential Medicines’ for humanity [WHO Model List of Essential Medicines 18th list, 
April 2013; WHO Model List of Essential Medicines for Children 4th list, April 2013].
However, in resource-poor settings within the developing world, the 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 
[Mousa, 2014]. Although single-use, oxytocin prefilled, syringes for IM injection are 
available in many developing countries (e.g. UNIJECT device), the development of a 
needle-free and self-administered inhaled (IH) oxytocin product, which delivers 
comparable systemic exposure to 10 I.U. IM, would be a major step-change in the 
administration of this life-saving medicine to pregnant women in resource-poor regions 
of the developing world. This would be particularly relevant in rural areas where the 
mother has no routine access to a trained HCP and/or where there is no reliable electricity 
supply to permit refrigerated storage of oxytocin injection vials. 
We have developed a stable, dry-powder formulation of oxytocin to be administered via 
the oral inhaled pulmonary route (compared to 10 I.U. of IM oxytocin) using a 
GlaxoSmithKline (GSK)-manufactured medical device (or device manufactured for GSK 
by a third party) which is a capsule-based inhaler (Modified Air Inlet ROTAHALERTM
Dry Powder Inhaler (DPI) device, hereafter referred to as ROTAHALER). This 
formulation and delivery method has the potential to be used in settings where effective 
oxytocin is currently unavailable to women in the third stage of labour (TSL).
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
14
2.1.
Study Rationale
This study will be the second investigation of oxytocin in humans via the IH route, which 
follows the first time in human (FTIH) study, 201558 [GlaxoSmithKline Document 
Number 2015N234711_01, 2015; see Section 2.2.1 for more information on the FTIH 
trial)]. Published literature on the pharmacokinetics (PK) of oxytocin in non-pregnant and 
pregnant women is limited.  There is some evidence to suggest that the metabolic 
clearance of oxytocin may increase during pregnancy; potentially related to degradation 
by the circulating aminopeptidase, oxytocinase, and/or pregnancy related changes in 
hepatic and renal function [Syntocinon Summary of Product Characteristics, Novartis, 
2014; Thornton, 1990].  In addition, endogenous oxytocin plasma concentrations have 
been reported to either increase or remain constant after the delivery of the fetal anterior 
shoulder [Thornton, 1988]. As a result of these pregnancy related changes, systemic 
exposure to oxytocin may differ between healthy non-pregnant women and women in the 
TSL for a given dose and route of administration of oxytocin. To further understand the 
effect of pregnancy on the PK of oxytocin, this study will investigate the PK of oxytocin 
in pregnant women in TSL following either IH (400 micrograms [mcg]) or 10 I.U. IM 
(17 mcg) administration. A greater understanding of the PK of oxytocin in TSL will help 
facilitate extrapolation of data obtained in healthy non-pregnant women to women in 
TSL. An additional group of  non-pregnant non-lactating female volunteers will also be 
included as a control group and will receive 400 mcg IH oxytocin and 5 I.U. intravenous 
(IV) oxytocin. This second group will enrol one cohort of subjects taking the combined 
oral contraceptive (COC), and another cohort using a non-hormonal form of 
contraception. This will assess if women need to be on an oral contraceptive vs. other 
methods of birth control in future clinical studies, since although the COC is believed to 
suppress endogenous oxytocin levels the literature is not consistent about this 
observation. As the requirement to be taking the COC makes recruitment more of a 
challenge it will be helpful to know if this inclusion is essential, or if women using non-
hormonal forms of birth control might also have sufficiently low systemic oxytocin levels 
suitable for PK studies.
2.2.
Brief Background
Oxytocin is a nonapeptide which is produced by the hypothalamus and released into the 
systemic circulation by the posterior pituitary gland. Within the brain, oxytocin, like most 
hypothalamic synthesized hormones, acts as a neurotransmitter. In human pregnancy,
during the later phases of the third trimester, increasing circulating levels of oxytocin act 
as a potent endogenous uterotonic which facilitates the initiation of labour. Furthermore, 
a neurohormonal positive feedback loop exists between dilatation of the cervico-vaginal 
canal by fetal passage and the hypothalamus (i.e. Fergusson reflex) which augments 
oxytocin production, thus increasing uterine contraction intensity and frequency which 
facilitates vaginal delivery. However, once the fetus is delivered, plasma oxytocin levels 
rapidly diminish probably due to a combination of increased circulating levels of 
oxytocinase (the principal oxytocin deactivating enzyme), in the plasma, an overall 
reduction in hypothalamic oxytocin synthesis (Figure 1), and a reduction in uterine 
oxytocin receptor (OTR) density. This oxytocin-depleted, relatively auterotonic, 
physiological environment puts the mother at risk of PPH during the subsequent placental 
delivery phase (i.e. TSL). 
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
15
Figure 1
Oxytocin During Physiological Fetal Delivery
Oxytocin receptors are constitutively expressed in smooth muscle cells (SMCs) in the 
uterine myometrium, muscular walls of the bronchi and upper digestive tract, 
myoepithelial cells of the breast duct which are essential for the oxytocin-dependent 
postpartum breast milk let-down reflex, and in different regions of the brain.  Although 
uterine OTR expression increases during the later stages of pregnancy, it is not known 
whether pregnancy increases OTR expression at non-uterine sites, such as the maternal 
brain, where neuronal oxytocin signalling has been implicated in postpartum bonding 
behaviour with the baby. Within the kidney, oxytocin is known to bind to vasopressin 
(V2) receptors, rather than OTR, in the medullary renal collecting duct which triggers an 
antidiuretic effect.
Binding of oxytocin to OTR triggers an increase in intracellular calcium (Ca2+), which is 
partly mediated through oxytocin-dependent up-regulation of prostaglandin F (PGF)2α 
synthesis, which in the uterine myometrium leads to physiological uterine contractions 
during 3rd-stage labour.
More recent research has shown oxytocin to be present in broncho-alveloar lavage fluid 
collected from the respiratory tract of adult humans of both sexes, but oxytocinase 
expression was not assessed. In an in vivo pharmacology study [Prankerd , 2013] in
pregnant ewes intratracheal insufflation of a dry-powder formulation of oxytocin was 
associated with poor absolute bioavailability (ca 5%), but despite low systemic exposure, 
this still caused a pharmacodynamic response that was manifested by increased electrical 
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
16
uterine activity measured by electromyography, probably as a result of increased OTR 
stimulation in the pregnant uterus.
2.2.1.
IH Oxytocin FTIH Study 201558
Study 201558 [GlaxoSmithKline Document Number 2016N277949_00] was the FTIH 
study to evaluate safety, tolerability, and characterize the PK profile of 4 dose strengths 
of IH oxytocin compared to oxytocin 10 I.U. IM. The study enrolled 16 healthy, non-
pregnant, premenopausal female subjects. One subject was withdrawn prior to IH 
oxytocin dosing due to inability to cannulate. Subjects were administered 10 I.U. IM 
oxytocin, IH placebo containing (only) the excipients found in the IH oxytocin 
formulation, and IH oxytocin. A minimum washout period of 48 hours (h) was required 
between each dose of active drug. This dose escalation study evaluated 4 doses of IH 
oxytocin: 50 mcg, 200 mcg, 400 mcg, and 600 mcg. The most frequently reported 
Adverse Event (AE) was headache, and occurred in at least one subject in each treatment 
arm. In general, IH oxytocin was well-tolerated, no safety concerns with IH dosing were 
identified, no clinically significant effect on respiratory parameters were observed, and 
no Serious Adverse Events (SAEs) were reported. The PK profile of the 400 mcg IH 
oxytocin dose was similar to that of 10 I.U. IM, and has been selected for further 
evaluation. See Section 4.5 for further information on PK characteristics.
3.
OBJECTIVES AND ENDPOINTS
3.1.
Group 1: Women in TSL
Objectives
Endpoints
Primary

To characterize the pharmacokinetics of 
single doses of IH oxytocin and 10 I.U. IM 
oxytocinin women in TSL.

Plasma concentration time profile for IH 
oxytocin and 10 I.U. IM oxytocin.

PK parameters: Maximum observed plasma 
concentration (Cmax), Observed plasma 
concentrations at 10 minutes (min) post-
dose (Cp10), Observed plasma 
concentrations at 20 min post-dose (Cp20), 
Observed plasma concentrations at 30 min 
post-dose (Cp30), Time to Cmax (tmax), 
Area under concentration-time curve (AUC), 
and Terminal phase half-life (t1/2) will be 
calculated as data permit.
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
17
Objectives
Endpoints
Secondary

To evaluate the safety and tolerability of 
inhaled oxytocin.

General safety parameters: adverse events; 
absolute values and changes over time of 
vital signs (blood pressure, heart rate, 
respiratory rate, temperature).

To compare pharmacokinetics of IH 
oxytocin to 10 I.U. IM oxytocin in women in 
TSL.

Cmax ,Cp10, Cp20, Cp30, Area under the 
concentration-time curve from time zero 
(pre-dose) to three hours (h) (AUC[0-3h])
will be compared as data permit.
Exploratory 

Pharmacodynamic effect of IH oxytocin 
and 10 I.U. IM in women in TSL.

Pre and post-delivery haemoglobin. 

Participant feedback regarding ease of
use, instructions, and perceived ability of 
patients to use the ROTAHALER.

Questionnaire results from participants.
3.2.
Group 2: Non-pregnant, non-lactating females of child 
bearing potential
Objectives
Endpoints
Primary

To evaluate the safety and tolerability of IH 
and IV oxytocin.

General safety parameters: adverse events; 
absolute values and changes over time of 
vital signs (blood pressure, heart rate) and 
12-lead electrocardiogram (ECG) 
parameters (PR, QRS, QT, Corrected QT 
interval [QTc] intervals) from pre-dose 
values. 

Specific respiratory safety parameters: 
adverse respiratory events as monitored by 
spirometry including Forced expiratory 
volume at 1 minute (FEV1.0), respiratory 
rate, and pulse oximetry.

To characterize the pharmacokinetics of 
single doses of IH oxytocin and 5 I.U. IV 
oxytocin.

Plasma concentration time profile for IH 
oxytocin and 5 I.U. IV oxytocin.

PK parameters: Cmax, Cp10, Cp20, Cp30, 
tmax, AUC, Plasma clearance (CL), volume 
of distribution and t1/2 will be calculated as 
data permit.
Exploratory 

To evaluate endogenous plasma oxytocin 
concentrations in non-pregnant females in 

Pre-dose plasma concentrations of 
oxytocin.
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
18
Objectives
Endpoints
the presence and absence of the combined 
oral contraceptive.

To compare the IH pharmacokinetics of 
oxytocin between Cohort A (subjects on 
combined oral contraceptive) and Cohort B 
(subjects using a non-hormonal form of 
contraception).

Cp10, Cp20, Cp30, AUC(0-3h) Cmax, 
AUC(0-3h), Area under the concentration-
time curve from time zero to infinity 
(AUC[0-∞]) and t1/2, will be compared as 
data permit.

To compare the IV pharmacokinetics of 
oxytocin between Cohort A and Cohort B.

Cmax, AUC, t1/2, CL and Volume of 
distribution (VOD) will be compared as 
data permit.
3.3.
Groups 1 and 2: Women in TSL and Non-pregnant, non-
lactating females of child bearing potential
Objectives
Endpoints
Exploratory 

To compare pharmacokinetics of IH 
oxytocin between Group 1 and Group 2.

Cp10, Cp20, Cp30, AUC(0-3h) Cmax, 
AUC(0-3h) AUC(0-∞), and t1/2 will be 
compared as data permit.
4.
STUDY DESIGN
4.1.
Overall Design
4.1.1.
Study Schematic Group 1: Women in TSL
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
19
4.1.2.
Study Schematic Group 2: Non-pregnant, non-lactating females 
of child bearing potential
4.1.3.
Study Design Detail
This study will enrol two groups. 
Group 1 - Women in TSL
Group 1 will enrol women with an uncomplicated pregnancy, and main phase procedures 
will occur during TSL. Subjects will be randomized to receive either IH or IM oxytocin 
as active management of TSL.  The specific timing of this dose will be as per local 
standard of care.1
Group 2 - Non-pregnant, non-lactating females of child bearing potential
Group 2 will enrol healthy, non-pregnant, non-lactating female subjects of childbearing 
potential, and each subject will participate in 2 dosing sessions. Group 2 will be divided 
into two cohorts: Cohort A will enrol women on a combined oral contraceptive, and 
Cohort B will enrol women who are not using a hormonal form of contraceptive. Group 2 
subjects will receive IH oxytocin at one dosing session, and IV oxytocin at the other 
dosing session; the order of IH versus IV oxytocin administration will be randomly 
assigned.
PK samples will be analysed periodically throughout the study duration to enable 
development of the population PK model and derivation of PK parameters via non-
compartmental methods, as data permits.
No formal interim analysis is planned, however, PK samples will be analysed and 
preliminary PK parameters derived following completion of approximately 5 women on 
each treatment group: IH, IM in Group 1 and IH in Group 2 Cohort A in order to assess if 
dose escalation is required.  
                                                
1 For information only: Standard of care at proposed clinical site is to administer the oxytocic drug by IM 
injection with the birth of the anterior shoulder, or immediately after the birth of the baby and before the 
cord is clamped and cut.
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
20
4.1.3.1.
Pregnant Females (Group 1)
Subjects will review the study information and if they agree to participate, sign the
informed consent form. For most subjects this is expected to take place at an outpatient
antenatal visit, or additional study-specific screening visit. If a subject meets all 
inclusion/exclusion criteria for the study, she will be eligible for enrolment in the study.
To facilitate recruitment, and provide subjects ample time to consider participation, 
screening may occur any time after 18 weeks gestation (based on estimated date of 
delivery). See time and events (T&E) table in Section 7.1 for details.
4.1.3.2.
Non-pregnant Females (Group 2)
Subjects will review the study information and if they agree to participate, sign the 
informed consent form. If a subject meets all inclusion/exclusion criteria for the study, 
she will be enrolled in the study.
Screening may occur within 28 days prior to randomization for non-pregnant volunteers. 
If a subject falls outside this window prior to randomization and enrolment, she must be 
re-screened. Certain screening procedures may not be required to be repeated; see T&E 
(Section 7.1) for details.
Group 2 subjects will take part in 2 dosing sessions, which must be conducted a 
minimum of 48 hours apart. It is recommended that subjects complete Session 2 within 
14 days of Session 1. Subjects will be randomized to receive either IH or IV oxytocin 
during Session 1, and to receive the other treatment during Session 2, such that all 
subjects in Group 2 receive both treatments over the course of the 2 sessions.
4.1.4.
ROTAHALER Inhaler Training
The investigator/designee will be trained to load the ROTACAPS powder capsule into 
the device, prime the dose and instruct the subjects to inhale from the ROTAHALER 
inhaler in the appropriate manner (refer to Section 6.7). Subjects will be instructed by the 
investigator/designee to use an inspiration technique (2 inhalations) that enables maximal 
inhalation of the ROTACAPS powder capsule contents (refer to Section 6.7 for full 
details). This will ensure optimal and consistent drug delivery (full instructions available 
in the Study Reference Manual [SRM]). 
4.1.5.
Length of Stay for All Subjects
Group 1 - Women in TSL
Subjects in Group 1 will be admitted to hospital during labour as part of their routine 
care, and will be required to remain inpatient for a minimum of 4 hours after receiving 
any study-related dose of oxytocin. After final PK collection, subjects will be finished 
with study procedures and the main phase of the study will be considered complete. 
Discharge from hospital will be determined by the subject’s medical provider. 
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
21
Group 2 - Non-pregnant, non-lactating females of child bearing potential
Subjects in Group 2 will be admitted to the clinical unit prior to dosing on Day 1 and are 
to remain inpatient until at least 4 hours after dosing. Discharge will occur at the 
discretion of the investigator.
4.2.
Treatment Arms and Duration
Screening
Group 1: All screening assessments to be completed after the 18th
week of pregnancy (based on estimated date of delivery)
Group 2: All screening assessments to be completed within 28 days
prior to the first dose
Treatment Session
Group 1: Each subject will take part in 1 dosing session.
Group 2: Each subject will take part in 2 dosing sessions
Treatment Arms1
Group 1: Subjects will be randomised to receive one of the following 
study treatments:

400 mcg IH oxytocin

10 I.U. IM oxytocin
Group 2: Subjects will receive both of the following study treatments 
over the course of two dosing sessions:

400 mcg IH oxytocin

5 I.U. IV oxytocin
Follow-up
Group 1: Follow Up 1 – Within approximately 24 hours post dose.
Group 1: Follow Up 2 –  At least 7 days and no greater than 14 days 
after study drug administration.
Both visits may be conducted in-person or via telephone. Group 2: At 
least 7 days and no greater than 21 days after last study drug 
administration.
This visit will be conducted in-person.
If warranted, additional follow-up visits may be scheduled for both 
Groups.
Total Duration
Group 1: Screening after 18th week of pregnancy (i.e. within 168 days of 
1 dosing session) + follow up of 7 - 14 days = approximately 183 days
Group 2: Screening within 28 days of dosing session 1 + 2 dosing 
sessions with a maximum of 14 days between dosing + follow-up of 7 –
21 days = 64 days
1 See Section 6.4 for possible dose adjustment to IH oxytocin.
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
22
4.3.
Type and Number of Subjects
Sufficient subjects will be screened such that approximately 20 subjects complete all 
study procedures in Group 1, and approximately 10 subjects complete all study 
procedures in Group 2 (approximately 5 in each cohort of Group 2). Refer to Section 6.3
for treatment assignment information.
If subjects prematurely discontinue the study, additional replacement subjects may be 
recruited and assigned to the same treatment at the discretion of the Sponsor. 
Replacement subjects will complete all study procedures as outlined in Section 7.1.
If the PK variability between subjects in Group 1 is higher than expected, it may be 
required to increase the sample size up to a maximum of 10 additional subjects per 
treatment group for IH and IM. In the event of this, sufficient subjects will be screened 
such that a maximum of 45 subjects complete Group 1.
If a dose adjustment is required in either group, additional subjects may be recruited such 
that a full 10 subjects receive the final IH or IV dose. See Section 6.4.1 for more details.
4.4.
Design Justification
Group 1 - Women in TSL
This trial uses a randomized, single-dose approach to assign women in TSL to receive 
oxytocin by one of two routes: IM or IH. No placebo is being used, as the current 
standard of care is to administer oxytocin as active management of TSL to prevent PPH.
Group 2 - Non-pregnant, non-lactating females of child bearing potential
A group of non-pregnant, non-lactating women of childbearing potential will receive IH 
and IV oxytocin. This group will be divided into two cohorts: Cohort A will enrol women 
on the combined oral contraceptive. This cohort will serve as a control group, as they 
most closely resemble the population enrolled in the FTIH study. Cohort B will enrol 
women using a non-hormonal form of contraception. This comparison group will help 
characterize the effect of oral contraceptives on endogenous oxytocin production and the 
PK profile of oxytocin.
Blinding
This study uses an open-label design. 
4.5.
Dose Justification
Single inhaled doses of oxytocin (50-600 mcg) have been generally well tolerated in the 
FTIH study, with no emerging safety signals, in healthy, non-pregnant, premenopausal 
female subjects (Study 201558) [GlaxoSmithKline Document Number 
2016N277949_00; see also Section 2.2.1].  Following inhaled administration oxytocin 
was rapidly absorbed into the systemic circulation (tmax ranging from 0.05 to 0.50 h) 
with systemic exposure (Cmax and AUC) increasing with inhaled dose in an 
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
23
approximately proportional manner between 200 and 600 mcg.  In general, the shape of 
the observed oxytocin concentration-time profile following inhaled administration was 
consistent with that following IM administration.
Based on the data from the FTIH study, and assuming that the PK characteristics of IH 
and IM oxytocin are similar in TSL compared with non-pregnant women, the 400 mcg 
inhaled dose is predicted to be an effective dose in women in TSL by ensuring that the 
systemic exposure (Cp10, Cp30 and AUC(0-3 h) following IH dosing is at least that 
following IM administration at the approved dose of 10 I.U. This would be based on the
adjusted geometric mean ratio (90% Confidence Interval [CI]) treatment comparisons for
Cp10, Cp30 and AUC (0-3 h) following 400 mcg IH compared with 10 I.U. IM, namely 
1.10 (0.85,1.43), 1.65 (1.30, 2.09) and 1.27 (1.07, 1.50) respectively in study 201558. 
The PK parameters (Cp10, Cp30 and AUC(0-3 h)) have been selected to ensure onset and 
duration of action of the IH product is at least comparable to IM.
The clinical safety and reported AEs with oxytocin correlates to Cmax, with the Cmax of 
10 I.U. IV representing the upper bounds of what could be considered safe in current 
clinical practice (AEs include flushing, which can cause a transient decrease in blood 
pressure and reflex tachycardia; see the Oxytocin Summary of Product Characteristics for 
more information). The recommendation in the United Kingdom (UK) in clinical practice 
has been to reduce the IV dose to 5 I.U. IV or administer by a controlled IV infusion 
[Bolton, 2003].
Minimising the risk of high Cmax levels of oxytocin following the IH administration is 
therefore important.  Based on a comparison of  model predicted systemic exposure 
following IV administration to non-pregnant, premenopausal female subjects with 
observed PK profiles following 400 mcg IH oxytocin, it is anticipated that Cmax 
following administration of the 400 mcg dose will not markedly exceed values following 
5 I.U. IV bolus oxytocin (Figure 2). The inclusion of the 5 I.U. IV dose will allow an 
assessment of the potential safety and PK of the inhaled formulation compared to IV 
route of administration.
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
24
Figure 2
Model predicted profiles (median (95%PI)) following IM (10 I.U. and 
IV bolus (5 I.U. administration of oxytocin overlaid with observed 
plasma concentrations of oxytocin following 400 mcg IH oxytocin to 
healthy non-pregnant females
Whilst published literature on the PK of oxytocin in non-pregnant and pregnant women is 
limited there is some evidence to suggest that the metabolic clearance of oxytocin may 
increase during pregnancy. This may be related to degradation by the circulating 
aminopeptidase, oxytocinase, and/or pregnancy-related changes in hepatic and renal 
function [Syntocinon, 2014;Thornton, 1990]. In addition, there may be circulating levels 
of endogenous oxytocin in the plasma in women in TSL [Thornton, 1988] and increases 
in blood volume (40-50%) and total body water [Costantine, 2014]. As a result of these 
pregnancy related changes, systemic exposure to oxytocin may differ between healthy 
non-pregnant women and women in TSL for a given dose and route of administration of 
oxytocin. However, given that any pregnancy-related changes in systemic clearance, 
and/or distribution and baseline oxytocin levels, are considered to equally impact on each 
route of administration (IV, IM and IH), it is considered that the relative ratio of IV to IM 
and IH exposure observed in non-pregnant women is likely to be maintained in 
pregnancy. The only exception may be if pregnancy results in marked changes in 
absorption profiles.  However, in a study of inhalation profiles of non-pregnant and 
women in the third stage of labour, the inhalation endpoints appeared to be broadly 
similar across the two cohorts and any small changes are not considered to markedly 
impact the delivery of an inhaled product in the third stage of labour [GlaxoSmithKline 

= Observed 400 mcg IH oxytocin plasma concentration in study 201558
5  I.U. IV oxytocin
10 I.U. IM oxytocin
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
25
Document Number 2015N239682_00]. In addition, in a pre-clinical sheep model the ratio 
IH:IV was generally similar in non-pregnant and post-partum ewes (Data on file 
Monash). In the event of enhanced pulmonary absorption in pregnancy, the selected 
400 mcg inhaled dose is predicted to have an approximate 2-fold safe cover for Cmax 
compared with an 10 I.U. IV bolus oxytocin (assumes linearity from 5 -10 I.U. IV). 
4.6.
Benefit:Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
GR121619 can be found in the Investigator’s Brochure [GlaxoSmithKline Document 
Number 2015N240749_01] and oxytocin for parenteral administration [Syntocinon, 
2014]. The following section outlines the risk assessment and mitigation strategy for this 
protocol:  
4.6.1.
Risk Assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
Investigational Product (IP) – Inhaled Oxytocin – GR121619
Bronchospasm, cough and 
dyspnoea, with increased 
theoretical risk in asthmatic 
subjects.
Oxytocin receptors are known 
to be expressed in human 
bronchial smooth muscle and 
up regulated by interleukin 
(IL)-13. Therefore, there is a 
hypothetical risk of 
bronchospasm, cough and 
dyspnoea. 
See Section 5.2 for exclusion 
criteria.
The oxytocin summary of 
product characteristics (SPC) 
does not list asthma as a 
contraindication to 
administration. 
Symptomatic wheezing may 
be treated with bronchodilator 
at the discretion of the 
investigator.
Forced expiratory volume at 1 
minute (FEV1) monitoring for 
both paradoxical and oxytocin 
induced bronchospasm
Subjects with asthma or 
known pulmonary disease are 
excluded.
Hypotension, tachycardia and 
prolongation of QTc interval
Transient flushing, 
hypotension and tachycardia 
could be observed if the IH PK 
profile is comparable to an IM
or IV oxytocin profile. 
Effects of oxytocin on the 
Ongoing assessments of study 
subjects’ cardiovascular 
function including blood 
pressure (BP), heart rate (HR) 
and ECG.
Only single-dose IH, IM, or 
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
26
Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
Cardiovascular system (CVS) 
is unclear and contradictory in 
the literature but IV 
administered oxytocin can 
have a vasodilatory and 
negative inotropic effect in 
humans. Hypotension is 
thought to arise as a result of 
vascular smooth muscle 
relaxation and oxytocin 
binding to cardiac atrial OTR 
which leads to atrial natriuetic 
peptide (ANP) being 
transiently released into the 
systemic circulation. 
Prolongation of the QTc 
interval has been reported at 
the time of caesarean delivery  
with 10 IU IV oxytocin 
administration, rather than IM 
injection, in susceptible 
individuals
5 IU IV bolus injection routes 
of administration will be used 
as study treatment. Telemetry 
and frequent 12-lead ECGs 
will be used to monitor the 
healthy subject cohorts
The 5 IU IV dose of oxytocin is 
the standard dose 
administered at the Rosie 
Maternity hospital post 
Caesarean Section.
IV bolus will be given as a 
slow IV injection over 30 
seconds with the option to 
change to a 5 minute infusion 
if frequent CV adverse effects 
are observed
Exclusion of subjects with long 
QT syndrome, congenital 
cardiac abnormalities, and 
subjects taking anti-arrhythmic 
drugs.
12-lead ECG and telemetry 
covering Cmax in healthy 
subjects administered IH, IM 
and IV oxytocin
Insufficient uterotonic effect
The altered physiology and 
pharmacokinetics of women in 
the TSL my lead to a sub-
optimal dose of inhaled 
oxytocin, resulting in a 
reduced or absent uterotonic 
effect.
In this setting, women in TSL 
and post-delivery are 
intensively observed. 
Therefore, any adverse 
events, including excessive 
blood loss due to unenhanced 
uterine contraction, will be 
managed in accordance with 
current local practice 
guidelines. This will usually 
include administration of 
additional uterotonic agents in 
the first instance.
A follow-up within 24 h of 
discharge by the study team 
will be performed to 
specifically enquire if any late 
bleeding problems had 
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
27
Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
occurred.
An interim analysis of IH and 
IM PK in the TSL group will be 
performed to ensure that the 
PK is in the acceptable range 
for efficacy to be anticipated.
Reference Intervention - IM Oxytocin / IV Oxytocin
Hypotension, tachycardia and 
prolongation of QTc interval
See above section.
See above section.
Subjects receiving the IV 
Oxytocin are required to have 
a systolic BP ≥ 90 Millimeter of 
mercury (mmHg) prior to 
dosing.
Myocardial Ischaemia and ST 
change on ECG
ECG changes consistent with 
myocardial ischaemia have 
been observed with 10 IU 
oxytocin IV bolus in healthy 
women associated with 
hypotension and tachycardia.
Oxytocic cardiovascular effects 
appear to be transient
and persistent myocardial 
damage very rare and 
associated with 10 IU IV.
Study is only using 5 IU IV as a 
slow IV bolus which is 
associated with a short lived 
increase in heart rate and 
reduction in BP but not ST 
changes on ECG in women 
undergoing Caesarean 
Section.
Telemetry and 12-lead ECG 
monitoring in healthy subjects.
Abdominal pain
There is a hypothetical risk 
that IM oxytocin may trigger 
abdominal pain through 
contractions of the non-
pregnant uterus in healthy 
women. 
Given the short half-life of 
oxytocin (approximately 30 
minutes), the duration of a 
single abdominal pain episode 
This is a theoretical possibility 
and not expected to occur. 
Ongoing assessments of study 
subjects’ well-being along with 
vital signs and laboratory
evaluations will be completed 
throughout the duration of the 
study.  
Abdominal pain which is 
clinically uncomfortable to the 
subject may be treated with 
paracetamol at the local 
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
28
Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
would be expected to be brief, 
not sustained and not 
recurrent in the absence of 
further oxytocin administration.
Furthermore, no abdominal 
pain was observed in the FTiH 
study.
investigator’s discretion.  
4.6.2.
Immunogenicity Risk
The oxytocin material used in the inhaled product is produced synthetically and so does 
not include any other protein/cell impuritites which might be intrinsically immunogenic.
A review of the risk of immunogenicity of oxytocin and/or excipients was considered as 
part of the non-clinical safety studies but as the lymphoid tissues were not deemed to be 
pathologically affected and there were difficulties in generating a suitable assay, anti-
drug antibodies (ADAs) were not measured. The FTIH study involved repeat dosing, and 
did not reveal any unexpected differences in PK which may have signalled the 
development of ADAs.
Oxytocin is an endogenous human peptide with a short systemic half-life and there are no 
reports of immunogenicity with oxytocin via parenteral administration. Thus it is 
considered unlikely that inhaled delivery of a small molecular weight (MW) peptide 
molecule like oxytocin would invoke an immunogenic response.
However, blood samples will be retained for anti-oxytocin antibody analysis if required 
in the event of an anaphylactic / allergic reaction (refer to Section 5.4.2) or other 
observation which would suggest an immunogenic effect.
4.6.3.
Benefit Assessment and Overall Benefit:Risk Conclusion
Oxytocin has been administered to postpartum women for over 40 years via both the IM 
and IV routes, and has an established safety profile for each of these routes of 
administration. The FTIH study into IH oxytocin revealed no safety concerns for any of 
the subjects who received this new formulation. There are no direct clinical benefits to 
the volunteers within this study. The main contribution to their participation will be in the 
further development of a therapy (i.e. inhaled oxytocin) which may be ultimately used as 
a preventative therapy for postpartum haemorrhage in women during TSL in resource 
poor settings. It is fundamental to the project to clearly understand the PK of oxytocin 
following IH and IM administration to women in TSL in order to confirm the dose level 
that delivers a PK profile comparable to that of 10 I.U. IM (i.e. current standard of care in 
the developed world setting). Taking into account the measures taken to minimize risk to 
subjects participating in this study, the potential risks identified in association with 
oxytocin (IH IM, and IV) are justified by the supporting data and overall benefit 
anticipated for women’s health worldwide.
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
29
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the investigator brochure for 
GR121619 [GlaxoSmithKline Document Number 2015N240749_01] and SPC for 
oxytocin administered IM or IV.
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
5.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
AGE
All Groups: 
1. Between 18 and 40 years of age inclusive, at the time of signing the informed 
consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
All Groups: 
2. 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.
Note: At time of randomisation, investigator or designee should confirm the subject 
feels fit and well, and is safely able to participate in the study.
3. Subject clinical chemistry and haematology values within an acceptable range for the 
population recruited and not of abnormal clinical significance.
Note: Additional laboratory tests beyond those which are done as part of routine care 
(e.g. 28-week visit) are not required for subjects in Group 1. The 
investigator/designee may use his/her judgment in deciding whether to perform 
additional laboratory assessments to determine eligibility.
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. 
4. Adequate peripheral venous access for cannulation.
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
30
Group 1 Only: 
5. Currently pregnant, with an uncomplicated pregnancy as determined by the 
investigator or designee.
6. Estimated date of delivery within 24 weeks of screening.
7. Planned spontaneous vaginal birth and considered by investigator at low risk for PPH.
8. Planned birth in between the 37th and 42nd week of pregnancy.
Note: Subjects can only receive study treatment if the onset of labour is between 
approximately 37 and 42 weeks estimated gestation. If a subject goes into labour 
before or after this timeframe, she should not receive study treatment.
9. Women who qualify for oxytocin as appropriate for active management of TSL and 
who agree to have active management.
Group 2 Only:
10. ECG normal, or abnormal and not clinically significant.
11. FEV1 >80% of predicted.
12. Systolic blood pressure ≥90 mmHg.
WEIGHT
Group 2 Only:
13. Body mass index (BMI) within the range 18 – 32 Kilogram (kg)/ meter (m)2
(inclusive).
SEX
14. 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:
a.
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.
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
31
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:
a.
Is of reproductive potential and has been using the same non-hormonal 
contraceptive method (see List of Acceptable Nonhormonal Methods for Avoiding 
Pregnancy in Females of Reproductive Potential [see Appendix 5] from 3 months
prior to the first dose of study medication and until the follow-up contact.
b.
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.
c.
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.  
INFORMED CONSENT
All Groups: 
15. Capable of giving signed informed consent as described in Section 10.2 which 
includes compliance with the requirements and restrictions listed in the consent form 
and in this protocol.
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
32
5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL) 
All Groups: 
1. Postmenopausal as defined by gynaecological history.
2. Chronic lung condition of any etiology including asthma, Chronic obstructive 
pulmonary disease (COPD), emphysema, interstitial lung disease or active 
Tuberculosis (TB).
      Note: Childhood asthma (resolved) is not exclusionary.
3. Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones).
4. Blood pressure >140 systolic or >90 diastolic.
Group 1 Only:
5. Females with planned Caesarean Section.
6. Females with significant medical complications as determined by investigator.
Group 2 Only:
7. Currently breastfeeding or lactating.
8. QT duration corrected for heart rate by Fridericia’s formula (QTcF) 
>450 milliseconds (msec).
9. 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%).
10. Subjects with highly-active or symptomatic gynaecological disorders (such as large 
symptomatic fibroids).
CONCOMITANT MEDICATIONS
All Groups: 
11. Prescription or non-prescription drugs not approved by the investigator (refer to 
Section 6.12.1 for approved medications).
12. Oxytocin for any reason (including, but not limited to, induction or augmentation of 
labour) prior to administration of study-related oxytocin.
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
33
RELEVANT HABITS
All Groups: 
13. 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 (~240 milliliter [ml]) of beer, 1 glass (125 ml) of 
wine or 1 (25 ml) measure of spirits. 
14. 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.
a.
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.
CONTRAINDICATIONS 
All Groups: 
15. 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).
16. Participation in another clinical trial, which in the opinion of the investigator, 
jeopardizes the subject’s safety or study outcomes.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
All Groups: 
17. Where participation in the study would result in donation of blood or blood products 
in excess of 500 mL within 56 days.
18. 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).
19. Exposure to more than four new chemical entities within 12 months prior to the first 
dosing day.
Group 2 Only: 
20. Presence of hepatitis B surface antigen or positive hepatitis C antibody test result.
21. A positive Human Immunodeficiency Virus (HIV) antibody test.
22. A positive pre-study drugs of abuse test (not explained by diet or approved 
concomitant medications).
23. A positive alcohol breath test.
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
34
5.3.
Screening/Baseline/Run-in Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomized. In order to ensure transparent reporting of screen 
failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and respond to queries from Regulatory authorities, a minimal 
set of screen failure information is required including Demography, Screen Failure 
details, Eligibility Criteria, and Serious Adverse Events (see Section 7.3.1.4).
5.3.1.
Re-screening
If a subject fails screening, she may be rescreened one additional time.
5.4.
Withdrawal/Stopping Criteria
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as 
soon as possible. 

The site must counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or should 
continue in the study. 

In cases where the subject is deemed ‘lost to follow up’, the investigator or 
designee must make every effort to regain contact with the subject (where 
possible, 3 telephone calls and if necessary a certified letter to the subject’s last 
known mailing address or local equivalent methods). These contact attempts 
should be documented in the subject’s medical record. 

Should the subject continue to be unreachable, only then will she be considered to 
have withdrawn from the study with a primary reason of “Lost to Follow-up”. 
A subject may withdraw from study treatment at any time at her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioural or 
administrative reasons. If a subject withdraws from the study, she may request 
destruction of any samples taken, and the investigator must document this in the site 
study records. 
5.4.1.
Pregnancy Complication Stopping Criteria (Group 1 Only)
Any complication requiring clinical intervention which no longer allows for a vaginal 
delivery or safe completion of study procedures will be cause for immediate withdrawal 
from the study. Investigators should continue to manage any pregnancy complication per 
local guidelines, and record any associated AE/SAE or concomitant medication. This 
includes the need for additional uterotonic administration.
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
35
5.4.2.
Anaphylaxis Stopping Criteria
Clinical signs or symptoms of anaphylaxis / allergic reaction to IH oxytocin will be an 
automatic stopping criterion. Stored serum samples will be analysed for anti-oxytocin 
antibody analysis for affected subjects as detailed in Section 7.5.2. The samples will be 
analysed for Immunoglobulin E (IgE)/ Immunoglobulin G (IgG) anti-oxytocin titres 
biochemical markers of mast cell degranulation (e.g. tryptase) in the event of an 
anaphylactic / allergic reaction occurring.  
5.4.3.
QTc Stopping Criteria (Group 2 Only)

The same QT correction formula must be used for each individual subject to 
determine eligibility for and discontinuation from the study.  This formula may 
not be changed or substituted once the subject has been enrolled.

For example, if a subject is eligible for the protocol based on QTcF, then QTcF
must be used for discontinuation of this individual subject as well.

Once the QT correction formula has been chosen for a subject’s eligibility, the 
same formula must continue to be used for that subject for all QTc data being 
collected for data analysis.  Safety ECGs and other non-protocol specified 
ECGs are an exception.  

The QTc should be based on single or averaged QTc values of triplicate 
electrocardiograms obtained over a brief (e.g., 5-10 minute) recording period.  
QTcF is proposed to be used for this study. If a subject meets either of the following 
bulleted criterion below, she will be withdrawn from the study.  

QTcF > 500 msec,

Change from baseline: Increase in QTcF >60 msec.
Withdrawal of subjects is to be based on an average QTcF value of triplicate ECGs.  If an 
ECG demonstrates a prolonged QT interval, then obtain 2 more ECGs over a brief period 
of time and then use the averaged QTcF values of the 3 ECGs to determine whether the 
subject should be withdrawn from the study.
5.4.4.
Blood Pressure Stopping Criteria (Group 2 Only)
Subjects with a pre-dose systolic blood pressure of <90 mm Hg should not be dosed until 
systolic blood pressure is ≥90 mm Hg.
5.4.5.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
36
Study treatment will be discontinued for a subject if liver chemistry stopping criteria are 
met:
Phase I Liver Chemistry Stopping Criteria – Liver Stopping Event Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
*INR value not applicable to subjects on anticoagulants 
ALT ≥3xULN 
No
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments  section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in
Appendix 2.
5.5.
Subject and Study Completion
A completed subject is one who has completed all phases of the study including the 
follow-up visit(s).
6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design. Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments.
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
37
Table 1
Study Treatment Information
Study Treatment
Product name:
Oxytocin  (GR121619
capsule for inhalation)
Oxytocin
Oxytocin
Formulation 
description:
Powder Blend for Inhalation
Solution for Infusion
Solution for Infusion
Dosage form:
Inhalation powder, hard 
capsule
1ml ampoule
1ml ampoule
Unit dose 
strengths:
400 mcg
200 mcg
5 I.U./mL, or 10 
I.U./mL
5 I.U./mL, or 10 
I.U./mL
Route of 
Administration
For oral inhalation
Intramuscular (thigh)
Intravenous
Dosing 
instructions:
Capsule unit dose 
dispensed by ROTAHALER 
inhaler 
Standard 
intramuscular injection
Adminster as a 30-
second bolus
Physical 
description:
Colourless and clear 
HPMC capsules 
containing a white 
powder
Colourless and clear 
sterile solution
Colourless and clear 
sterile solution
Device:
ROTAHALER inhaler
Needle/Syringe 
Intravenous Infusion 
Device
6.2.
Medical Devices
The GSK manufactured medical device (or device manufactured for GSK by a third 
party) provided for use in this study is a high airflow resistance capsule-based inhaler 
(Modified Air Inlet ROTAHALER DPI device). Although this investigational device 
bears a CE mark, it has not been CE marked in accordance with the Medical 
Devices Directive 93/42/EEC.
Instructions for medical device use are provided in Section 6.7. Further details on use of 
the device are provided in the SRM.
GSK medical device incidents, including those resulting from malfunctions of the device, 
must be detected, documented, and reported by the investigator throughout the study –
see Section 12.4.
6.3.
Treatment Assignment
Subjects in Group 1 will be assigned to one of two treatments (IH oxytocin or IM 
oxytocin). Subjects in Group 2 will receive both IH and IV oxytocin in separate dosing 
sessions in a cross over design. Treatment assignment in Group 1, and order of dosing in 
Group 2, will be done in accordance with the randomization schedule generated by 
Clinical Statistics, prior to the start of the study, using validated internal software.
A description of each regimen is provided in Table 2:
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
38
Table 2
Treatment Assignment
Group
Session
Treatment 1
Number of Subjects2
Group 1
1
400 mcg IH oxytocin
10
10 I.U. IM Oxytocin
10
Group 2, Cohort A
1
400 mcg IH oxytocin or 
5 I.U. IV oxytocin
5
2
400 mcg IH oxytocin or 
5 I.U. IV oxytocin
Group 2, Cohort B
1
400mcg IH oxytocin or 
5 I.U. IV oxytocin
5
2
400 mcg IH oxytocin or 
5 I.U. IV oxytocin
1 See Section 6.4 for possible dose adjustment.
2 See Section 9.2.2 for possible adjustment to subject numbers to Group 1
6.4.
Planned Dose Adjustments
There is no plan to adjust the dose of IH oxytocin in this study. However, if systemic 
exposure seen in 400 mcg IH oxytocin in TSL subjects is less than expected and not 
comparable to the 10 I.U. IM profile, a consideration to escalate the dose to 600 mcg may 
be made as detailed in Section 6.4.1.
For Group 2, if an exaggerated physicological response is seen with the IV dose, such as 
increased heart rate and decreased blood pressure, then consideration will be given to 
changing to a 5-minute infusion.
6.4.1.
Dose Adjustment
The decision to adjust the IH dose in women in TSL will be determined by the GSK 
study team based on Group 1 PK data in TSL and Group 2, Cohort A PK data.  After a 
minimum of n=5 women in TSL have received 400 mcg IH and 10 I.U. IM and a 
minimum of n=5 non-pregnant women on the combined oral contraceptive (Group 2, 
Cohort A) have received 400 mcg IH oxytocin, PK samples will be analysed and PK 
parameters derived (including but not limited to Cp10, Cp30 and AUC(0-3h)).  
The median Cp10 will be estimated for women in TSL for each dose group (IH or IM) 
and the median ratio (IH/IM; n=5) derived.  Based on the estimated ratio, the dose of IH 
oxytocin to be administered to women in TSL will either remain at 400 mcg or be 
increased per the criteria described in Table 3:
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
39
Table 3
Dose Adjustment Decision Criteria
Median Ratio IH/IM
Decision
< 0.5
Consider study halt and review data.
≥ 0.5 to <0.7
Consider dose adjust to 600 mcg IH in women in TSL.
≥ 0.7
Continue with 400 mcg IH dose.
If a decision to increase the dose is made, additional subjects will be enrolled into Group 
1 such that 10 subjects receive the 600 mcg IH oxytocin dose.
6.5.
Blinding
This will be an open-label study.
6.6.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
6.7.
Preparation/Handling/Storage/Accountability

The investigator/designee will be trained to load the ROTACAPS powder capsule 
into the device, prime the dose and instruct the subjects to inhale from the 
ROTAHALER inhaler in the appropriate manner. The investigator/designee will 
always load and prime the ROTACAPS powder capsule in the device before the 
subject self-administers an IH oxytocin dose

All subjects will be taught by the investigator/designee to use the device in the 
“full-tilt” position and to use a “fast and deep” inspiration technique per 
inhalation, to achieve two rapidly consecutive maximal inhalations for IH 
oxytocin administration. This will ensure optimal and consistent treatment 
delivery. For subjects, the training session will be at any time during the 28-day 
Screening Period, as deemed appropriate by the investigator/designee. 

ROTACAPS powder capsules should be kept in their sealed packaging at room 
temperature (15-25°Centigrade [C]). The packaging should only be opened 
immediately prior to use.

ROTAHALER inhaler devices will be supplied in bulk and unlabelled to the site.
After dosing all ROTAHALER inhaler devices will be uniquely labelled and 
retained after each dosing session. The devices (which should not be opened up at 
the clinical study site) will be stored until further instruction from the sponsor is 
received.
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
40

The investigator or designee must confirm appropriate temperature conditions 
have been maintained during transit for all study treatment received and any 
discrepancies are reported and resolved before use of the study treatment.

Only subjects enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment.  All study 
treatments must be stored in a secure environmentally controlled and monitored 
(manual or automated) area in accordance with the labelled storage conditions 
with access limited to the investigator and authorized site staff. 

The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (i.e. receipt, reconciliation and final disposition records).  

Further guidance and information for final disposition of unused study treatment 
are provided in the SRM. 

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff. Take adequate precautions to 
avoid direct eye or skin contact and the generation of aerosols or mists. In the case 
of unintentional occupational exposure notify the monitor, Medical Monitor 
and/or GSK study contact.

A Material Safety Data Sheet (MSDS)/equivalent document describing 
occupational hazards and recommended handling precautions either will be 
provided to the investigator, where this is required by local laws, or is available 
upon request from GSK.
6.8.
Compliance with Study Treatment Administration
Per ROTACAPS powder capsule dose, each subject will be asked to inhale twice from 
the ROTAHALER inhaler to reduce the possibility of inadequate administration due to a 
single poor inhalation manoeuvre. If failure of the ROTACAPS powder capsule 
actuation is suspected by the investigator (i.e. due to failure to open the capsule during 
device priming), the investigator is permitted to rechallenge the individual with a 
maximum of two further administrations at the same dose using the same capsule. 
When subjects are dosed at the site, they will receive study treatment directly from the 
investigator or designee, under medical supervision.  The date and time of each dose 
administered in the clinic will be recorded in the source documents.  The dose of study 
treatment and study subject identification will be confirmed at the time of dosing by a
member of the study site staff other than the person administering the study treatment.  
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
41
Group 1 – Women in TSL
Following randomisation and any pre-dose procedures, subjects will receive a single 
study treatment as active management of TSL. The specific timing of this dose will be as 
per local standard of care.2
Administration will be documented in the source documents and reported in the Case 
report form (CRF).
Group 2 – Non-pregnant, non-lactating females of child bearing potential
Following randomisation and all pre-dose procedures, subjects will receive two doses of 
oxytocin, separated by at least 48 hours. Randomisation will determine the order in which 
the IH and IV formulation is administered. 
Administration will be documented in the source documents and reported in the Case 
report form (CRF).
6.9.
Treatment of Study Treatment Overdose
For this study, any dose of the following compounds will be considered an overdose 
when administered as part of study procedures: 

IH oxytocin > 400 mcg 
o
If study dose is increased to 600 mcg, then an overdose will be considered 
any dose > 600 mcg.

Oxytocin > 10 I.U. IM 

Oxytocin > 5 I.U. IV
Note: Group 1 subjects may receive additional doses of oxytocin (IM or IV) when 
required as part of their general care and as clinically indicated. Additional doses of 
oxytocin will be recorded as concomitant medications, as will any related AEs.
General medical management consists of supportive care. 
GSK does not recommend specific treatment for an overdose.
In the event of a study drug overdose the investigator or treating physician should:
1.
Contact the Medical Monitor immediately.
                                                
2 For information only: Standard of care at proposed clinical site is to administer the oxytocic drug by IM 
injection with the birth of the anterior shoulder, or immediately after the birth of the baby and before the 
cord is clamped and cut.
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
42
2. Closely monitor the subject for adverse events (AEs)/serious adverse events (SAEs) 
and laboratory abnormalities until oxytocin can no longer be detected systemically (at 
least 4 hours).
3. Obtain an additional plasma sample for pharmacokinetic (PK) analysis if requested 
by the Medical Monitor (determined on a case-by-case basis).
4. Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the subject.
6.10.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study because either only healthy volunteers are eligible for study participation, or there 
are other treatment options are available.
The investigator is responsible for ensuring that consideration has been given to the post-
study care of postpartum subjects’ medical conditions, whether or not GSK is providing 
specific post-study treatment.
6.11.
Lifestyle and/or Dietary Restrictions
6.11.1.
Meals and Dietary Restrictions
There are no dietary restrictions for subjects in either cohort.
6.11.2.
Caffeine and Alcohol
Group 1 – Women in TSL

There are no restrictions for Group 1.
Group 2 – Non-pregnant, non-lactating females of child bearing potential

During each dosing session, subjects will abstain from ingesting caffeine- or
xanthine-containing products (e.g., coffee, tea, cola drinks and chocolate) for 
12 hours prior to the start of dosing until collection of the final pharmacokinetic 
sample during each session. 

During each dosing session, subjects will abstain from alcohol for 12 hours prior to 
the start of dosing until collection of the final pharmacokinetic sample during each 
session. 
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
43
6.11.3.
Activity
Group 1 – Women in TSL
There are no activity restrictions.
Group 2 – Non-pregnant, non-lactating females of child bearing potential
Subjects will abstain from strenuous exercise for 48 hours prior to each blood collection 
for clinical laboratory tests.  Subjects may participate in light recreational activities 
during studies (e.g., watch television, read).
6.12.
Concomitant Medications and Non-Drug Therapies
6.12.1.
Permitted Medications and Non-Drug Therapies
Paracetamol, at doses equal to or below the maximum recommended daily dose, is 
permitted for use during the screening period or at any time deemed necessary by the 
investigator or subject. All concomitant medication related to routine care during 
pregnancy and delivery is allowed (including pain relief [e.g. gas/air mixture] and 
epidural), and other medication may be considered on a case by case basis by the 
investigator or designee (in consultation with the Medical Monitor if required). 
The start and stop time of any concomitant medications administered at any time during 
labour (including nitrous oxide gas/air mixtures) should be documented on the CRF.
6.12.2.
Prohibited Medications and Non-Drug Therapies
Use of the following medications will result in immediate withdrawal of subject:

Oxytocin for any reason (including, but not limited to, induction or augmentation 
of labour) before or after administration of study-related oxytocin.
7.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct.
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Table in Section 7.1.
The following points must be noted: 

If assessments are scheduled for the same nominal time, THEN the assessments 
are recommended to occur in the following order:
1. 12-lead ECG
2. vital signs
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
44
3. blood draws
Note: The timing of the assessments should allow the blood draw to occur at the 
exact nominal time.

The timing and number of planned study assessments, including safety, 
pharmacokinetic, pharmacodynamic, immunogenic or other assessments may be 
altered during the course of the study based on newly available data (e.g., to 
obtain data closer to the time of peak plasma concentrations) to ensure 
appropriate monitoring. 

The change in timing or addition of time points for any planned study 
assessments must be documented in a Note to File which is approved by the
relevant GSK study team member and then archived in the study sponsor and 
site study files, but this will not constitute a protocol amendment. 

The Institutional Review Board (IRB)/ Independent Ethics Committee (IEC)
will be informed of any safety issues that require alteration of the safety 
monitoring scheme or amendment of the Informed Consent Form. 

No more than 500 mL of blood will be collected over the duration of the study, 
including any extra assessments that may be required.
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
45
7.1.
Time and Events Table
7.1.1.
Time and Events Table – General Overview
Group 1
Study Day
Procedure
Screening4
Main Phase 
Follow – Up 1 (approx. 24 
hours post dose)
Follow – Up 2 (7-14 days post dose)
Informed Consent and Demography
X
Brief Physical Examination
X
Medical history (incl. substance abuse)
X
Inhaler device training / education session
X
Laboratory assessments1
X
Vital signs2
X
X
Pharmacokinetic blood sample
X
Oxytocin Administration (IM/IH)
X
Full blood count
X
Labour Events Documentation
X
Device acceptability questionnaire3
X
Prior / concomitant medication review
X
X
X
X
AE review
------------------------------ continuous review ------------------------------------------------------
SAE review
 ---------------------------------------------------------------- continuous review  -------------------------------------------------
1.
Only required if done as part of routine care. Additional study-specific laboratory assessments not required.
2.
Includes blood pressure, heart rate, temperature, respiratory rate
3.
Only to be used when randomized to IH oxytocin
4.
To be completed after 18th week of pregnancy (based on estimated date of delivery).
 
 
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
46
Group 2
Study Day
Procedure
Screening5
Main Phase
Follow - Up (7-21
days post 
dose)
Informed Consent and Demography
X
Brief Physical Examination
X
X
Medical history
X
Pregnancy test 
X
X
Alcohol Breath Test, Smokerlyzer, Urine Drug Screen1 
X
X
HIV, Hep B and Hep C screen2
X
Inhaler device training / education session
X
Laboratory assessments (including liver chemistries)
X
X
Immunogenicity sample
X
X
12-lead ECG
X4
X
CardiacTelemetry
X
Vital signs3
X
X
Spirometry (FEV-1)4
X
X
Admission to unit
X
Pharmacokinetic blood sample
X
X
Oxytocin Administration (IH or IV)
X
Prior / concomitant medication review
X
X
X
AE review
------ continuous review -----------------------------------
SAE review
 ----------------------------------- continuous review  --------------------------------
Discharge from unit
X
1.
Smokerlyzer at PI/designee discretion if smoking history in question.
2.
If test otherwise performed within 3 months prior to first dose of study treatment, repeat testing at screening is not required.
3.
Includes blood pressure, heart rate, temperature, respiratory rate, and SpO2.
4.
Performed in triplicate.
5.
To be completed within 28 days of randomization.
 
 
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
47
7.1.2.
Time and Events – Main Phase Procedures
Group 1 
Time post dose
Procedure
Pre-
dose
3 min
5 min
10 
min
15 min
20 
min
30 
min
1 hr
2 hr
2.5 hr
3 hr
4 hr
Vital signs1
X
X
Pharmacokinetic blood sample
X2
X
X
X
X
X
X
X
X
X
X
X
Prior  medication review
X
Concomitant  medication review
---------------------------------------------------------- continuous review  ---------------------------------------------------
AE review
--------------------------------------------------------- continuous review  ---------------------------------------------------
SAE Review
------------------------------------------------------------------------ continuous review  -----------------------------------------------------
Device Acceptability Questionnaire3
X
Full Blood Count
X
X
1.
Includes blood pressure, heart rate, temperature, respiratory rate
2.
Predose PK sample to be taken immediately prior to administration of study treatment 
3.
Only to be administered when randomized to IH oxytocin
 
 
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
48
Group 2 – Sessions 1 and 2
Time Post Dose
Procedure
Pre-
dose
2 
min
3 
min
5 
min
8 
min
10 
min
15 
min
20 
min
30 
min
45 
min
1 hr
1.5 hr
2 hr
2.5 hr
3 hr
4 hr
Brief Physical Exam
X
Pregnancy Test
X
Alcohol Breath Test, Smokerlyzer, Urine 
Drug Screen1
X
Vital signs2
X
X
X
X
X
X
12-lead ECG
X
X
X
X
X
X
X
CardiacTelemetry
---------------------------------------------Continuous-----------------------------------------------
Spirometry3
X
X
Pharmacokinetic blood sample
X5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Immunogenicity Sample
X
Laboratory assessments (including liver 
chemistries)
X
X
Prior medication review
X
Concomitant medication review
------------------------------------------------------------ continuous review  ----------------------------------------------------
AE review
----------------------------------------------------------- continuous review  ----------------------------------------------------
SAE Review
------------------------------------------------------------------------- continuous review  ----------------------------------------------------
Discharge from unit4
X
1.
Smokerlyzer at Principal Investigator (PI)/designee discretion if smoking history in question.
2.
Includes blood pressure, heart rate, temperature, respiratory rate, and SpO2
3.
FEV 1.0 will be performed in triplicate at each time point. Record all three values on source document, and record best effort in eCRF.
4.
Discharge at PI discretion, no sooner than 4-hours post-dose.
5.
3 pre-dose samples: approximately 1 hr pre-dose, 30 minutes pre-dose, and 15 minutes pre-dose
 
 
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
49
7.2.
Screening and Critical Baseline Assessments
Cardiovascular medical history/risk factors (as detailed in the CRF) will be assessed at 
screening.
The following demographic parameters will be captured: year of birth, sex, race and 
ethnicity.
Medical/medication/family history will be assessed as related to the inclusion/exclusion 
criteria listed in Section 5.  
Procedures conducted as part of the subject’s routine clinical management [e.g. brief 
physical exam, laboratory assessments] and obtained prior to signing of informed consent 
may be utilized for Screening or baseline purposes provided the procedure meets the 
protocol-defined criteria and has been performed within the timeframe defined in the 
Time and Events Schedule.
7.3.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1).  Additional time points for safety tests (such as vital signs, physical exams 
and laboratory safety tests) may be added during the course of the study based on newly 
available data to ensure appropriate safety monitoring.
7.3.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 3 (see Section 12.3).
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 
7.3.1.1.
Time period and Frequency for collecting AE and SAE information

Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK 
product will be recorded from the time a subject consents to participate in the 
study up to and including any follow-up contact. 

AEs will be collected from the start of Study Treatment until the follow-up 
contact (see Section 7.3.1.3), at the timepoints specified in the Time and Events 
Table (Section 7.1).

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the CRF or appropriate source document.

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in
Appendix 3.

Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects. However, if the investigator learns of any SAE, including a death, at any 
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
50
time after a subject has been discharged from the study, and she considers the 
event reasonably related to the study treatment or study participation, the 
investigator must promptly notify GSK.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Appendix 3.
7.3.1.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:

“How are you feeling?” 

“Have you had any (other) medical problems since your last visit/contact?”

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?” 
7.3.1.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All SAEs, and non-serious AEs of special interest 
(as defined in Section 4.6.1) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up 
(as defined in Section 5.4). Further information on follow-up procedures is given in
Appendix 3.
7.3.1.4.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK of SAEs related to study treatment (even 
for non- interventional post-marketing studies) is essential so that legal obligations and 
ethical responsibilities towards the safety of subjects and the safety of a product under 
clinical investigation are met. 
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, IRB/ IEC and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the Investigators Brochure (IB) and will notify the IRB/IEC, if appropriate according to 
local requirements.
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
51
7.3.2.
Adverse Events of Special Interest (AESI)
Any problem related to the delivery of the placenta or postpartum haemorrhage should be 
documented as an AESI using the appropriate case report form (CRF). 
7.3.3.
Pregnancy
Group 2 Only:

Details of all pregnancies will be collected after the start of dosing and until 
follow-up.

If a pregnancy is reported then the investigator should inform GSK within 2 
weeks of learning of the pregnancy and should follow the procedures outlined in
Appendix 5.
7.3.4.
Medical Device Incidents (Including Malfunctions)
GSK medical devices are being provided for use in this study.  In order to fulfil 
regulatory reporting obligations worldwide the investigator is responsible for the 
detection and documentation of events meeting the definitions of incident or malfunction 
that occur during the study with such devices. 
The definition of a Medical Device Incident can be found in Section 12.4.
NOTE: Incidents fulfilling the definition of an AE/SAE will also follow the processes 
outlined in Section 12.3.6 and Appendix 3 of the Protocol. 
7.3.4.1.
Time Period for Detecting Medical Device Incidents

Medical device incidents or malfunctions of the device that result in an incident will 
be detected, documented and reported during all periods of the study in which the 
GSK medical devices are available for use. 

If the investigator learns of any incident at any time after a subject has been 
discharged from the study, and such incident is reasonably related to a GSK medical 
device provided for the study, the investigator will promptly notify GSK.
NOTE: The method of documenting Medical Device Incidents is provided in 
Appendix 4.
7.3.4.2.
Follow-up of Medical Device Incidents

All medical device incidents involving an AE will be followed until resolution of the 
event, until the condition stabilizes, until the condition is otherwise explained, or 
until the subject is lost to follow-up (as defined in Section 5.4). This applies to all 
subjects, including those withdrawn prematurely. 

The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as may be indicated to elucidate as completely as practical the nature 
and/or causality of the incident.
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
52

New or updated information will be recorded on the originally completed form with 
all changes signed and dated by the investigator.
7.3.4.3.
Prompt Reporting of Medical Device Incidents to GSK

Medical device incidents will be reported to GSK within 24 hours once the 
investigator determines that the event meets the protocol definition of a medical 
device incident.

Facsimile transmission of the "Medical Device Incident Report Form" is the 
preferred method to transmit this information to the Medical Monitor or SAE 
coordinator.

The same individual will be the contact for receipt of medical device reports and 
SAEs.

In the absence of facsimile equipment, notification by telephone is acceptable for 
incidents, with a copy of the "Medical Device Incident Report Form" sent by 
overnight mail. 
7.3.4.4.
Regulatory Reporting Requirements for Medical Device Incidents

The investigator will promptly report all incidents occurring with any GSK medical 
device provided for use in the study in order for GSK to fulfil the legal responsibility 
to notify appropriate regulatory bodies and other entities about certain safety 
information relating to medical devices being used in clinical studies.

The investigator, or responsible person according to local requirements (e.g., the 
head of the medical institution in Japan), will comply with the applicable local 
regulatory requirements relating to the reporting of incidents to the IRB/IEC.
7.3.5.
Physical Exams

A brief physical examination will include, at a minimum assessments of the lungs, 
cardiovascular system, and abdomen (liver and spleen if palpable).

Investigators should pay special attention to clinical signs related to previous 
serious illnesses
7.3.6.
Vital Signs
Vital signs will be measured in semi-supine position after 5 minutes rest and will 
include temperature, systolic and diastolic blood pressure, pulse rate and respiratory 
rate (unless otherwise specified in T&E). 
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
53
7.3.7.
Documentation of Labour Events
The time that the following labour events occurred will be collected:

Time of crowning

Time of birth

Time of delivery of placenta
7.3.8.
Electrocardiogram (ECG) (Group 2 Only)

Triplicate 12-lead ECGs will be obtained at screening as listed in Section 7.1.1.

Single 12-lead ECGs will be obtained at each timepoint as listed in Section 7.1.2
using an ECG machine that automatically calculates the heart rate and measures 
PR, QRS, QT, and QTc intervals.  Refer to Section 5.4.3 for QTc withdrawal 
criteria and additional QTc readings that may be necessary.

At all single 12-lead ECG time-points if QTc >450, repeat twice and take average 
reading.
7.3.9.
Continuous Cardiac Telemetry (Group 2 Only)
Continuous cardiac telemetry will be started at least 10 minutes pre-dose (to obtain a 
stable reading) and continue until at least the first hour after IV and IH placebo / 
oxytocin administration and then as deemed necessary by the investigator.  Full 
disclosures will be reviewed in detail and the review maintained as part of the 
subject’s source documents.
7.3.10.
Device Acceptability Questionnaire (Group 1 Only)
A device acceptability questionnaire will be administered to subjects in Group 1 
following use of the ROTAHALER (Appendix 7). 
7.3.11.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as required by Section 7.1 and defined in 
Table 4, must be conducted in accordance with the Laboratory Manual, and Protocol 
Time and Events Schedule. Laboratory requisition forms must be completed and samples 
must be clearly labelled with the subject number, protocol number, site/centre number, 
and visit date. Details for the preparation and shipment of samples will be provided by 
the laboratory and are detailed in the SRM. Reference ranges for all safety parameters 
will be provided to the site by the laboratory responsible for the assessments.
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the CRF.
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
54
Refer to the SRM for appropriate processing and handling of samples to avoid duplicate 
and/or additional blood draws.
All study-required laboratory assessments will be performed by a central laboratory, apart 
from:

Tests performed as part of routine care in Group 1.
NOTE:  Local laboratory results are only required in the event that the central laboratory
results are not available in time for either a treatment and/or response evaluation to be 
performed. Additionally if the local laboratory results are used to make either a treatment 
or response evaluation, the results must be entered into the CRF.
Subjects in Group 1 are not required to undergo additional laboratory assessments beyond 
those done as part of their routine care. However, the investigator/designee may conduct 
any of the tests listed in Table 4 in order to confirm eligibility. Haematology, clinical 
chemistry, and additional parameters to be tested in all Group 2 subjects are listed in 
Table 4.
Table 4
Protocol Required Safety Laboratory Assessments
Laboratory
Assessments
Parameters
Haematology
Platelet Count
RBC Indices:
White Blood Cell (WBC) count 
with Differential:
Red Blood Cell (RBC)
Count
Mean 
Corpuscular 
Volume 
(MCV)
Neutrophils
Hemoglobin
Mean 
Corpuscular 
Hemoglobin 
(MCH)
Lymphocytes
Hematocrit
Monocytes
Eosinophils
Basophils
Clinical 
Chemistry 1
Blood Urea 
Nitrogen 
(BUN)
Potassium
Aspartate 
aminotransferase 
(AST) (SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
Alanine 
aminotransferase 
(ALT) (SGPT)
Total Protein
Glucose 
Calcium
Alkaline phosphatise
Albumin
Other 
Screening 
Tests
HIV
Hepatitis B (HBsAg)
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
55
Laboratory
Assessments
Parameters
Hepatitis C (Hep C antibody)
Follicle Stimulating Hormone (FSH) and estradiol (as needed in women 
of suspected non-child bearing potential only)
Alcohol and drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines)
Serum or urine hCG Pregnancy test (Group 2 only) 2
NOTES :
1.
Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up 
Assessments after liver stopping or monitoring event are given in Section 12.2 and
Appendix 2
2.
Local urine testing will be standard for the protocol unless serum testing is required 
by local regulation or ethics committee.
All laboratory tests with values that are considered clinically significantly abnormal 
during participation in the study should be repeated until the values return to normal or
baseline.  If such values do not return to normal within a period judged reasonable by the 
investigator, the etiology should be identified and the sponsor notified.
7.4.
Pharmacokinetics
7.4.1.
Blood Sample Collection
Blood samples for pharmacokinetic (PK) analysis of oxytocin will be collected at the 
time points indicated in Section 7.1, Time and Events Table.  The actual date and time of 
each blood sample collection will be recorded.  The timing of PK samples may be altered 
and/or PK samples may be obtained at additional time points to ensure thorough PK 
monitoring.  
At each time point, 4 mL of blood will be collected into K2 or K3 
Ethylenediaminetetraacetic acid (EDTA) tubes and stored on ice for up to 2 hours prior to 
centrifugation in a refrigerated centrifuge. Further details regarding collection/shipping 
procedures are provided in the SRM
7.4.2.
Sample Analysis
Plasma analysis will be performed under the control of PTS-DMPK, GlaxoSmithKline, 
the details of which will be included in the SRM. Concentrations of oxytocin will be 
determined in plasma samples using the currently approved bioanalytical methodology.
Raw data will be archived at the bioanalytical site (detailed in the SRM).
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
56
7.5.
Biomarkers
7.5.1.
Pharmacodynamic Markers
Pre and post-delivery full blood counts will be collected from Group 1 subjects to assess 
for a change in haemoglobin levels.
7.5.2.
Immunogenicity
Blood samples will be taken at the time points specified in the Time and Events Table 
(Section 7.1) to assess the immunogenicity of oxytocin.
Pre- and post-dose samples will be retained in the event that further immunologic tests 
are deemed necessary to support observations of unexpected anaphylaxis/
hypersensitivity, and / or a PK profile for IH oxytocin in any Dosing Session which is 
regarded by the GSK Study Team to be reasonably attributable to circulating anti-
oxytocin antibodies.
Details of the collection / shipping procedures are provided in the SRM.
8.
DATA MANAGEMENT

For this study subject data will be entered into GSK defined CRFs, transmitted 
electronically to GSK or designee and combined with data provided from other 
sources in a validated data system.  

Management of clinical data will be performed in accordance with applicable 
GSK standards and data cleaning procedures to ensure the integrity of the data, 
e.g., removing errors and inconsistencies in the data.

Adverse events and concomitant medications terms will be coded using MedDRA 
(Medical Dictionary for Regulatory Activities) and an internal validated 
medication dictionary, GSKDrug.  

CRFs (including queries and audit trails) will be retained by GSK, and copies will 
be sent to the investigator to maintain as the investigator copy.  Subject initials 
will not be collected or transmitted to GSK according to GSK policy.
9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
9.1.
Hypotheses
The primary objective of this study is to characterize the pharmacokinetics of 400 mcg IH 
oxytocin and 10 I.U. IM oxytocin in women in TSL. 
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
57
No formal hypotheses will be tested, however, the following comparisons are of interest,
within Group 1, (IH vs. IM) and between Group 1 and Group 2 (IH oxytocin comparison 
in TSL vs. non-pregnant women on oral contraception) and between Cohorts A and B in 
Group 2 (IH and IV oxytocin comparison in non-pregnant women in the presence and 
absence of oral contraceptive). For each PK endpoint of interest, point estimates and 
corresponding two-sided 90% confidence intervals will be constructed for the ratio of the 
geometric mean of the test treatment to the geometric mean of the reference treatment, 
μ(test)/μ(reference) to provide the range of plausible values for the comparisons of 
interest. 
9.2.
Sample Size Considerations
A sufficient number of subjects will be enrolled to ensure approximately 20 evaluable 
subjects (10 in each of the IM and IH groups) complete all dosing and critical 
assessments in Group 1, as well as 5 subjects in each cohort in Group 2. Whilst sample 
size is based on feasibility, precision calculation was also done to approximate the 
estimate of the expected half width of 90% CI around point estimate for the main 
comparison of interest (IH oxytocin to 10 I.U. IM oxytocin in women in TSL) using a t-
test. 
Table 5 illustrates the associated 90% CIs for the mean treatment ratios, assuming 
between subject SDs of 0.424 and 0.601 (SDs are based on log transformed data) for 
AUC (0-3h) and CP10 respectively, for the comparisons of interest detailed in Section 
9.1. Calculations are based on a symmetric two-tailed procedure on the loge scale and a 
type I error rate of 10%. These values represent estimates of the between-subject 
variability observed in the FTIH study 201558 [GlaxoSmithKline Document Number 
2016N277949_00].
Table 5
Estimated 90% Confidence Intervals for Treatment Ratios
N
Parameter
Between
Subject 
Standard 
Deviation 
(SD)
Estimated 
Treatment 
Ratio
Precision
Expected 
90% CI
10
AUC(0-3h)
0.424 
(CVb=44.35%)
1
38.30%
(0.72, 1.38)
10
Cp10
0.601 
(Cvb=65.96%)
1
58.20%
(0.63,1.58)
The precision estimates are deemed acceptable to assess the study objectives at this stage
of development.
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
58
9.2.1.
Sample Size Sensitivity
Considering the variability of AUC(0-3h) and Cp10, Table 6 shows the scenarios for 
different sample size and the precision estimates for IH vs. IM in Group 1.
Table 6
Estimated 90% Confidence Intervals for Treatment Ratios for Sample 
Size Sensitivity
%CVb
N
Precision
Assuming ratio 1, the 
confidence interval
44.35%
5
61.90%
(0.61, 1.61)
15
29.80%
(0.77,1.29)
65.96%
5
98.00%
(0.50, 1.98)
15
44.80%
(0.69, 1.44)
20
37.40%
(0.72,1.37)
85.35%*
5
131.90%
(0.43, 2.31)
10
75.90%
(0.56, 1.75)
15
57.60%
(0.63, 1.57)
20
48.00%
(0.67, 1.48)
* 85.35%  was the largest between subject CV for AUC(0-10) observed for FTIH study 201558 
[GlaxoSmithKline Document Number:2016N277949_00]
9.2.2.
Sample Size Re-estimation or Adjustment
No formal sample size re-estimation is planned for this study. However, if the variability 
is high (for example approaching 85%) then the sample size for Group 1 may be 
increased to a maximum of 10 additional subjects per treatment arm (IH and IM only).
9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations
Enrolled Population

Defined as all subjects who were enrolled for the trial 
irrespective of whether they were randomized or not and 
for whom a record exist on the study database. This 
population will be used for summarizing screening failure 
reasons.
All Subjects Population

Comprise of subjects who receive at least one dose of 
study medication. This population will be used for the 
study population and safety displays.
Pharmacokinetic 
Population

Subjects in the ‘All Subjects’ population for whom a 
pharmacokinetic sample was obtained and analysed.  PK 
population will be the population for reporting PK data.
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
59
9.3.2.
Interim Analysis
No formal interim analysis is planned. However, PK samples will be analysed and 
preliminary PK parameters derived following completion of 5 women on each of the 
following treatments: 400 mcg IH and 10 I.U. IM to women in TSL (Group 1) and 
400 mcg IH to non-pregnant women on the combined  oral contraceptive (Group 2 
Cohort A).  Based on the PK profiles the dose of IH oxytocin to be administered to 
women in TSL will either remain at 400 mcg or be increased (to 600 mcg) (See Section 
6.4.1). This decision will be made by the study team in collaboration with the Principal 
Investigator. 
9.4.
Key Elements of Analysis Plan
9.4.1.
Primary Analyses
9.4.1.1.
Safety Analysis
Safety data will be presented in tabular and/or graphical format and summarized 
descriptively according to GSK’s Integrated Data Standards Library (IDSL) standards.
9.4.1.2.
Pharmacokinetic Analysis
Pharmacokinetics analysis will be the responsibility of the Clinical Pharmacokinetics 
Modeling & Simulation department within GlaxoSmithKline.  Plasma oxytocin
concentration-time data will be analyzed by non-compartmental methods with 
WinNonlin V6.3 or greater.  Calculations will be based on the actual sampling times 
recorded during the study. 
From the plasma concentration-time data, the following pharmacokinetic parameters will 
be determined, as data permit: maximum observed plasma concentration (Cmax), time to 
Cmax (tmax), area under the plasma concentration-time curve [AUC(0-3h) and AUC(0-
∞)], the last observed quantifiable concentration (Clast), time of the last quantifiable 
concentration (tlast), Cp10, Cp20, Cp30 (observed plasma concentrations at 10, 20 and 
30minutes post-dose, respectively), plasma clearance (CL; IV only), volume of 
distribution (V; IV only) and apparent terminal phase half-life (t1/2).  Other PK 
parameters may also be determined.
Pharmacokinetic data will be presented in graphical and/or tabular form and will be
summarized descriptively. All pharmacokinetic data will be stored in the Archives, 
GlaxoSmithKline Pharmaceuticals, R&D. 
If appropriate, a population PK analysis may also be conducted, in addition the oxytocin 
plasma concentration-time data may be merged with historical data and analysed as part 
of a population PK meta-analysis.
9.4.2.
Secondary Analyses
Statistical analyses of the PK parameter data will be performed by, or under direct 
auspices of Clinical Statistics, QSci.
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
60
9.4.2.1.
Pharmacokinetic Analysis
For evaluating pharmacokinetic treatment comparisons within Group 1 IH vs. IM, point 
estimates and corresponding two-sided 90% confidence intervals will be computed using 
a mixed effect model. Loge-transformed PK parameters will be analysed using the model 
with a fixed effect term for treatment and a random effect term for subject.
Further details of analysis and reporting of PK data will be given in the Reporting 
Analysis Plan (RAP).
9.4.3.
Exploratory Analyses
9.4.3.1.
Pharmacokinetic Analysis
For evaluating pharmacokinetic treatment comparisons between Group 1 and Group 2 
(IH oxytocin comparison in TSL vs. non-pregnant women on the combined oral 
contraceptive), and within Group 2 between Cohorts A and B (IH and IV oxytocin 
comparison in non-pregnant women in the presence and absence of oral contraceptive),
point estimates and corresponding two-sided 90% confidence intervals will be computed 
using a mixed effect model. Loge-transformed PK parameters will be analysed using the 
model with a fixed effect term for treatment and a random effect term for subject.
Further details of analysis and reporting of PK data will be given in the Reporting 
Analysis Plan (RAP).
9.4.3.2.
Device Acceptability Questionnaire
In Group 1, subject satisfaction with device, including instructions and ease of use, will 
be assessed. The questionnaire is located in Section 12.7
10.
STUDY GOVERNANCE CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and the guiding principles of the current 
version of the Declaration of Helsinki.  This includes, but is not limited to, the following:
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
61

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable

Obtaining signed informed consent

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol 
deviations to IRB/IEC)

GSK will provide full details of the above procedures, either verbally, in writing, 
or both.

Signed informed consent must be obtained for each subject prior to participation 
in the study

The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.  

Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.  

Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities.  In this situation, 
written approval of the clinical protocol should state that approval of optional 
assessments is being deferred and the study, with the exception of the optional 
assessments, can be initiated.
10.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK monitors will contact the site prior to the start of the study to review with the 
site staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and GSK requirements.  

When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the CRF will 
serve as the source document.

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRFs <or> entered in the eCRFs that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study; also current medical 
records must be available.
GSK will monitor the study and site activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
62

Study is conducted in accordance with the currently approved protocol and any 
other study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents.
10.4.
Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK 
may conduct a quality assurance assessment and/or audit of the site records, and 
the regulatory agencies may conduct a regulatory inspection at any time during or 
after completion of the study. 

In the event of an assessment, audit or inspection, the investigator (and institution) 
must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all 
relevant documents and to allocate their time and the time of their staff to discuss 
the conduct of the study, any findings/relevant issues and to implement any 
corrective and/or preventative actions to address any findings/issues identified.
10.5.
Study and Site Closure

Upon completion or premature discontinuation of the study, the GSK monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and GSK Standard 
Operating Procedures.

GSK reserves the right to temporarily suspend or prematurely discontinue this 
study at any time for reasons including, but not limited to, safety or ethical issues 
or severe non-compliance. For multicenter studies, this can occur at one or more 
or at all sites.  

If GSK determines such action is needed, GSK will discuss the reasons for taking 
such action with the investigator or the head of the medical institution (where 
applicable).  When feasible, GSK will provide advance notification to the 
investigator or the head of the medical institution, where applicable, of the 
impending action.

If the study is suspended or prematurely discontinued for safety reasons, GSK will 
promptly inform all investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study. GSK will also promptly 
inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action.  

If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation.
10.6.
Records Retention

Following closure of the study, the investigator or the head of the medical 
institution (where applicable) must maintain all site study records (except for 
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
63
those required by local regulations to be maintained elsewhere), in a safe and 
secure location.  

The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review 
in conjunction with assessment of the facility, supporting systems, and relevant 
site staff.  

Where permitted by local laws/regulations or institutional policy, some or all of 
these records can be maintained in a format other than hard copy (e.g., microfiche, 
scanned, electronic); however, caution needs to be exercised before such action is 
taken.  

The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, 
including re-generating a hard copy, if required.  Furthermore, the investigator 
must ensure there is an acceptable back-up of these reproductions and that an 
acceptable quality control process exists for making these reproductions.

GSK will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements.  The minimum retention time 
will meet the strictest standard applicable to that site for the study, as dictated by 
any institutional requirements or local laws or regulations, GSK 
standards/procedures, and/or institutional requirements. 

The investigator must notify GSK of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of 
ownership of the records in the event the investigator is no longer associated with 
the site.
10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy.
A manuscript will be progressed for publication in the scientific literature if the results 
provide important scientific or medical knowledge.
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
64
11.
REFERENCES
Costantine MM. Physiologic and pharmacokinetic changes in pregnancy. Frontiers in
Pharmacology. 2014. Volume 5. Article 65: 1-5. 
GlaxoSmithKline Document Number 2015N234711_01. Study ID 201558. Clinical 
Pharmacology Study Protocol. A single centre, single blind study to investigate the 
safety, tolerability and pharmacokinetics of single doses of oxytocin (GR121619) 
administered via an inhaled route in healthy female volunteers. 16-NOV-2015.
GlaxoSmithKline Document Number 2015N239682_00. Study ID 201248 – Clinical
Pharmacology Study Report. An enabling study to compare the inhalation profiles of 
women in the third stage of labour to those of non-pregnant female volunteers and to 
explore whether there are any  differences which could impact the delivery of an inhaled 
medicinal product, 16-OCT-2016.
GlaxoSmithKline Document Number 2015N240749_01. GR121619 Investigator's 
Brochure, AUG-2015.  
GlaxoSmithKline Document Number 2016N277949_00. Study ID 201558 – Clinical 
Study Report.. 30-JUN-2016.
Khan KS, Wojdyla D, Say L, Gülmezoglu AM, Van Look PF. WHO analysis of causes 
of maternal death: a systematic review. Lancet. 2006;367(9516):1066-74.
Mousa HA, Blum J, Abou El Senoun G, Shakur H, Alfirevic Z. Treatment for primary 
postpartum haemorrhage. Cochrane Database of Systematic Reviews. 2014, Issue 2. Art. 
No.: CD003249. DOI: 10.1002/14651858.CD003249.pub3.
Prankerd RJ, Nguyen T, Ibrahim JP, et al. Pulmonary Delivery of an Ultra-Fine Oxytocin 
Dry Powder Formulation: Potential for Treatment of Postpartum Haemorrhage in 
Developing Countries. 2013; PLoS One. Vol 8: 12: Article e82965
Syntocinon Summary of Product Characteristics, Novartis, 2014
Thornton S, Davison JM, Baylis PH. Effect of human pregnancy on metabolic clearance 
rate of oxytocin. American Physiological Society. 1990. 0363-6119: R21-R24.
Thornton S, Davison JM, Baylis PH. Plasma oxytocin during third stage of labour: 
comparison of natural and active management.BMJ. 1988. Volume 297:167-169.
WHO Model List of Essential Medicines 18th list (April 2013). Available at: 
http://www.who.int/medicines/publications/essentialmedicines/en/. Accessed May 26, 
2015.
WHO Model List of Essential Medicines for Children 4th list (April 2013). Available at: 
http://www.who.int/medicines/publications/essentialmedicines/en/. Accessed May 26, 
2015.
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
65
WHO, UNICEF, UNFPA. The World Bank World Health Organization (WHO) Press. 
Trends in Maternal Mortality: 1990 to 2008: Estimates Developed by WHO, UNICEF, 
UNFPA and The World Bank. Geneva: WHO, 2010.
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
66
12.
APPENDICES
12.1.
Appendix 1
Abbreviations and Trademarks
Abbreviations
ADAs
Anti drug antibodies
AE
Adverse Event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase (SGPT)
ANP
Atrial natriuretic peptide
AST
Aspartate aminotransferase (SGOT)
AUC
Area under concentration-time curve
AUC(0-3)
Area under the concentration-time curve from time zero 
(pre-dose) to three hours
AUC(0-∞)
Area under the concentration-time curve from time zero to 
infinity
BMI
Body mass index
BP
Blood pressure
BUN
Blood urea nitrogen
C
Centigrade
Ca2+
Intracellular calcium
CI
Confidence Interval
CL
Plasma clearance
Clast
last observed quantifiable concentration
Cmax
Maximum observed plasma concentration
COC
Combined oral contraceptive
CONSORT
Consolidated Standards of Reporting Trials
COPD
Chronic obstructive pulmonary disease
Cp10
Observed plasma concentrations at 10 minutes post-dose
Cp20
Observed plasma concentrations at 20 minutes post-dose
Cp30
Observed plasma concentrations at 30 minutes post-dose
CPK
Creatinine phosphokinase
CRF
Case report form
CVS
Cardiovascular system
DMPK
Drug Metabolism and Pharmacokinetics
DPI
Dry powder inhaler
ECG
Electrocardiogram
EDTA
Ethylenediaminetetraacetic acid
FDA
Food and Drug Administration
FEV1.0
Forced expiratory volume at 1 minute
FRP
Females of Reproductive Potential
FSH
Follicle Stimulating Hormone
FTIH
First time in human
g
Gram
GCP
Good Clinical Practice
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
67
GSK
GlaxoSmithKline
h/hr
Hour(s)
HBsAg
Hepatitis B surface antigen
hCG
Human chorionic gonadotropin
HCP
Health care professional
HIV
Human Immunodeficiency Virus
HPLC
High Performance Liquid Chromatography
HR
Heart rate
I.U.
International units
IB
Investigators Brochure
ICH
International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for 
Human Use
IDSL
Integrated Data Standards Library
IEC
Independent Ethics Committee
IgG
Immunoglobulin G
IgM
Immunoglobulin M
IH
Inhaled
IL
Interleukin
IM
Intramuscular
INR
International normalized ratio
IP
Investigational product
IRB
Institutional Review Board
IV
Intravenous
Kg
kilogram
LDH
Lactate dehydrogenase
m
Meter
mcg
Micrograms
MCH
Mean Corpuscular Hemoglobin
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
ml
Millilitre
mmHg
Millimeter of mercury
MSDS
Material Safety Data Sheet
Msec
Milliseconds
MW
Molecular weight
OTR
Oxytocin receptor
PGF
Prostaglandin F
PI
Principal Investigator
PK
Pharmacokinetics
PPH
Post-partum haemorrhage
QTc
Corrected QT interval
QTcF
QT duration corrected for heart rate by Fridericia’s formula
RAP
Reporting and Analysis plan
RBC
Red blood cells
SAE
Serious Adverse Event
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
68
SD
Standard deviation
SMC
Smooth muscle cells
SPC
Summary of product characteristics
SpO2
Peripheral capillary oxygen saturation
SRM
Study reference manual
T&E
Time and event
t1/2
Terminal phase half-life
TB
Tuberculosis
tmax
Time to Cmax
TSL
Third stage of labour
UK
United Kingdom
ULN
Upper Limit of Normal
V
Vassopresin
VOD
Volume of distribution
WBC
White blood cells
WHO
World Health Organization
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
ROTACAPS
Syntocinon
ROTAHALER
Uniject
WinNonlin
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
69
12.2.
Appendix 2
Liver Safety Required Actions and Follow up 
Assessments
Phase I Liver chemistry stopping criteria have been designed to assure subject safety and 
to evaluate liver event etiology (in alignment with the Food and Drug Administration
[FDA] premarketing clinical liver safety guidance).
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Phase I liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria – Liver Stopping Event
ALT-absolute
ALT≥3xULN
If  ALT≥3xULN  AND bilirubin1,2 2xULN (>35% direct bilirubin) or  INR >1.5, 
Report as an SAE.
See additional Actions and Follow Up Assessments listed below
Required Actions and Follow up Assessments following Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue study treatment 

Report the event to GSK within 24 hours

Complete the liver event CRF, and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries 
resolve, stabilise, or return to within baseline 
(see MONITORING below)
MONITORING:
If ALT≥3xULN AND bilirubin 2xULN  or INR 
>1.5

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24 
hrs

Monitor subjects twice weekly until liver 
chemistries resolve, stabilise or return to 
within baseline

A specialist or hepatology consultation is 

Viral hepatitis serology3

Blood sample for pharmacokinetic (PK) 
analysis, obtained within 4h of the last 
dose4

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on 
the concomitant medications report form 
including acetaminophen, herbal remedies, 
other over the counter medications.

Record alcohol use on the liver event 
alcohol intake case report form
If ALT≥3xULN AND bilirubin 2xULN  or 
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
70
recommended
If ALT≥3xULN AND bilirubin < 2xULN  and 
INR ≤1.5:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24-
72 hrs

Monitor subjects weekly until liver 
chemistries resolve, stabilize or return to 
within baseline
INR >1.5:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG or gamma 
globulins).

Serum acetaminophen adduct High 
Performance Liquid Chromatography
(HPLC) assay (quantifies potential 
acetaminophen contribution to liver injury 
in subjects with definite or likely 
acetaminophen use in the preceding week 
[James, 2009]. NOTE: not required in 
China.

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured, which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); International normalized ratio (INR) measurement is not required 
and the threshold value stated will not apply to subjects receiving anticoagulants
3.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody
4.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
71
12.3.
Appendix 3
Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.3.1.
Definition of Adverse Events
Adverse Event Definition:

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.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae).

The signs and symptoms and/or clinical sequelae resulting from lack of efficacy will 
be reported if they fulfil the definition of an AE or SAE.  Also, "lack of efficacy" or 
"failure of expected pharmacological action" also constitutes an AE or SAE.
Events NOT meeting definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 
condition.
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
72

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
12.3.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
a.
Results in death
b.
Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c.
Requires hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting.  Complications that occur during hospitalization are 
AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d.
Results in disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
73
and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday 
life functions but do not constitute a substantial disruption
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition.  These should also be considered 
serious.

Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse
g.
Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** > 1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick.  If fractionation is unavailable and ALT 3xULN 
and total bilirubin 2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.
12.3.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
74

Deep venous thrombosis/pulmonary embolism

Revascularization
12.3.4.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the CRF

It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to GSK in lieu of completion of the GSK, AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK.  In this instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to 
submission of to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.
12.3.5.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. - an AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
75
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled 
out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of his/her assessment.

For each AE/SAE the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK.  However, it is very important 
that the investigator always make an assessment of causality for every event 
prior to the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.

The investigator is obligated to assist.  This may include additional laboratory tests 
or investigations, histopathological examinations or consultation with other health 
care professionals.

If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide GSK with a copy of any post-mortem findings, 
including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
76
12.3.6.
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data collection 
tool

If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and fax it to the Medical Monitor

Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.

The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of 
the SAE.

After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) will be taken off-line to prevent the entry of new data or changes to 
existing data

If a site receives a report of a new SAE from a study subject or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, the site can report this information on a paper SAE form or to the Medical 
Monitor or the SAE coordinator by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
77
12.4.
Appendix 4
Definition of and Procedures for 
Documenting Medical Device Incidents
12.4.1.
Definitions of a Medical Device Incident
The detection and documentation procedures described in this protocol apply to all GSK 
medical devices provided for use in the study (see Section 6.2 for the list of GSK medical 
devices).
Medical Device Incident Definition:

Incident – Any malfunction or deterioration in the characteristics and/or performance 
of a device, as well as any inadequacy in the labeling or the instructions for use 
which, directly or indirectly, might lead to or might have led to the death of a 
patient/user/other persons or to a serious deterioration in their state of health.

Not all incidents lead to death or serious deterioration in health.  The non-occurrence 
of such a result might have been due to other fortunate circumstances or to the 
intervention of health care personnel.
It is sufficient that:

an incident associated with a device happened and

the incident was such that, if it occurred again, might lead to death or a serious 
deterioration in health.
A serious deterioration in state of health can include:

life-threatening illness

permanent impairment of body function or permanent damage to a body structure

a condition necessitating medical or surgical intervention to prevent one of the above 

fetal distress, fetal death or any congenital abnormality or birth defects
Examples of incidents

a patient, user, care giver or professional is injured as a result of a medical device 
failure or its misuse

a patient’s treatment is interrupted or compromised by a medical device failure

misdiagnosis due to medical device failure leads to inappropriate treatment

a patient’s health deteriorates due to medical device failure
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
78
12.4.2.
Documenting Medical Device Incidents
Medical Device Incident Documenting:

Any medical device incident occurring during the study will be documented in the 
subject’s medical records, in accordance with the investigator’s normal clinical 
practice, and on the appropriate form.

For incidents fulfilling the definition of an AE or an SAE, the appropriate AE/SAE 
CRF page will be completed as described in Appendix 3.

The form will be completed as thoroughly as possible and signed by the investigator 
before transmittal to GSK.

It is very important that the investigator provides his/her assessment of causality to 
the medical device provided by GSK at the time of the initial report, and describes 
any corrective or remedial actions taken to prevent recurrence of the incident.

A remedial action is any action other than routine maintenance or servicing of a 
device where such action is necessary to prevent recurrence of an incident. This 
includes any amendment to the design to prevent recurrence.
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
79
12.5.
Appendix 5
List of Acceptable Methods for Avoiding 
Pregnancy in FRP and Collection of Pregnancy Information
12.5.1.
Group 2, Cohort B Only: List of Acceptable Non-hormonal
Methods for Avoiding Pregnancy in Females of Reproductive 
Potential (FRP)
The list does not apply to FRP with same sex partners or for subjects 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.
1.
Nonhormonal Intrauterine device or 
2.
Male condom combined with vaginal spermicide
3.
Male partner sterilization with documentation of azoospermia prior to the female 
subject's entry into the study, and this male is the sole partner for that subject 
[Hatcher, 2011]. The documentation on male sterility can come from the site 
personnel’s: review of subject’s medical records, medical examination and/or semen 
analysis, or medical history interview provided by her or her partner.
These allowed 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 these methods of contraception.
12.5.2.
Collection of Pregnancy Information
Group 2 Only

Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study

Information will be recorded on the appropriate form and submitted to GSK within 2 
weeks of learning of a subject's pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on mother and infant, which will be 
forwarded to GSK.  Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date. 

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
80

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK 
as described in Section 12.3. While the investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.
Any female subject who becomes pregnant while participating 

will discontinue study medication or be withdrawn from the study.
12.5.3.
References
Bolton TJ, Randall K, Yentis SM. Effect of the Confidential Enquiries into Maternal 
Deaths on the use of Syntocinon at Caesarean section in the UK. Anaesthesia 2003(58-
3):277-9.
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, Policar MS, 
editors. Contraceptive Technology. 20th edition. Atlanta, Georgia: Ardent Media, Inc., 
2011: 50. Table 3-2.
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
81
12.6.
Appendix 6
Country Specific Requirements
No country-specific requirements exist.
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
82
12.7.
Appendix 7
Device Acceptability Questionnaire
Device Acceptability Questionnaire
Please answer the following questions regarding your use of the ROTAHALER inhaler
for oxytocin.
1. Did you feel confident you had received the medicine?
Yes
No
Neutral
Decline to answer
2. Did you find the inhaler easy to use?
Yes
No
Neutral
Decline to answer
3. Did you prefer to have your medicine from an inhaler instead of an injection?
Yes
No
Neutral
Decline to answer
4. Do you feel using this inhaler is an acceptable way to administer the medicine?
Yes
No
Neutral
Decline to answer
Thank you for answering these questions.
 
2019N402257_00


2016N281575_01
CONFIDENTIAL
205920
83
12.8.
Appendix 8
Protocol Changes
Protocol Amendment 01
As part of the Medical Device Notification assessment process, the Medicines and 
Healthcare products Regulatory Agency (MHRA) requested that the protocol 
prominently reflect that although the investigational device (the ROTAHALER) bears a 
CE mark, it has not been CE marked in accordance with the Medical Device Directive 
93/42/EEC as updated. This change applies to all sites.
Section 6.2 Medical Devices 
Change From:
The GSK manufactured medical device (or device manufactured for GSK by a third 
party) provided for use in this study is a high airflow resistance capsule-based inhaler 
(Modified Air Inlet ROTAHALER DPI device). 
Instructions for medical device use are provided in Section 6.7. Further details on use of 
the device are provided in the SRM.
GSK medical device incidents, including those resulting from malfunctions of the device, 
must be detected, documented, and reported by the investigator throughout the study –
see Section 12.4.
Change to:
The GSK manufactured medical device (or device manufactured for GSK by a third 
party) provided for use in this study is a high airflow resistance capsule-based inhaler 
(Modified Air Inlet ROTAHALER DPI device). Although this investigational device 
bears a CE mark, it has not been CE marked in accordance with the Medical 
Devices Directive 93/42/EEC.
Instructions for medical device use are provided in Section 6.7. Further details on use of 
the device are provided in the SRM.
GSK medical device incidents, including those resulting from malfunctions of the device, 
must be detected, documented, and reported by the investigator throughout the study –
see Section 12.4.
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
GlaxoSmithKline group of companies
205920
1
TITLE PAGE
Division:  Worldwide Development
Information Type: Clinical Protocol
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.
Compound Number:
GR121619
Development Phase
I
Effective Date:
22-AUG-2016
Author(s):
(Respiratory TAU); 
(GCSP); 
 
(MNHU), 
Clinical Statistics); 
 
(GCSP); 
(QSci CPMS); 
(CPSSO)
Copyright 2016 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
2019N402257_00
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


 
2019N402257_00
PPD
PPD


2016N281575_00
CONFIDENTIAL
205920
3
MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information:
Role
Name
Day Time Phone Number and 
email address
After-hours 
Phone/Cell/
Pager 
Number
Fax 
Number
Site 
Address
Primary 
Medical 
Monitor
GSK
Gunnels 
Wood 
Road
Stevenage
SG1 2NY
UK
Secondary 
Medical 
Monitor
GSK
Gunnels 
Wood 
Road
Stevenage
SG1 2NY
UK
SAE 
contact  
information 
Medical 
monitor as 
above 
Sponsor Legal Registered Address:
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline (GSK)
Affiliate Company (or designee). If applicable, the details of the alternative Sponsor and 
contact person in the territory will be provided to the relevant regulatory authority as part 
of the clinical trial application.   
Regulatory Agency Identifying Number(s): EudraCT 2016-002672-27
 
2019N402257_00
PPD


2016N281575_00
CONFIDENTIAL
205920
4
INVESTIGATOR PROTOCOL AGREEMENT PAGE

I confirm agreement to conduct the study in compliance with the protocol.

I acknowledge that I am responsible for overall study conduct. I agree to 
personally conduct or supervise the described study.

I agree to ensure that all associates, colleagues and employees assisting in the 
conduct of the study are informed about their obligations. Mechanisms are in 
place to ensure that site staff receives the appropriate information throughout the 
study.
Investigator Name:  ______________________________
Investigator Signature
Date
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
5
TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 205920........................................................9
2.
INTRODUCTION....................................................................................................13
2.1.
Study Rationale ..........................................................................................14
2.2.
Brief Background ........................................................................................14
2.2.1.
IH Oxytocin FTIH Study 201558 ..................................................16
3.
OBJECTIVES AND ENDPOINTS...........................................................................16
3.1.
Group 1: Women in TSL .............................................................................16
3.2.
Group 2: Non-pregnant, non-lactating females of child bearing 
potential......................................................................................................17
3.3.
Groups 1 and 2: Women in TSL and Non-pregnant, non-lactating 
females of child bearing potential................................................................18
4.
STUDY DESIGN ....................................................................................................18
4.1.
Overall Design ............................................................................................18
4.1.1.
Study Schematic Group 1: Women in TSL...................................18
4.1.2.
Study Schematic Group 2: Non-pregnant, non-lactating 
females of child bearing potential.................................................19
4.1.3.
Study Design Detail .....................................................................19
4.1.3.1.
Pregnant Females (Group 1)......................................20
4.1.3.2.
Non-pregnant Females (Group 2)...............................20
4.1.4.
ROTAHALER Inhaler Training .....................................................20
4.1.5.
Length of Stay for All Subjects.....................................................20
4.2.
Treatment Arms and Duration.....................................................................21
4.3.
Type and Number of Subjects.....................................................................22
4.4.
Design Justification.....................................................................................22
4.5.
Dose Justification........................................................................................23
4.6.
Benefit:Risk Assessment ............................................................................25
4.6.1.
Risk Assessment .........................................................................25
4.6.2.
Immunogenicity Risk....................................................................28
4.6.3.
Benefit Assessment and Overall Benefit:Risk Conclusion............28
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............29
5.1.
Inclusion Criteria.........................................................................................29
5.2.
Exclusion Criteria........................................................................................32
5.3.
Screening/Baseline/Run-in Failures............................................................34
5.3.1.
Re-screening ...............................................................................34
5.4.
Withdrawal/Stopping Criteria.......................................................................34
5.4.1.
Pregnancy Complication Stopping Criteria (Group 1 Only) ..........34
5.4.2.
Anaphylaxis Stopping Criteria......................................................35
5.4.3.
QTc Stopping Criteria (Group 2 Only)..........................................35
5.4.4.
Blood Pressure Stopping Criteria (Group 2 Only).........................35
5.4.5.
Liver Chemistry Stopping Criteria ................................................36
5.5.
Subject and Study Completion....................................................................36
6.
STUDY TREATMENT ............................................................................................36
6.1.
Investigational Product and Other Study Treatment....................................36
6.2.
Medical Devices..........................................................................................37
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
6
6.3.
Treatment Assignment................................................................................37
6.4.
Planned Dose Adjustments.........................................................................38
6.4.1.
Dose Adjustment .........................................................................38
6.5.
Blinding.......................................................................................................39
6.6.
Packaging and Labeling..............................................................................39
6.7.
Preparation/Handling/Storage/Accountability..............................................39
6.8.
Compliance with Study Treatment Administration.......................................40
6.9.
Treatment of Study Treatment Overdose....................................................41
6.10.
Treatment after the End of the Study ..........................................................42
6.11.
Lifestyle and/or Dietary Restrictions............................................................42
6.11.1.
Meals and Dietary Restrictions ....................................................42
6.11.2.
Caffeine and Alcohol....................................................................42
6.11.3.
Activity .........................................................................................43
6.12.
Concomitant Medications and Non-Drug Therapies....................................43
6.12.1.
Permitted Medications and Non-Drug Therapies..........................43
6.12.2.
Prohibited Medications and Non-Drug Therapies.........................43
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................43
7.1.
Time and Events Table...............................................................................45
7.1.1.
Time and Events Table – General Overview................................45
7.1.2.
Time and Events – Main Phase Procedures ................................47
7.2.
Screening and Critical Baseline Assessments ............................................49
7.3.
Safety .........................................................................................................49
7.3.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........49
7.3.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................49
7.3.1.2.
Method of Detecting AEs and SAEs ...........................50
7.3.1.3.
Follow-up of AEs and SAEs........................................50
7.3.1.4.
Regulatory Reporting Requirements for SAEs............50
7.3.2.
Adverse Events of Special Interest (AESI)...................................51
7.3.3.
Pregnancy ...................................................................................51
7.3.4.
Medical Device Incidents (Including Malfunctions).......................51
7.3.4.1.
Time Period for Detecting Medical Device 
Incidents.....................................................................51
7.3.4.2.
Follow-up of Medical Device Incidents........................51
7.3.4.3.
Prompt Reporting of Medical Device Incidents 
to GSK........................................................................52
7.3.4.4.
Regulatory Reporting Requirements for 
Medical Device Incidents............................................52
7.3.5.
Physical Exams ...........................................................................52
7.3.6.
Vital Signs....................................................................................52
7.3.7.
Documentation of Labour Events.................................................53
7.3.8.
Electrocardiogram (ECG) (Group 2 Only) ....................................53
7.3.9.
Continuous Cardiac Telemetry (Group 2 Only) ............................53
7.3.10.
Device Acceptability Questionnaire (Group 1 Only) .....................53
7.3.11.
Clinical Safety Laboratory Assessments ......................................53
7.4.
Pharmacokinetics .......................................................................................55
7.4.1.
Blood Sample Collection..............................................................55
7.4.2.
Sample Analysis ..........................................................................55
7.5.
Biomarkers .................................................................................................56
7.5.1.
Pharmacodynamic Markers .........................................................56
7.5.2.
Immunogenicity............................................................................56
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
7
8.
DATA MANAGEMENT ...........................................................................................56
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................56
9.1.
Hypotheses.................................................................................................56
9.2.
Sample Size Considerations.......................................................................57
9.2.1.
Sample Size Sensitivity................................................................58
9.2.2.
Sample Size Re-estimation or Adjustment...................................58
9.3.
Data Analysis Considerations .....................................................................58
9.3.1.
Analysis Populations....................................................................58
9.3.2.
Interim Analysis ...........................................................................59
9.4.
Key Elements of Analysis Plan ...................................................................59
9.4.1.
Primary Analyses.........................................................................59
9.4.1.1.
Safety Analysis...........................................................59
9.4.1.2.
Pharmacokinetic Analysis...........................................59
9.4.2.
Secondary Analyses ....................................................................59
9.4.2.1.
Pharmacokinetic Analysis...........................................60
9.4.3.
Exploratory Analyses ...................................................................60
9.4.3.1.
Pharmacokinetic Analysis...........................................60
9.4.3.2.
Device Acceptability Questionnaire ............................60
10. STUDY GOVERNANCE CONSIDERATIONS........................................................60
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............60
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................60
10.3.
Quality Control (Study Monitoring) ..............................................................61
10.4.
Quality Assurance.......................................................................................62
10.5.
Study and Site Closure ...............................................................................62
10.6.
Records Retention......................................................................................62
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................63
11. REFERENCES.......................................................................................................64
12. APPENDICES........................................................................................................66
12.1.
Appendix 1 Abbreviations and Trademarks.................................................66
12.2.
Appendix 2 Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................69
12.3.
Appendix 3 Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................71
12.3.1.
Definition of Adverse Events........................................................71
12.3.2.
Definition of Serious Adverse Events...........................................72
12.3.3.
Definition of Cardiovascular Events .............................................73
12.3.4.
Recording of AEs and SAEs ........................................................74
12.3.5.
Evaluating AEs and SAEs............................................................74
12.3.6.
Reporting of SAEs to GSK...........................................................76
12.4.
Appendix 4  Definition of and Procedures for Documenting Medical 
Device Incidents .........................................................................................77
12.4.1.
Definitions of a Medical Device Incident.......................................77
12.4.2.
Documenting Medical Device Incidents .......................................78
12.5.
Appendix 5 List of Acceptable Methods for Avoiding Pregnancy in 
FRP and Collection of Pregnancy Information ............................................79
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
8
12.5.1.
Group 2, Cohort B Only:  List of Acceptable Non-hormonal 
Methods for Avoiding Pregnancy in Females of 
Reproductive Potential (FRP) ......................................................79
12.5.2.
Collection of Pregnancy Information ............................................79
12.5.3.
References ..................................................................................80
12.6.
Appendix 6 Country Specific Requirements................................................81
12.7.
Appendix 7 Device Acceptability Questionnaire ..........................................82
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
9
1.
PROTOCOL SYNOPSIS FOR STUDY 205920
Rationale
Post-partum hemorrhage is one of the main causes of maternal mortality in the 
developing world. The World Health Organization (WHO) lists oxytocin on its list of 
‘Essential Medicines’ for Humanity as a preventative treatment for post-partum 
hemorrhage; however, because of its cold-chain storage requirement and parenteral 
administration route, high-quality oxytocin is not always available in resource-poor 
settings. GlaxoSmithKline (GSK) has developed a stable, dry-powder formulation of 
oxytocin to address this unmet need, with the goal of reducing post-partum hemorrhage 
morbidity and mortality in these settings.
This study is being conducted to further assess safety and tolerability of inhaled oxytocin, 
and to characterize the pharmacokinetic (PK) profile of inhaled oxytocin 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 inhaled
(IH) or intramuscular (IM) oxytocin as active management of the third stage of labour. 
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.
Objectives/Endpoints
Group 1 – Women in Third Stage of Labour (TSL)
Objectives
Endpoints
Primary

To characterize the pharmacokinetics of 
single doses of IH oxytocin and
10 International Units (I.U.) IM oxytocin in 
women in TSL.

Plasma concentration time profile for IH 
oxytocin and 10 I.U. IM oxytocin.

PK parameters: Maximum observed plasma 
concentration (Cmax), Observed plasma 
concentrations at 10 minutes (min) post-
dose (Cp10), Observed plasma 
concentrations at 20 min post-dose (Cp20), 
Observed plasma concentrations at 30 min 
post-dose (Cp30), Time to Cmax (tmax), 
Area under concentration-time curve (AUC), 
and Terminal phase half-life (t1/2) will be 
calculated as data permit.
Secondary

To evaluate the safety and tolerability of 
inhaled oxytocin.

General safety parameters: adverse events
(AE); absolute values and changes over 
time of vital signs (blood pressure, heart 
rate, respiratory rate, temperature).

To compare pharmacokinetics of IH 
oxytocin to 10 I.U. IM oxytocin in women in 
TSL.

Cmax ,Cp10, Cp20, Cp30, Area under the 
concentration-time curve from time zero 
(pre-dose) to three hours (h) (AUC[0-3h])
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
10
Objectives
Endpoints
will be compared as data permit.
Exploratory 

Pharmacodynamic effect of IH oxytocin
and 10 I.U. IM oxytocin in women in TSL.

Pre and post-delivery haemoglobin. 

Participant feedback regarding ease of 
use, instructions, and perceived ability of 
patients to use the ROTAHALER.

Questionnaire results from participants.
Group 2 – Non-pregnant, non-lactating females of child bearing potential
Objectives
Endpoints
Primary

To evaluate the safety and tolerability of IH 
and IV oxytocin.

General safety parameters: adverse events; 
absolute values and changes over time of 
vital signs (blood pressure, heart rate) and 
12-lead electrocardiogram (ECG) 
parameters (PR, QRS, QT, Corrected QT 
interval [QTc] intervals) from pre-dose 
values. 

Specific respiratory safety parameters: 
adverse respiratory events as monitored by 
spirometry including Forced expiratory 
volume at 1 minute (FEV1.0), respiratory 
rate, and pulse oximetry.

To characterize the pharmacokinetics of 
single doses of IH oxytocin and 5 I.U. IV 
oxytocin.

Plasma concentration time profile for IH 
oxytocin and 5 I.U. IV oxytocin.

PK parameters: Cmax, Cp10, Cp20, Cp30, 
tmax, AUC, Plasma clearance (CL), volume 
of distribution and t1/2 will be calculated as 
data permit.
Exploratory 

To evaluate endogenous plasma oxytocin 
concentrations in non-pregnant females in 
the presence and absence of the combined 
oral contraceptive.

Pre-dose plasma concentrations of 
oxytocin.

To compare the IH pharmacokinetics of 
oxytocin between Cohort A (subjects on 
combined oral contraceptive) and Cohort B 
(subjects using a non-hormonal form of 
contraception).

Cp10, Cp20, Cp30, AUC(0-3h) Cmax, 
AUC(0-3h), Area under the concentration-
time curve from time zero to infinity
(AUC[0-∞]) and t1/2, will be compared as 
data permit.

To compare the IV pharmacokinetics of 

Cmax, AUC, t1/2, CL and Volume of 
distribution (VOD) will be compared as 
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
11
Objectives
Endpoints
oxytocin between Cohort A and Cohort B.
data permit.
Groups 1 and 2 – Women in TSL and Non-pregnant, non-lactating females of child bearing 
potential
Objectives
Endpoints
Exploratory 

To compare pharmacokinetics of IH 
oxytocin between Group 1 and Group 2

Cp10, Cp20, Cp30, AUC(0-3h) Cmax, 
AUC(0-3h) AUC(0-∞), and t1/2 will be 
compared as data permit.
Overall Design
Group 1 – Women in TSL
Group 2 – Non-pregnant, non-lactating females of child bearing potential
Treatment Arms and Duration
Screening
Group 1: All screening assessments to be completed after the 18th
week of pregnancy (based on estimated date of delivery).
Group 2: All screening assessments to be completed within 28 days
prior to the first dose.
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
12
Treatment Session
Group 1: Each subject will take part in 1 dosing session.
Group 2: Each subject will take part in 2 dosing sessions.
Treatment Arms1
Group 1: Subjects will be randomised to receive one of the following 
study treatments:

400 micrograms (mcg) IH oxytocin

10 I.U. IM oxytocin
Group 2: Subjects will receive both of the following study treatments 
over the course of two dosing sessions:

400 mcg IH oxytocin

5 I.U. IV oxytocin
Follow-up
Group 1: Follow Up 1 – Within approximately 24 h post dose.
Group 1: Follow Up 2 –  At least 7 days and no greater than 14 days 
after study drug administration.
Both visits may be conducted in-person or via telephone.
Group 2: At least 7 days and no greater than 21 days after last study 
drug administration.
This visit will be conducted in-person.
If warranted, additional follow-up visits may be scheduled for both 
Groups.
Total Duration
Group 1: Screening after 18th week of pregnancy (i.e. within 168 days of 
1 dosing session) + follow up of 7 - 14 days = approximately 183 days
Group 2: Screening within 28 days of dosing session 1 + 2 dosing 
sessions with a maximum of 14 days between dosing + follow-up of 7 –
21 days = 64 days
Type and Number of Subjects
Sufficient subjects will be screened such that approximately 20 subjects complete all 
study procedures in Group 1, and approximately 10 subjects complete all study 
procedures in Group 2 (approximately 5 in each cohort of Group 2). 
If subjects prematurely discontinue the study, additional replacement subjects may be 
recruited and assigned to the same treatment sequence at the discretion of the Sponsor.
Replacement subjects will complete all study procedures.
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
13
If the PK variability between subjects in Group 1 is higher than expected, it may be 
required to increase the sample size up to a maximum of 10 additional subjects per 
treatment group for inhaled and intramuscular oxytocin. In the event of this, sufficient 
subjects will be screened such that a maximum of 45 subjects complete Group 1.
If a dose adjustment is required in either group, additional subjects may be recruited such 
that a full 10 subjects receive the final IH or IV dose.
Analysis
The primary objective of this study is to characterize pharmacokinetics of IH oxytocin
and IM oxytocin in women in the third stage of labour.
No formal hypotheses will be tested, however, comparisons of interest, within Group 1,
and between Group 1 and Group 2 and between Cohorts A and B in Group 2 will be 
made and the point estimates and corresponding two-sided 90% confidence intervals (CI)
will be presented to provide the range of plausible values for the comparisons. 
2.
INTRODUCTION
Maternal mortality associated with post partum hemorrhage (PPH) is one of the major 
public health problems in the developing world. Approximately half a million women 
worldwide die annually from causes directly related to pregnancy and childbirth, and up 
to one third of these deaths in Africa and Asia are caused by complications as a result of 
PPH [Khan, 2006;WHO, 2010]. A Cochrane Review meta-analysis of the data from 
multiple preventative trials with oxytocin at 10 international units (I.U.) given via the 
intramuscular (IM) route has confirmed this specific uterotonic, and this particular route 
of administration, to be the gold standard prophylactic therapy for PPH [Mousa, 2014]. 
For this reason, the World Health Organization (WHO) has designated oxytocin as one of 
its ‘Essential Medicines’ for humanity [WHOModel List of Essential Medicines 18th list, 
April 2013; WHOModel List of Essential Medicines for Children 4th list, April 2013].
However, in resource-poor settings within the developing world, the 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
[Mousa, 2014]. Although single-use, oxytocin prefilled, syringes for IM injection are 
available in many developing countries (e.g. UNIJECT device), the development of a 
needle-free and self-administered inhaled (IH) oxytocin product, which delivers 
comparable systemic exposure to 10 I.U. IM, would be a major step-change in the 
administration of this life-saving medicine to pregnant women in resource-poor regions 
of the developing world. This would be particularly relevant in rural areas where the 
mother has no routine access to a trained HCP and/or where there is no reliable electricity 
supply to permit refrigerated storage of oxytocin injection vials. 
We have developed a stable, dry-powder formulation of oxytocin to be administered via 
the oral inhaled pulmonary route (compared to 10 I.U. of IM oxytocin) using a 
GlaxoSmithKline (GSK)-manufactured medical device (or device manufactured for GSK 
by a third party) which is a capsule-based inhaler (Modified Air Inlet ROTAHALERTM
Dry Powder Inhaler (DPI) device, hereafter referred to as ROTAHALER). This 
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
14
formulation and delivery method has the potential to be used in settings where effective
oxytocin is currently unavailable to women in the third stage of labour (TSL).
2.1.
Study Rationale
This study will be the second investigation of oxytocin in humans via the IH route, which 
follows the first time in human (FTIH) study, 201558 [GlaxoSmithKline Document 
Number 2015N234711_01, 2015; see Section 2.2.1 for more information on the FTIH 
trial)]. Published literature on the pharmacokinetics (PK) of oxytocin in non-pregnant and 
pregnant women is limited.  There is some evidence to suggest that the metabolic 
clearance of oxytocin may increase during pregnancy; potentially related to degradation 
by the circulating aminopeptidase, oxytocinase, and/or pregnancy related changes in 
hepatic and renal function [Syntocinon Summary of Product Characteristics, Novartis, 
2014; Thornton, 1990].  In addition, endogenous oxytocin plasma concentrations have 
been reported to either increase or remain constant after the delivery of the fetal anterior 
shoulder [Thornton, 1988]. As a result of these pregnancy related changes, systemic 
exposure to oxytocin may differ between healthy non-pregnant women and women in the
TSL for a given dose and route of administration of oxytocin. To further understand the 
effect of pregnancy on the PK of oxytocin, this study will investigate the PK of oxytocin 
in pregnant women in TSL following either IH (400 micrograms [mcg]) or 10 I.U. IM 
(17 mcg) administration. A greater understanding of the PK of oxytocin in TSL will help 
facilitate extrapolation of data obtained in healthy non-pregnant women to women in 
TSL. An additional group of  non-pregnant non-lactating female volunteers will also be 
included as a control group and will receive 400 mcg IH oxytocin and 5 I.U. intravenous 
(IV) oxytocin. This second group will enrol one cohort of subjects taking the combined 
oral contraceptive (COC), and another cohort using a non-hormonal form of 
contraception. This will assess if women need to be on an oral contraceptive vs. other 
methods of birth control in future clinical studies, since although the COC is believed to 
suppress endogenous oxytocin levels the literature is not consistent about this 
observation. As the requirement to be taking the COC makes recruitment more of a 
challenge it will be helpful to know if this inclusion is essential, or if women using non-
hormonal forms of birth control might also have sufficiently low systemic oxytocin levels 
suitable for PK studies.
2.2.
Brief Background
Oxytocin is a nonapeptide which is produced by the hypothalamus and released into the 
systemic circulation by the posterior pituitary gland. Within the brain, oxytocin, like most 
hypothalamic synthesized hormones, acts as a neurotransmitter. In human pregnancy,
during the later phases of the third trimester, increasing circulating levels of oxytocin act 
as a potent endogenous uterotonic which facilitates the initiation of labour. Furthermore, 
a neurohormonal positive feedback loop exists between dilatation of the cervico-vaginal 
canal by fetal passage and the hypothalamus (i.e. Fergusson reflex) which augments 
oxytocin production, thus increasing uterine contraction intensity and frequency which 
facilitates vaginal delivery. However, once the fetus is delivered, plasma oxytocin levels 
rapidly diminish probably due to a combination of increased circulating levels of 
oxytocinase (the principal oxytocin deactivating enzyme), in the plasma, an overall 
reduction in hypothalamic oxytocin synthesis (Figure 1), and a reduction in uterine 
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
15
oxytocin receptor (OTR) density. This oxytocin-depleted, relatively auterotonic, 
physiological environment puts the mother at risk of PPH during the subsequent placental 
delivery phase (i.e. TSL). 
Figure 1
Oxytocin During Physiological Fetal Delivery
Oxytocin receptors are constitutively expressed in smooth muscle cells (SMCs) in the 
uterine myometrium, muscular walls of the bronchi and upper digestive tract, 
myoepithelial cells of the breast duct which are essential for the oxytocin-dependent 
postpartum breast milk let-down reflex, and in different regions of the brain.  Although 
uterine OTR expression increases during the later stages of pregnancy, it is not known 
whether pregnancy increases OTR expression at non-uterine sites, such as the maternal 
brain, where neuronal oxytocin signalling has been implicated in postpartum bonding 
behaviour with the baby. Within the kidney, oxytocin is known to bind to vasopressin 
(V2) receptors, rather than OTR, in the medullary renal collecting duct which triggers an 
antidiuretic effect.
Binding of oxytocin to OTR triggers an increase in intracellular calcium (Ca2+), which is 
partly mediated through oxytocin-dependent up-regulation of prostaglandin F (PGF)2α 
synthesis, which in the uterine myometrium leads to physiological uterine contractions 
during 3rd-stage labour.
More recent research has shown oxytocin to be present in broncho-alveloar lavage fluid 
collected from the respiratory tract of adult humans of both sexes, but oxytocinase 
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
16
expression was not assessed. In an in vivo pharmacology study [Prankerd , 2013] in
pregnant ewes intratracheal insufflation of a dry-powder formulation of oxytocin was 
associated with poor absolute bioavailability (ca 5%), but despite low systemic exposure, 
this still caused a pharmacodynamic response that was manifested by increased electrical 
uterine activity measured by electromyography, probably as a result of increased OTR 
stimulation in the pregnant uterus.
2.2.1.
IH Oxytocin FTIH Study 201558
Study 201558 [GlaxoSmithKline Document Number 2016N277949_00] was the FTIH 
study to evaluate safety, tolerability, and characterize the PK profile of 4 dose strengths 
of IH oxytocin compared to oxytocin 10 I.U. IM. The study enrolled 16 healthy, non-
pregnant, premenopausal female subjects. One subject was withdrawn prior to IH 
oxytocin dosing due to inability to cannulate. Subjects were administered 10 I.U. IM 
oxytocin, IH placebo containing (only) the excipients found in the IH oxytocin 
formulation, and IH oxytocin. A minimum washout period of 48 hours (h) was required 
between each dose of active drug. This dose escalation study evaluated 4 doses of IH 
oxytocin: 50 mcg, 200 mcg, 400 mcg, and 600 mcg. The most frequently reported 
Adverse Event (AE) was headache, and occurred in at least one subject in each treatment 
arm. In general, IH oxytocin was well-tolerated, no safety concerns with IH dosing were 
identified, no clinically significant effect on respiratory parameters were observed, and 
no Serious Adverse Events (SAEs) were reported. The PK profile of the 400 mcg IH 
oxytocin dose was similar to that of 10 I.U. IM, and has been selected for further 
evaluation. See Section 4.5 for further information on PK characteristics.
3.
OBJECTIVES AND ENDPOINTS
3.1.
Group 1: Women in TSL
Objectives
Endpoints
Primary

To characterize the pharmacokinetics of
single doses of IH oxytocin and 10 I.U. IM 
oxytocinin women in TSL.

Plasma concentration time profile for IH 
oxytocin and 10 I.U. IM oxytocin.

PK parameters: Maximum observed plasma 
concentration (Cmax), Observed plasma 
concentrations at 10 minutes (min) post-
dose (Cp10), Observed plasma 
concentrations at 20 min post-dose (Cp20), 
Observed plasma concentrations at 30 min 
post-dose (Cp30), Time to Cmax (tmax), 
Area under concentration-time curve (AUC), 
and Terminal phase half-life (t1/2) will be 
calculated as data permit.
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
17
Objectives
Endpoints
Secondary

To evaluate the safety and tolerability of 
inhaled oxytocin.

General safety parameters: adverse events; 
absolute values and changes over time of 
vital signs (blood pressure, heart rate, 
respiratory rate, temperature).

To compare pharmacokinetics of IH 
oxytocin to 10 I.U. IM oxytocin in women in 
TSL.

Cmax ,Cp10, Cp20, Cp30, Area under the 
concentration-time curve from time zero 
(pre-dose) to three hours (h) (AUC[0-3h])
will be compared as data permit.
Exploratory 

Pharmacodynamic effect of IH oxytocin
and 10 I.U. IM in women in TSL.

Pre and post-delivery haemoglobin. 

Participant feedback regarding ease of 
use, instructions, and perceived ability of 
patients to use the ROTAHALER.

Questionnaire results from participants.
3.2.
Group 2: Non-pregnant, non-lactating females of child 
bearing potential
Objectives
Endpoints
Primary

To evaluate the safety and tolerability of IH 
and IV oxytocin.

General safety parameters: adverse events; 
absolute values and changes over time of 
vital signs (blood pressure, heart rate) and 
12-lead electrocardiogram (ECG) 
parameters (PR, QRS, QT, Corrected QT 
interval [QTc] intervals) from pre-dose 
values. 

Specific respiratory safety parameters: 
adverse respiratory events as monitored by 
spirometry including Forced expiratory 
volume at 1 minute (FEV1.0), respiratory 
rate, and pulse oximetry.

To characterize the pharmacokinetics of 
single doses of IH oxytocin and 5 I.U. IV 
oxytocin.

Plasma concentration time profile for IH 
oxytocin and 5 I.U. IV oxytocin.

PK parameters: Cmax, Cp10, Cp20, Cp30, 
tmax, AUC, Plasma clearance (CL), volume 
of distribution and t1/2 will be calculated as 
data permit.
Exploratory 

To evaluate endogenous plasma oxytocin 
concentrations in non-pregnant females in 

Pre-dose plasma concentrations of 
oxytocin.
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
18
Objectives
Endpoints
the presence and absence of the combined 
oral contraceptive.

To compare the IH pharmacokinetics of 
oxytocin between Cohort A (subjects on 
combined oral contraceptive) and Cohort B 
(subjects using a non-hormonal form of 
contraception).

Cp10, Cp20, Cp30, AUC(0-3h) Cmax, 
AUC(0-3h), Area under the concentration-
time curve from time zero to infinity
(AUC[0-∞]) and t1/2, will be compared as 
data permit.

To compare the IV pharmacokinetics of 
oxytocin between Cohort A and Cohort B.

Cmax, AUC, t1/2, CL and Volume of 
distribution (VOD) will be compared as 
data permit.
3.3.
Groups 1 and 2: Women in TSL and Non-pregnant, non-
lactating females of child bearing potential
Objectives
Endpoints
Exploratory 

To compare pharmacokinetics of IH 
oxytocin between Group 1 and Group 2.

Cp10, Cp20, Cp30, AUC(0-3h) Cmax, 
AUC(0-3h) AUC(0-∞), and t1/2 will be 
compared as data permit.
4.
STUDY DESIGN
4.1.
Overall Design
4.1.1.
Study Schematic Group 1: Women in TSL
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
19
4.1.2.
Study Schematic Group 2: Non-pregnant, non-lactating females 
of child bearing potential
4.1.3.
Study Design Detail
This study will enrol two groups. 
Group 1 - Women in TSL
Group 1 will enrol women with an uncomplicated pregnancy, and main phase procedures 
will occur during TSL. Subjects will be randomized to receive either IH or IM oxytocin 
as active management of TSL. The specific timing of this dose will be as per local 
standard of care.1
Group 2 - Non-pregnant, non-lactating females of child bearing potential
Group 2 will enrol healthy, non-pregnant, non-lactating female subjects of childbearing 
potential, and each subject will participate in 2 dosing sessions. Group 2 will be divided 
into two cohorts: Cohort A will enrol women on a combined oral contraceptive, and 
Cohort B will enrol women who are not using a hormonal form of contraceptive. Group 2 
subjects will receive IH oxytocin at one dosing session, and IV oxytocin at the other
dosing session; the order of IH versus IV oxytocin administration will be randomly 
assigned.
PK samples will be analysed periodically throughout the study duration to enable 
development of the population PK model and derivation of PK parameters via non-
compartmental methods, as data permits.
No formal interim analysis is planned, however, PK samples will be analysed and 
preliminary PK parameters derived following completion of approximately 5 women on
each treatment group: IH, IM in Group 1 and IH in Group 2 Cohort A in order to assess if 
dose escalation is required.  
                                                
1 For information only: Standard of care at proposed clinical site is to administer the oxytocic drug by IM 
injection with the birth of the anterior shoulder, or immediately after the birth of the baby and before the 
cord is clamped and cut.
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
20
4.1.3.1.
Pregnant Females (Group 1)
Subjects will review the study information and if they agree to participate, sign the
informed consent form. For most subjects this is expected to take place at an outpatient
antenatal visit, or additional study-specific screening visit. If a subject meets all 
inclusion/exclusion criteria for the study, she will be eligible for enrolment in the study.
To facilitate recruitment, and provide subjects ample time to consider participation, 
screening may occur any time after 18 weeks gestation (based on estimated date of 
delivery). See time and events (T&E) table in Section 7.1 for details.
4.1.3.2.
Non-pregnant Females (Group 2)
Subjects will review the study information and if they agree to participate, sign the 
informed consent form. If a subject meets all inclusion/exclusion criteria for the study, 
she will be enrolled in the study.
Screening may occur within 28 days prior to randomization for non-pregnant volunteers. 
If a subject falls outside this window prior to randomization and enrolment, she must be 
re-screened. Certain screening procedures may not be required to be repeated; see T&E
(Section 7.1) for details.
Group 2 subjects will take part in 2 dosing sessions, which must be conducted a 
minimum of 48 hours apart. It is recommended that subjects complete Session 2 within 
14 days of Session 1. Subjects will be randomized to receive either IH or IV oxytocin 
during Session 1, and to receive the other treatment during Session 2, such that all 
subjects in Group 2 receive both treatments over the course of the 2 sessions.
4.1.4.
ROTAHALER Inhaler Training
The investigator/designee will be trained to load the ROTACAPS powder capsule into 
the device, prime the dose and instruct the subjects to inhale from the ROTAHALER 
inhaler in the appropriate manner (refer to Section 6.7). Subjects will be instructed by the 
investigator/designee to use an inspiration technique (2 inhalations) that enables maximal 
inhalation of the ROTACAPS powder capsule contents (refer to Section 6.7 for full 
details). This will ensure optimal and consistent drug delivery (full instructions available 
in the Study Reference Manual [SRM]). 
4.1.5.
Length of Stay for All Subjects
Group 1 - Women in TSL
Subjects in Group 1 will be admitted to hospital during labour as part of their routine
care, and will be required to remain inpatient for a minimum of 4 hours after receiving 
any study-related dose of oxytocin. After final PK collection, subjects will be finished 
with study procedures and the main phase of the study will be considered complete. 
Discharge from hospital will be determined by the subject’s medical provider. 
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
21
Group 2 - Non-pregnant, non-lactating females of child bearing potential
Subjects in Group 2 will be admitted to the clinical unit prior to dosing on Day 1 and are 
to remain inpatient until at least 4 hours after dosing. Discharge will occur at the 
discretion of the investigator.
4.2.
Treatment Arms and Duration
Screening
Group 1: All screening assessments to be completed after the 18th
week of pregnancy (based on estimated date of delivery)
Group 2: All screening assessments to be completed within 28 days
prior to the first dose
Treatment Session
Group 1: Each subject will take part in 1 dosing session.
Group 2: Each subject will take part in 2 dosing sessions
Treatment Arms1
Group 1: Subjects will be randomised to receive one of the following 
study treatments:

400 mcg IH oxytocin

10 I.U. IM oxytocin
Group 2: Subjects will receive both of the following study treatments 
over the course of two dosing sessions:

400 mcg IH oxytocin

5 I.U. IV oxytocin
Follow-up
Group 1: Follow Up 1 – Within approximately 24 hours post dose.
Group 1: Follow Up 2 –  At least 7 days and no greater than 14 days 
after study drug administration.
Both visits may be conducted in-person or via telephone. Group 2: At 
least 7 days and no greater than 21 days after last study drug 
administration.
This visit will be conducted in-person.
If warranted, additional follow-up visits may be scheduled for both 
Groups.
Total Duration
Group 1: Screening after 18th week of pregnancy (i.e. within 168 days of
1 dosing session) + follow up of 7 - 14 days = approximately 183 days
Group 2: Screening within 28 days of dosing session 1 + 2 dosing 
sessions with a maximum of 14 days between dosing + follow-up of 7 –
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
22
21 days = 64 days
1 See Section 6.4 for possible dose adjustment to IH oxytocin.
4.3.
Type and Number of Subjects
Sufficient subjects will be screened such that approximately 20 subjects complete all 
study procedures in Group 1, and approximately 10 subjects complete all study 
procedures in Group 2 (approximately 5 in each cohort of Group 2). Refer to Section 6.3
for treatment assignment information.
If subjects prematurely discontinue the study, additional replacement subjects may be 
recruited and assigned to the same treatment at the discretion of the Sponsor.
Replacement subjects will complete all study procedures as outlined in Section 7.1.
If the PK variability between subjects in Group 1 is higher than expected, it may be 
required to increase the sample size up to a maximum of 10 additional subjects per 
treatment group for IH and IM. In the event of this, sufficient subjects will be screened 
such that a maximum of 45 subjects complete Group 1.
If a dose adjustment is required in either group, additional subjects may be recruited such 
that a full 10 subjects receive the final IH or IV dose. See Section 6.4.1 for more details.
4.4.
Design Justification
Group 1 - Women in TSL
This trial uses a randomized, single-dose approach to assign women in TSL to receive 
oxytocin by one of two routes: IM or IH. No placebo is being used, as the current 
standard of care is to administer oxytocin as active management of TSL to prevent PPH.
Group 2 - Non-pregnant, non-lactating females of child bearing potential
A group of non-pregnant, non-lactating women of childbearing potential will receive IH 
and IV oxytocin. This group will be divided into two cohorts: Cohort A will enrol women 
on the combined oral contraceptive. This cohort will serve as a control group, as they 
most closely resemble the population enrolled in the FTIH study. Cohort B will enrol
women using a non-hormonal form of contraception. This comparison group will help 
characterize the effect of oral contraceptives on endogenous oxytocin production and the 
PK profile of oxytocin.
Blinding
This study uses an open-label design.
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
23
4.5.
Dose Justification
Single inhaled doses of oxytocin (50-600 mcg) have been generally well tolerated in the 
FTIH study, with no emerging safety signals, in healthy, non-pregnant, premenopausal 
female subjects (Study 201558) [GlaxoSmithKline Document Number
2016N277949_00; see also Section 2.2.1].  Following inhaled administration oxytocin 
was rapidly absorbed into the systemic circulation (tmax ranging from 0.05 to 0.50 h) 
with systemic exposure (Cmax and AUC) increasing with inhaled dose in an 
approximately proportional manner between 200 and 600 mcg.  In general, the shape of 
the observed oxytocin concentration-time profile following inhaled administration was 
consistent with that following IM administration.
Based on the data from the FTIH study, and assuming that the PK characteristics of IH 
and IM oxytocin are similar in TSL compared with non-pregnant women, the 400 mcg 
inhaled dose is predicted to be an effective dose in women in TSL by ensuring that the 
systemic exposure (Cp10, Cp30 and AUC(0-3 h) following IH dosing is at least that 
following IM administration at the approved dose of 10 I.U. This would be based on the
adjusted geometric mean ratio (90% Confidence Interval [CI]) treatment comparisons for
Cp10, Cp30 and AUC (0-3 h) following 400 mcg IH compared with 10 I.U. IM, namely 
1.10 (0.85,1.43), 1.65 (1.30, 2.09) and 1.27 (1.07, 1.50) respectively in study 201558. 
The PK parameters (Cp10, Cp30 and AUC(0-3 h)) have been selected to ensure onset and 
duration of action of the IH product is at least comparable to IM.
The clinical safety and reported AEs with oxytocin correlates to Cmax, with the Cmax of 
10 I.U. IV representing the upper bounds of what could be considered safe in current 
clinical practice (AEs include flushing, which can cause a transient decrease in blood 
pressure and reflex tachycardia; see the Oxytocin Summary of Product Characteristics for 
more information). The recommendation in the United Kingdom (UK) in clinical practice
has been to reduce the IV dose to 5 I.U. IV or administer by a controlled IV infusion 
[Bolton, 2003].
Minimising the risk of high Cmax levels of oxytocin following the IH administration is 
therefore important. Based on a comparison of  model predicted systemic exposure 
following IV administration to non-pregnant, premenopausal female subjects with 
observed PK profiles following 400 mcg IH oxytocin, it is anticipated that Cmax 
following administration of the 400 mcg dose will not markedly exceed values following 
5 I.U. IV bolus oxytocin (Figure 2). The inclusion of the 5 I.U. IV dose will allow an 
assessment of the potential safety and PK of the inhaled formulation compared to IV 
route of administration.
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
24
Figure 2
Model predicted profiles (median (95%PI)) following IM (10 I.U. and 
IV bolus (5 I.U. administration of oxytocin overlaid with observed 
plasma concentrations of oxytocin following 400 mcg IH oxytocin to 
healthy non-pregnant females
Whilst published literature on the PK of oxytocin in non-pregnant and pregnant women is 
limited there is some evidence to suggest that the metabolic clearance of oxytocin may 
increase during pregnancy. This may be related to degradation by the circulating
aminopeptidase, oxytocinase, and/or pregnancy-related changes in hepatic and renal 
function [Syntocinon, 2014;Thornton, 1990]. In addition, there may be circulating levels 
of endogenous oxytocin in the plasma in women in TSL [Thornton, 1988] and increases 
in blood volume (40-50%) and total body water [Costantine, 2014]. As a result of these 
pregnancy related changes, systemic exposure to oxytocin may differ between healthy 
non-pregnant women and women in TSL for a given dose and route of administration of 
oxytocin. However, given that any pregnancy-related changes in systemic clearance, 
and/or distribution and baseline oxytocin levels, are considered to equally impact on each 
route of administration (IV, IM and IH), it is considered that the relative ratio of IV to IM 
and IH exposure observed in non-pregnant women is likely to be maintained in 
pregnancy. The only exception may be if pregnancy results in marked changes in 
absorption profiles.  However, in a study of inhalation profiles of non-pregnant and 
women in the third stage of labour, the inhalation endpoints appeared to be broadly
similar across the two cohorts and any small changes are not considered to markedly 
impact the delivery of an inhaled product in the third stage of labour [GlaxoSmithKline 

= Observed 400 mcg IH oxytocin plasma concentration in study 201558
5  I.U. IV oxytocin
10 I.U. IM oxytocin
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
25
Document Number 2015N239682_00]. In addition, in a pre-clinical sheep model the ratio 
IH:IV was generally similar in non-pregnant and post-partum ewes (Data on file 
Monash). In the event of enhanced pulmonary absorption in pregnancy, the selected 
400 mcg inhaled dose is predicted to have an approximate 2-fold safe cover for Cmax 
compared with an 10 I.U. IV bolus oxytocin (assumes linearity from 5 -10 I.U. IV).
4.6.
Benefit:Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
GR121619 can be found in the Investigator’s Brochure [GlaxoSmithKline Document 
Number 2015N240749_01] and oxytocin for parenteral administration [Syntocinon, 
2014] . The following section outlines the risk assessment and mitigation strategy for this 
protocol:  
4.6.1.
Risk Assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
Investigational Product (IP) – Inhaled Oxytocin – GR121619 
Bronchospasm, cough and 
dyspnoea, with increased 
theoretical risk in asthmatic 
subjects.
Oxytocin receptors are known 
to be expressed in human 
bronchial smooth muscle and 
up regulated by interleukin
(IL)-13. Therefore, there is a 
hypothetical risk of 
bronchospasm, cough and 
dyspnoea. 
See Section 5.2 for exclusion 
criteria.
The oxytocin summary of 
product characteristics (SPC)
does not list asthma as a 
contraindication to 
administration. 
Symptomatic wheezing may 
be treated with bronchodilator 
at the discretion of the 
investigator.
Forced expiratory volume at 1 
minute (FEV1) monitoring for 
both paradoxical and oxytocin 
induced bronchospasm
Subjects with asthma or 
known pulmonary disease are 
excluded.
Hypotension, tachycardia and 
prolongation of QTc interval
Transient flushing, 
hypotension and tachycardia 
could be observed if the IH PK 
profile is comparable to an IM
or IV oxytocin profile. 
Effects of oxytocin on the 
Ongoing assessments of study 
subjects’ cardiovascular 
function including blood 
pressure (BP), heart rate (HR) 
and ECG.
Only single-dose IH, IM, or 
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
26
Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
Cardiovascular system (CVS)
is unclear and contradictory in 
the literature but IV 
administered oxytocin can 
have a vasodilatory and 
negative inotropic effect in 
humans. Hypotension is 
thought to arise as a result of 
vascular smooth muscle 
relaxation and oxytocin 
binding to cardiac atrial OTR 
which leads to atrial natriuetic 
peptide (ANP) being 
transiently released into the 
systemic circulation. 
Prolongation of the QTc 
interval has been reported at 
the time of caesarean delivery  
with 10 IU IV oxytocin 
administration, rather than IM 
injection, in susceptible 
individuals
5 IU IV bolus injection routes 
of administration will be used 
as study treatment. Telemetry 
and frequent 12-lead ECGs 
will be used to monitor the 
healthy subject cohorts
The 5 IU IV dose of oxytocin is 
the standard dose 
administered at the Rosie 
Maternity hospital post 
Caesarean Section.
IV bolus will be given as a 
slow IV injection over 30 
seconds with the option to 
change to a 5 minute infusion 
if frequent CV adverse effects 
are observed
Exclusion of subjects with long 
QT syndrome, congenital 
cardiac abnormalities, and 
subjects taking anti-arrhythmic 
drugs.
12-lead ECG and telemetry 
covering Cmax in healthy 
subjects administered IH, IM 
and IV oxytocin
Insufficient uterotonic effect
The altered physiology and 
pharmacokinetics of women in 
the TSL my lead to a sub-
optimal dose of inhaled 
oxytocin, resulting in a 
reduced or absent uterotonic 
effect.
In this setting, women in TSL 
and post-delivery are 
intensively observed. 
Therefore, any adverse 
events, including excessive 
blood loss due to unenhanced 
uterine contraction, will be 
managed in accordance with 
current local practice 
guidelines. This will usually 
include administration of 
additional uterotonic agents in 
the first instance.
A follow-up within 24 h of 
discharge by the study team 
will be performed to 
specifically enquire if any late 
bleeding problems had 
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
27
Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
occurred.
An interim analysis of IH and 
IM PK in the TSL group will be 
performed to ensure that the 
PK is in the acceptable range 
for efficacy to be anticipated.
Reference Intervention - IM Oxytocin / IV Oxytocin
Hypotension, tachycardia and 
prolongation of QTc interval
See above section.
See above section.
Subjects receiving the IV 
Oxytocin are required to have 
a systolic BP ≥ 90 Millimeter of 
mercury (mmHg) prior to 
dosing.
Myocardial Ischaemia and ST 
change on ECG
ECG changes consistent with 
myocardial ischaemia have 
been observed with 10 IU 
oxytocin IV bolus in healthy 
women associated with 
hypotension and tachycardia.
Oxytocic cardiovascular effects 
appear to be transient
and persistent myocardial 
damage very rare and 
associated with 10 IU IV.
Study is only using 5 IU IV as a 
slow IV bolus which is 
associated with a short lived 
increase in heart rate and 
reduction in BP but not ST 
changes on ECG in women 
undergoing Caesarean 
Section.
Telemetry and 12-lead ECG 
monitoring in healthy subjects.
Abdominal pain
There is a hypothetical risk 
that IM oxytocin may trigger 
abdominal pain through 
contractions of the non-
pregnant uterus in healthy 
women. 
Given the short half-life of 
oxytocin (approximately 30 
minutes), the duration of a 
single abdominal pain episode 
This is a theoretical possibility 
and not expected to occur. 
Ongoing assessments of study 
subjects’ well-being along with 
vital signs and laboratory
evaluations will be completed 
throughout the duration of the 
study.  
Abdominal pain which is 
clinically uncomfortable to the 
subject may be treated with 
paracetamol at the local 
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
28
Potential Risk of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
would be expected to be brief, 
not sustained and not 
recurrent in the absence of 
further oxytocin administration.
Furthermore, no abdominal 
pain was observed in the FTiH 
study.
investigator’s discretion.  
4.6.2.
Immunogenicity Risk
The oxytocin material used in the inhaled product is produced synthetically and so does 
not include any other protein/cell impuritites which might be intrinsically immunogenic.
A review of the risk of immunogenicity of oxytocin and/or excipients was considered as 
part of the non-clinical safety studies but as the lymphoid tissues were not deemed to be 
pathologically affected and there were difficulties in generating a suitable assay, anti-
drug antibodies (ADAs) were not measured. The FTIH study involved repeat dosing, and
did not reveal any unexpected differences in PK which may have signalled the 
development of ADAs.
Oxytocin is an endogenous human peptide with a short systemic half-life and there are no 
reports of immunogenicity with oxytocin via parenteral administration. Thus it is 
considered unlikely that inhaled delivery of a small molecular weight (MW) peptide 
molecule like oxytocin would invoke an immunogenic response.
However, blood samples will be retained for anti-oxytocin antibody analysis if required 
in the event of an anaphylactic / allergic reaction (refer to Section 5.4.2) or other 
observation which would suggest an immunogenic effect.
4.6.3.
Benefit Assessment and Overall Benefit:Risk Conclusion
Oxytocin has been administered to postpartum women for over 40 years via both the IM 
and IV routes, and has an established safety profile for each of these routes of 
administration. The FTIH study into IH oxytocin revealed no safety concerns for any of 
the subjects who received this new formulation. There are no direct clinical benefits to 
the volunteers within this study. The main contribution to their participation will be in the 
further development of a therapy (i.e. inhaled oxytocin) which may be ultimately used as 
a preventative therapy for postpartum haemorrhage in women during TSL in resource 
poor settings. It is fundamental to the project to clearly understand the PK of oxytocin 
following IH and IM administration to women in TSL in order to confirm the dose level 
that delivers a PK profile comparable to that of 10 I.U. IM (i.e. current standard of care in 
the developed world setting). Taking into account the measures taken to minimize risk to 
subjects participating in this study, the potential risks identified in association with 
oxytocin (IH IM, and IV) are justified by the supporting data and overall benefit 
anticipated for women’s health worldwide.
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
29
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the investigator brochure for 
GR121619 [GlaxoSmithKline Document Number 2015N240749_01] and SPC for 
oxytocin administered IM or IV.
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
5.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
AGE
All Groups: 
1. Between 18 and 40 years of age inclusive, at the time of signing the informed 
consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
All Groups: 
2. 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.
Note: At time of randomisation, investigator or designee should confirm the subject 
feels fit and well, and is safely able to participate in the study.
3. Subject clinical chemistry and haematology values within an acceptable range for the 
population recruited and not of abnormal clinical significance.
Note: Additional laboratory tests beyond those which are done as part of routine care
(e.g. 28-week visit) are not required for subjects in Group 1. The 
investigator/designee may use his/her judgment in deciding whether to perform 
additional laboratory assessments to determine eligibility.
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. 
4. Adequate peripheral venous access for cannulation.
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
30
Group 1 Only: 
5. Currently pregnant, with an uncomplicated pregnancy as determined by the 
investigator or designee.
6. Estimated date of delivery within 24 weeks of screening.
7. Planned spontaneous vaginal birth and considered by investigator at low risk for PPH.
8. Planned birth in between the 37th and 42nd week of pregnancy.
Note: Subjects can only receive study treatment if the onset of labour is between
approximately 37 and 42 weeks estimated gestation. If a subject goes into labour 
before or after this timeframe, she should not receive study treatment.
9. Women who qualify for oxytocin as appropriate for active management of TSL and 
who agree to have active management.
Group 2 Only:
10. ECG normal, or abnormal and not clinically significant.
11. FEV1 >80% of predicted.
12. Systolic blood pressure ≥90 mmHg.
WEIGHT
Group 2 Only:
13. Body mass index (BMI) within the range 18 – 32 Kilogram (kg)/ meter (m)2
(inclusive).
SEX
14. 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:
a.
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.
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
31
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:
a.
Is of reproductive potential and has been using the same non-hormonal 
contraceptive method (see List of Accep+ Nonhormonal Methods for Avoiding 
Pregnancy in Females of Reproductive Potential [see Appendix 5] from 3 months
prior to the first dose of study medication and until the follow-up contact.
b.
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.
c.
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.  
INFORMED CONSENT
All Groups: 
15. Capable of giving signed informed consent as described in Section 10.2 which 
includes compliance with the requirements and restrictions listed in the consent form 
and in this protocol.
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
32
5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL) 
All Groups: 
1. Postmenopausal as defined by gynaecological history.
2. Chronic lung condition of any etiology including asthma, Chronic obstructive 
pulmonary disease (COPD), emphysema, interstitial lung disease or active 
Tuberculosis (TB).
      Note: Childhood asthma (resolved) is not exclusionary.
3. Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones).
4. Blood pressure >140 systolic or >90 diastolic.
Group 1 Only:
5. Females with planned Caesarean Section.
6. Females with significant medical complications as determined by investigator.
Group 2 Only:
7. Currently breastfeeding or lactating.
8. QT duration corrected for heart rate by Fridericia’s formula (QTcF)
>450 milliseconds (msec).
9. 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%).
10. Subjects with highly-active or symptomatic gynaecological disorders (such as large 
symptomatic fibroids).
CONCOMITANT MEDICATIONS
All Groups: 
11. Prescription or non-prescription drugs not approved by the investigator (refer to 
Section 6.12.1 for approved medications).
12. Oxytocin for any reason (including, but not limited to, induction or augmentation of 
labour) prior to administration of study-related oxytocin.
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
33
RELEVANT HABITS
All Groups: 
13. 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 (~240 milliliter [ml]) of beer, 1 glass (125 ml) of 
wine or 1 (25 ml) measure of spirits. 
14. 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.
a.
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.
CONTRAINDICATIONS 
All Groups: 
15. 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).
16. Participation in another clinical trial, which in the opinion of the investigator, 
jeopardizes the subject’s safety or study outcomes.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
All Groups: 
17. Where participation in the study would result in donation of blood or blood products 
in excess of 500 mL within 56 days.
18. 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).
19. Exposure to more than four new chemical entities within 12 months prior to the first 
dosing day.
Group 2 Only: 
20. Presence of hepatitis B surface antigen or positive hepatitis C antibody test result.
21. A positive Human Immunodeficiency Virus (HIV) antibody test.
22. A positive pre-study drugs of abuse test (not explained by diet or approved 
concomitant medications).
23. A positive alcohol breath test.
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
34
5.3.
Screening/Baseline/Run-in Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomized. In order to ensure transparent reporting of screen 
failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and respond to queries from Regulatory authorities, a minimal 
set of screen failure information is required including Demography, Screen Failure 
details, Eligibility Criteria, and Serious Adverse Events (see Section 7.3.1.4).
5.3.1.
Re-screening
If a subject fails screening, she may be rescreened one additional time.
5.4.
Withdrawal/Stopping Criteria
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as 
soon as possible. 

The site must counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or should 
continue in the study. 

In cases where the subject is deemed ‘lost to follow up’, the investigator or 
designee must make every effort to regain contact with the subject (where 
possible, 3 telephone calls and if necessary a certified letter to the subject’s last 
known mailing address or local equivalent methods). These contact attempts 
should be documented in the subject’s medical record. 

Should the subject continue to be unreachable, only then will she be considered to 
have withdrawn from the study with a primary reason of “Lost to Follow-up”. 
A subject may withdraw from study treatment at any time at her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioural or 
administrative reasons. If a subject withdraws from the study, she may request 
destruction of any samples taken, and the investigator must document this in the site 
study records. 
5.4.1.
Pregnancy Complication Stopping Criteria (Group 1 Only)
Any complication requiring clinical intervention which no longer allows for a vaginal 
delivery or safe completion of study procedures will be cause for immediate withdrawal 
from the study. Investigators should continue to manage any pregnancy complication per 
local guidelines, and record any associated AE/SAE or concomitant medication. This 
includes the need for additional uterotonic administration.
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
35
5.4.2.
Anaphylaxis Stopping Criteria
Clinical signs or symptoms of anaphylaxis / allergic reaction to IH oxytocin will be an 
automatic stopping criterion. Stored serum samples will be analysed for anti-oxytocin 
antibody analysis for affected subjects as detailed in Section 7.5.2. The samples will be 
analysed for Immunoglobulin E (IgE)/ Immunoglobulin G (IgG) anti-oxytocin titres 
biochemical markers of mast cell degranulation (e.g. tryptase) in the event of an 
anaphylactic / allergic reaction occurring.  
5.4.3.
QTc Stopping Criteria (Group 2 Only)

The same QT correction formula must be used for each individual subject to 
determine eligibility for and discontinuation from the study.  This formula may 
not be changed or substituted once the subject has been enrolled.

For example, if a subject is eligible for the protocol based on QTcF, then QTcF
must be used for discontinuation of this individual subject as well.

Once the QT correction formula has been chosen for a subject’s eligibility, the 
same formula must continue to be used for that subject for all QTc data being 
collected for data analysis.  Safety ECGs and other non-protocol specified 
ECGs are an exception.  

The QTc should be based on single or averaged QTc values of triplicate 
electrocardiograms obtained over a brief (e.g., 5-10 minute) recording period.  
QTcF is proposed to be used for this study. If a subject meets either of the following 
bulleted criterion below, she will be withdrawn from the study.  

QTcF > 500 msec,

Change from baseline: Increase in QTcF >60 msec.
Withdrawal of subjects is to be based on an average QTcF value of triplicate ECGs.  If an 
ECG demonstrates a prolonged QT interval, then obtain 2 more ECGs over a brief period 
of time and then use the averaged QTcF values of the 3 ECGs to determine whether the 
subject should be withdrawn from the study.
5.4.4.
Blood Pressure Stopping Criteria (Group 2 Only)
Subjects with a pre-dose systolic blood pressure of <90 mm Hg should not be dosed until 
systolic blood pressure is ≥90 mm Hg.
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
36
5.4.5.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
Study treatment will be discontinued for a subject if liver chemistry stopping criteria are 
met:
Phase I Liver Chemistry Stopping Criteria – Liver Stopping Event Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
*INR value not applicable to subjects on anticoagulants 
ALT ≥3xULN 
No
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments  section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in
Appendix 2.
5.5.
Subject and Study Completion
A completed subject is one who has completed all phases of the study including the 
follow-up visit(s).
6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design. Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments.
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
37
Table 1
Study Treatment Information
Study Treatment
Product name:
Oxytocin  (GR121619
capsule for inhalation)
Oxytocin
Oxytocin
Formulation 
description:
Powder Blend for Inhalation
Solution for Infusion
Solution for Infusion
Dosage form:
Inhalation powder, hard 
capsule
1ml ampoule
1ml ampoule
Unit dose 
strengths:
400 mcg
200 mcg
5 I.U./mL, or 10 
I.U./mL
5 I.U./mL, or 10 
I.U./mL
Route of 
Administration
For oral inhalation
Intramuscular (thigh)
Intravenous
Dosing 
instructions:
Capsule unit dose 
dispensed by ROTAHALER 
inhaler 
Standard 
intramuscular injection
Adminster as a 30-
second bolus
Physical 
description:
Colourless and clear 
HPMC capsules 
containing a white 
powder
Colourless and clear 
sterile solution
Colourless and clear 
sterile solution
Device:
ROTAHALER inhaler
Needle/Syringe 
Intravenous Infusion 
Device
6.2.
Medical Devices
The GSK manufactured medical device (or device manufactured for GSK by a third 
party) provided for use in this study is a high airflow resistance capsule-based inhaler 
(Modified Air Inlet ROTAHALER DPI device).
Instructions for medical device use are provided in Section 6.7. Further details on use of 
the device are provided in the SRM.
GSK medical device incidents, including those resulting from malfunctions of the device, 
must be detected, documented, and reported by the investigator throughout the study –
see Section 12.4.
6.3.
Treatment Assignment
Subjects in Group 1 will be assigned to one of two treatments (IH oxytocin or IM 
oxytocin). Subjects in Group 2 will receive both IH and IV oxytocin in separate dosing 
sessions in a cross over design. Treatment assignment in Group 1, and order of dosing in 
Group 2, will be done in accordance with the randomization schedule generated by 
Clinical Statistics, prior to the start of the study, using validated internal software.
A description of each regimen is provided in Table 2:
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
38
Table 2
Treatment Assignment
Group
Session
Treatment 1
Number of Subjects2
Group 1
1
400 mcg IH oxytocin
10
10 I.U. IM Oxytocin
10
Group 2, Cohort A
1
400 mcg IH oxytocin or 
5 I.U. IV oxytocin
5
2
400 mcg IH oxytocin or 
5 I.U. IV oxytocin
Group 2, Cohort B
1
400mcg IH oxytocin or 
5 I.U. IV oxytocin
5
2
400 mcg IH oxytocin or 
5 I.U. IV oxytocin
1 See Section 6.4 for possible dose adjustment.
2 See Section 9.2.2 for possible adjustment to subject numbers to Group 1
6.4.
Planned Dose Adjustments
There is no plan to adjust the dose of IH oxytocin in this study. However, if systemic 
exposure seen in 400 mcg IH oxytocin in TSL subjects is less than expected and not 
comparable to the 10 I.U. IM profile, a consideration to escalate the dose to 600 mcg may 
be made as detailed in Section 6.4.1.
For Group 2, if an exaggerated physicological response is seen with the IV dose, such as 
increased heart rate and decreased blood pressure, then consideration will be given to 
changing to a 5-minute infusion.
6.4.1.
Dose Adjustment
The decision to adjust the IH dose in women in TSL will be determined by the GSK 
study team based on Group 1 PK data in TSL and Group 2, Cohort A PK data.  After a 
minimum of n=5 women in TSL have received 400 mcg IH and 10 I.U. IM and a 
minimum of n=5 non-pregnant women on the combined oral contraceptive (Group 2, 
Cohort A) have received 400 mcg IH oxytocin, PK samples will be analysed and PK 
parameters derived (including but not limited to Cp10, Cp30 and AUC(0-3h)).  
The median Cp10 will be estimated for women in TSL for each dose group (IH or IM) 
and the median ratio (IH/IM; n=5) derived.  Based on the estimated ratio, the dose of IH 
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
39
oxytocin to be administered to women in TSL will either remain at 400 mcg or be 
increased per the criteria described in Table 3:
Table 3
Dose Adjustment Decision Criteria
Median Ratio IH/IM
Decision
< 0.5
Consider study halt and review data.
≥ 0.5 to <0.7
Consider dose adjust to 600 mcg IH in women in TSL.
≥ 0.7
Continue with 400 mcg IH dose.
If a decision to increase the dose is made, additional subjects will be enrolled into Group 
1 such that 10 subjects receive the 600 mcg IH oxytocin dose.
6.5.
Blinding
This will be an open-label study.
6.6.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
6.7.
Preparation/Handling/Storage/Accountability

The investigator/designee will be trained to load the ROTACAPS powder capsule 
into the device, prime the dose and instruct the subjects to inhale from the 
ROTAHALER inhaler in the appropriate manner. The investigator/designee will 
always load and prime the ROTACAPS powder capsule in the device before the
subject self-administers an IH oxytocin dose

All subjects will be taught by the investigator/designee to use the device in the 
“full-tilt” position and to use a “fast and deep” inspiration technique per 
inhalation, to achieve two rapidly consecutive maximal inhalations for IH 
oxytocin administration. This will ensure optimal and consistent treatment 
delivery. For subjects, the training session will be at any time during the 28-day 
Screening Period, as deemed appropriate by the investigator/designee. 

ROTACAPS powder capsules should be kept in their sealed packaging at room 
temperature (15-25°Centigrade [C]). The packaging should only be opened 
immediately prior to use.

ROTAHALER inhaler devices will be supplied in bulk and unlabelled to the site.
After dosing all ROTAHALER inhaler devices will be uniquely labelled and 
retained after each dosing session. The devices (which should not be opened up at 
the clinical study site) will be stored until further instruction from the sponsor is 
received.
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
40

The investigator or designee must confirm appropriate temperature conditions 
have been maintained during transit for all study treatment received and any 
discrepancies are reported and resolved before use of the study treatment.

Only subjects enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment.  All study 
treatments must be stored in a secure environmentally controlled and monitored 
(manual or automated) area in accordance with the labelled storage conditions 
with access limited to the investigator and authorized site staff. 

The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (i.e. receipt, reconciliation and final disposition records).  

Further guidance and information for final disposition of unused study treatment 
are provided in the SRM.

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff. Take adequate precautions to 
avoid direct eye or skin contact and the generation of aerosols or mists. In the case 
of unintentional occupational exposure notify the monitor, Medical Monitor 
and/or GSK study contact.

A Material Safety Data Sheet (MSDS)/equivalent document describing 
occupational hazards and recommended handling precautions either will be 
provided to the investigator, where this is required by local laws, or is available 
upon request from GSK.
6.8.
Compliance with Study Treatment Administration
Per ROTACAPS powder capsule dose, each subject will be asked to inhale twice from 
the ROTAHALER inhaler to reduce the possibility of inadequate administration due to a 
single poor inhalation manoeuvre. If failure of the ROTACAPS powder capsule 
actuation is suspected by the investigator (i.e. due to failure to open the capsule during 
device priming), the investigator is permitted to rechallenge the individual with a 
maximum of two further administrations at the same dose using the same capsule. 
When subjects are dosed at the site, they will receive study treatment directly from the 
investigator or designee, under medical supervision.  The date and time of each dose 
administered in the clinic will be recorded in the source documents.  The dose of study 
treatment and study subject identification will be confirmed at the time of dosing by a 
member of the study site staff other than the person administering the study treatment.  
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
41
Group 1 – Women in TSL
Following randomisation and any pre-dose procedures, subjects will receive a single 
study treatment as active management of TSL. The specific timing of this dose will be as 
per local standard of care.2
Administration will be documented in the source documents and reported in the Case 
report form (CRF).
Group 2 – Non-pregnant, non-lactating females of child bearing potential
Following randomisation and all pre-dose procedures, subjects will receive two doses of
oxytocin, separated by at least 48 hours. Randomisation will determine the order in which 
the IH and IV formulation is administered. 
Administration will be documented in the source documents and reported in the Case 
report form (CRF).
6.9.
Treatment of Study Treatment Overdose
For this study, any dose of the following compounds will be considered an overdose
when administered as part of study procedures: 

IH oxytocin > 400 mcg 
o
If study dose is increased to 600 mcg, then an overdose will be considered 
any dose > 600 mcg.

Oxytocin > 10 I.U. IM

Oxytocin > 5 I.U. IV
Note: Group 1 subjects may receive additional doses of oxytocin (IM or IV) when 
required as part of their general care and as clinically indicated. Additional doses of 
oxytocin will be recorded as concomitant medications, as will any related AEs.
General medical management consists of supportive care. 
GSK does not recommend specific treatment for an overdose.
In the event of a study drug overdose the investigator or treating physician should:
1.
Contact the Medical Monitor immediately.
                                                
2 For information only: Standard of care at proposed clinical site is to administer the oxytocic drug by IM 
injection with the birth of the anterior shoulder, or immediately after the birth of the baby and before the 
cord is clamped and cut.
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
42
2. Closely monitor the subject for adverse events (AEs)/serious adverse events (SAEs) 
and laboratory abnormalities until oxytocin can no longer be detected systemically (at 
least 4 hours).
3. Obtain an additional plasma sample for pharmacokinetic (PK) analysis if requested 
by the Medical Monitor (determined on a case-by-case basis).
4. Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the subject.
6.10.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study because either only healthy volunteers are eligible for study participation, or there 
are other treatment options are available.
The investigator is responsible for ensuring that consideration has been given to the post-
study care of postpartum subjects’ medical conditions, whether or not GSK is providing 
specific post-study treatment.
6.11.
Lifestyle and/or Dietary Restrictions
6.11.1.
Meals and Dietary Restrictions
There are no dietary restrictions for subjects in either cohort.
6.11.2.
Caffeine and Alcohol
Group 1 – Women in TSL

There are no restrictions for Group 1.
Group 2 – Non-pregnant, non-lactating females of child bearing potential

During each dosing session, subjects will abstain from ingesting caffeine- or 
xanthine-containing products (e.g., coffee, tea, cola drinks and chocolate) for 
12 hours prior to the start of dosing until collection of the final pharmacokinetic 
sample during each session. 

During each dosing session, subjects will abstain from alcohol for 12 hours prior to 
the start of dosing until collection of the final pharmacokinetic sample during each 
session. 
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
43
6.11.3.
Activity
Group 1 – Women in TSL
There are no activity restrictions.
Group 2 – Non-pregnant, non-lactating females of child bearing potential
Subjects will abstain from strenuous exercise for 48 hours prior to each blood collection 
for clinical laboratory tests.  Subjects may participate in light recreational activities 
during studies (e.g., watch television, read).
6.12.
Concomitant Medications and Non-Drug Therapies
6.12.1.
Permitted Medications and Non-Drug Therapies
Paracetamol, at doses equal to or below the maximum recommended daily dose, is 
permitted for use during the screening period or at any time deemed necessary by the 
investigator or subject. All concomitant medication related to routine care during 
pregnancy and delivery is allowed (including pain relief [e.g. gas/air mixture] and 
epidural), and other medication may be considered on a case by case basis by the 
investigator or designee (in consultation with the Medical Monitor if required). 
The start and stop time of any concomitant medications administered at any time during 
labour (including nitrous oxide gas/air mixtures) should be documented on the CRF.
6.12.2.
Prohibited Medications and Non-Drug Therapies
Use of the following medications will result in immediate withdrawal of subject:

Oxytocin for any reason (including, but not limited to, induction or augmentation 
of labour) before or after administration of study-related oxytocin.
7.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct.
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Table in Section 7.1.
The following points must be noted: 

If assessments are scheduled for the same nominal time, THEN the assessments 
are recommended to occur in the following order:
1. 12-lead ECG
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
44
2. vital signs
3. blood draws
Note: The timing of the assessments should allow the blood draw to occur at the 
exact nominal time.

The timing and number of planned study assessments, including safety, 
pharmacokinetic, pharmacodynamic, immunogenic or other assessments may be 
altered during the course of the study based on newly available data (e.g., to 
obtain data closer to the time of peak plasma concentrations) to ensure 
appropriate monitoring. 

The change in timing or addition of time points for any planned study 
assessments must be documented in a Note to File which is approved by the
relevant GSK study team member and then archived in the study sponsor and 
site study files, but this will not constitute a protocol amendment. 

The Institutional Review Board (IRB)/ Independent Ethics Committee (IEC)
will be informed of any safety issues that require alteration of the safety 
monitoring scheme or amendment of the Informed Consent Form. 

No more than 500 mL of blood will be collected over the duration of the study, 
including any extra assessments that may be required.
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
45
7.1.
Time and Events Table
7.1.1.
Time and Events Table – General Overview
Group 1
Study Day
Procedure
Screening4
Main Phase 
Follow – Up 1 (approx. 24 
hours post dose)
Follow – Up 2 (7-14 days post dose)
Informed Consent and Demography
X
Brief Physical Examination
X
Medical history (incl. substance abuse)
X
Inhaler device training / education session
X
Laboratory assessments1
X
Vital signs2
X
X
Pharmacokinetic blood sample
X
Oxytocin Administration (IM/IH)
X
Full blood count
X
Labour Events Documentation
X
Device acceptability questionnaire3
X
Prior / concomitant medication review
X
X
X
X
AE review
------------------------------ continuous review ------------------------------------------------------
SAE review
 ---------------------------------------------------------------- continuous review  -------------------------------------------------
1.
Only required if done as part of routine care. Additional study-specific laboratory assessments not required.
2.
Includes blood pressure, heart rate, temperature, respiratory rate
3.
Only to be used when randomized to IH oxytocin
4.
To be completed after 18th week of pregnancy (based on estimated date of delivery).
 
 
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
46
Group 2
Study Day
Procedure
Screening5
Main Phase
Follow - Up (7-21
days post 
dose)
Informed Consent and Demography
X
Brief Physical Examination
X
X
Medical history
X
Pregnancy test 
X
X
Alcohol Breath Test, Smokerlyzer, Urine Drug Screen1 
X
X
HIV, Hep B and Hep C screen2
X
Inhaler device training / education session
X
Laboratory assessments (including liver chemistries)
X
X
Immunogenicity sample
X
X
12-lead ECG
X4
X
CardiacTelemetry
X
Vital signs3
X
X
Spirometry (FEV-1)4
X
X
Admission to unit
X
Pharmacokinetic blood sample
X
X
Oxytocin Administration (IH or IV)
X
Prior / concomitant medication review
X
X
X
AE review
------ continuous review -----------------------------------
SAE review
 ----------------------------------- continuous review  --------------------------------
Discharge from unit
X
1.
Smokerlyzer at PI/designee discretion if smoking history in question.
2.
If test otherwise performed within 3 months prior to first dose of study treatment, repeat testing at screening is not required.
3.
Includes blood pressure, heart rate, temperature, respiratory rate, and SpO2.
4.
Performed in triplicate.
5.
To be completed within 28 days of randomization.
 
 
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
47
7.1.2.
Time and Events – Main Phase Procedures
Group 1
Time post dose
Procedure
Pre-
dose
3 min
5 min
10 
min
15 min
20 
min
30 
min
1 hr
2 hr
2.5 hr
3 hr
4 hr
Vital signs1
X
X
Pharmacokinetic blood sample
X2
X
X
X
X
X
X
X
X
X
X
X
Prior  medication review
X
Concomitant  medication review
---------------------------------------------------------- continuous review  ---------------------------------------------------
AE review
--------------------------------------------------------- continuous review  ---------------------------------------------------
SAE Review
------------------------------------------------------------------------ continuous review  -----------------------------------------------------
Device Acceptability Questionnaire3
X
Full Blood Count
X
X
1.
Includes blood pressure, heart rate, temperature, respiratory rate
2.
Predose PK sample to be taken immediately prior to administration of study treatment
3.
Only to be administered when randomized to IH oxytocin
 
 
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
48
Group 2 – Sessions 1 and 2
Time Post Dose
Procedure
Pre-
dose
2 
min
3 
min
5 
min
8 
min
10 
min
15 
min
20 
min
30 
min
45 
min
1 hr
1.5 hr
2 hr
2.5 hr
3 hr
4 hr
Brief Physical Exam
X
Pregnancy Test
X
Alcohol Breath Test, Smokerlyzer, Urine 
Drug Screen1
X
Vital signs2
X
X
X
X
X
X
12-lead ECG
X
X
X
X
X
X
X
CardiacTelemetry
---------------------------------------------Continuous-----------------------------------------------
Spirometry3
X
X
Pharmacokinetic blood sample
X5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Immunogenicity Sample
X
Laboratory assessments (including liver 
chemistries)
X
X
Prior medication review
X
Concomitant medication review
------------------------------------------------------------ continuous review  ----------------------------------------------------
AE review
----------------------------------------------------------- continuous review  ----------------------------------------------------
SAE Review
------------------------------------------------------------------------- continuous review  ----------------------------------------------------
Discharge from unit4
X
1.
Smokerlyzer at Principal Investigator (PI)/designee discretion if smoking history in question.
2.
Includes blood pressure, heart rate, temperature, respiratory rate, and SpO2
3.
FEV 1.0 will be performed in triplicate at each time point. Record all three values on source document, and record best effort in eCRF.
4.
Discharge at PI discretion, no sooner than 4-hours post-dose.
5.
3 pre-dose samples: approximately 1 hr pre-dose, 30 minutes pre-dose, and 15 minutes pre-dose
 
 
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
49
7.2.
Screening and Critical Baseline Assessments
Cardiovascular medical history/risk factors (as detailed in the CRF) will be assessed at 
screening.
The following demographic parameters will be captured: year of birth, sex, race and 
ethnicity.
Medical/medication/family history will be assessed as related to the inclusion/exclusion 
criteria listed in Section 5.  
Procedures conducted as part of the subject’s routine clinical management [e.g. brief 
physical exam, laboratory assessments] and obtained prior to signing of informed consent 
may be utilized for Screening or baseline purposes provided the procedure meets the 
protocol-defined criteria and has been performed within the timeframe defined in the 
Time and Events Schedule.
7.3.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1).  Additional time points for safety tests (such as vital signs, physical exams 
and laboratory safety tests) may be added during the course of the study based on newly 
available data to ensure appropriate safety monitoring.
7.3.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 3 (see Section 12.3).
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 
7.3.1.1.
Time period and Frequency for collecting AE and SAE information

Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK 
product will be recorded from the time a subject consents to participate in the 
study up to and including any follow-up contact. 

AEs will be collected from the start of Study Treatment until the follow-up 
contact (see Section 7.3.1.3), at the timepoints specified in the Time and Events 
Table (Section 7.1).

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the CRF or appropriate source document.

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in
Appendix 3.

Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects. However, if the investigator learns of any SAE, including a death, at any 
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
50
time after a subject has been discharged from the study, and she considers the 
event reasonably related to the study treatment or study participation, the 
investigator must promptly notify GSK.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Appendix 3.
7.3.1.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:

“How are you feeling?” 

“Have you had any (other) medical problems since your last visit/contact?”

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?” 
7.3.1.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All SAEs, and non-serious AEs of special interest 
(as defined in Section 4.6.1) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up 
(as defined in Section 5.4). Further information on follow-up procedures is given in
Appendix 3.
7.3.1.4.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK of SAEs related to study treatment (even 
for non- interventional post-marketing studies) is essential so that legal obligations and 
ethical responsibilities towards the safety of subjects and the safety of a product under 
clinical investigation are met. 
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, IRB/ IEC and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the Investigators Brochure (IB) and will notify the IRB/IEC, if appropriate according to 
local requirements.
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
51
7.3.2.
Adverse Events of Special Interest (AESI)
Any problem related to the delivery of the placenta or postpartum haemorrhage should be 
documented as an AESI using the appropriate case report form (CRF). 
7.3.3.
Pregnancy
Group 2 Only:

Details of all pregnancies will be collected after the start of dosing and until 
follow-up.

If a pregnancy is reported then the investigator should inform GSK within 2 
weeks of learning of the pregnancy and should follow the procedures outlined in
Appendix 5.
7.3.4.
Medical Device Incidents (Including Malfunctions)
GSK medical devices are being provided for use in this study.  In order to fulfil 
regulatory reporting obligations worldwide the investigator is responsible for the 
detection and documentation of events meeting the definitions of incident or malfunction 
that occur during the study with such devices. 
The definition of a Medical Device Incident can be found in Section 12.4.
NOTE: Incidents fulfilling the definition of an AE/SAE will also follow the processes 
outlined in Section 12.3.6 and Appendix 3 of the Protocol. 
7.3.4.1.
Time Period for Detecting Medical Device Incidents

Medical device incidents or malfunctions of the device that result in an incident will 
be detected, documented and reported during all periods of the study in which the 
GSK medical devices are available for use. 

If the investigator learns of any incident at any time after a subject has been 
discharged from the study, and such incident is reasonably related to a GSK medical 
device provided for the study, the investigator will promptly notify GSK.
NOTE: The method of documenting Medical Device Incidents is provided in 
Appendix 4.
7.3.4.2.
Follow-up of Medical Device Incidents

All medical device incidents involving an AE will be followed until resolution of the 
event, until the condition stabilizes, until the condition is otherwise explained, or 
until the subject is lost to follow-up (as defined in Section 5.4). This applies to all 
subjects, including those withdrawn prematurely. 

The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as may be indicated to elucidate as completely as practical the nature 
and/or causality of the incident.
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
52

New or updated information will be recorded on the originally completed form with 
all changes signed and dated by the investigator.
7.3.4.3.
Prompt Reporting of Medical Device Incidents to GSK

Medical device incidents will be reported to GSK within 24 hours once the 
investigator determines that the event meets the protocol definition of a medical 
device incident.

Facsimile transmission of the "Medical Device Incident Report Form" is the 
preferred method to transmit this information to the Medical Monitor or SAE 
coordinator.

The same individual will be the contact for receipt of medical device reports and 
SAEs.

In the absence of facsimile equipment, notification by telephone is acceptable for 
incidents, with a copy of the "Medical Device Incident Report Form" sent by 
overnight mail. 
7.3.4.4.
Regulatory Reporting Requirements for Medical Device Incidents

The investigator will promptly report all incidents occurring with any GSK medical 
device provided for use in the study in order for GSK to fulfil the legal responsibility 
to notify appropriate regulatory bodies and other entities about certain safety 
information relating to medical devices being used in clinical studies.

The investigator, or responsible person according to local requirements (e.g., the 
head of the medical institution in Japan), will comply with the applicable local 
regulatory requirements relating to the reporting of incidents to the IRB/IEC.
7.3.5.
Physical Exams

A brief physical examination will include, at a minimum assessments of the lungs, 
cardiovascular system, and abdomen (liver and spleen if palpable).

Investigators should pay special attention to clinical signs related to previous 
serious illnesses
7.3.6.
Vital Signs
Vital signs will be measured in semi-supine position after 5 minutes rest and will 
include temperature, systolic and diastolic blood pressure, pulse rate and respiratory 
rate (unless otherwise specified in T&E). 
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
53
7.3.7.
Documentation of Labour Events
The time that the following labour events occurred will be collected:

Time of crowning

Time of birth

Time of delivery of placenta
7.3.8.
Electrocardiogram (ECG) (Group 2 Only)

Triplicate 12-lead ECGs will be obtained at screening as listed in Section 7.1.1.

Single 12-lead ECGs will be obtained at each timepoint as listed in Section 7.1.2
using an ECG machine that automatically calculates the heart rate and measures 
PR, QRS, QT, and QTc intervals.  Refer to Section 5.4.3 for QTc withdrawal 
criteria and additional QTc readings that may be necessary.

At all single 12-lead ECG time-points if QTc >450, repeat twice and take average 
reading.
7.3.9.
Continuous Cardiac Telemetry (Group 2 Only)
Continuous cardiac telemetry will be started at least 10 minutes pre-dose (to obtain a 
stable reading) and continue until at least the first hour after IV and IH placebo / 
oxytocin administration and then as deemed necessary by the investigator.  Full 
disclosures will be reviewed in detail and the review maintained as part of the 
subject’s source documents.
7.3.10.
Device Acceptability Questionnaire (Group 1 Only)
A device acceptability questionnaire will be administered to subjects in Group 1
following use of the ROTAHALER (Appendix 7).
7.3.11.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as required by Section 7.1 and defined in
Table 4, must be conducted in accordance with the Laboratory Manual, and Protocol 
Time and Events Schedule. Laboratory requisition forms must be completed and samples 
must be clearly labelled with the subject number, protocol number, site/centre number, 
and visit date. Details for the preparation and shipment of samples will be provided by 
the laboratory and are detailed in the SRM. Reference ranges for all safety parameters 
will be provided to the site by the laboratory responsible for the assessments.
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the CRF.
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
54
Refer to the SRM for appropriate processing and handling of samples to avoid duplicate 
and/or additional blood draws.
All study-required laboratory assessments will be performed by a central laboratory, apart 
from:

Tests performed as part of routine care in Group 1.
NOTE: Local laboratory results are only required in the event that the central laboratory
results are not available in time for either a treatment and/or response evaluation to be 
performed. Additionally if the local laboratory results are used to make either a treatment 
or response evaluation, the results must be entered into the CRF.
Subjects in Group 1 are not required to undergo additional laboratory assessments beyond 
those done as part of their routine care. However, the investigator/designee may conduct 
any of the tests listed in Table 4 in order to confirm eligibility. Haematology, clinical 
chemistry, and additional parameters to be tested in all Group 2 subjects are listed in 
Table 4.
Table 4
Protocol Required Safety Laboratory Assessments
Laboratory
Assessments
Parameters
Haematology
Platelet Count
RBC Indices:
White Blood Cell (WBC) count 
with Differential:
Red Blood Cell (RBC)
Count
Mean 
Corpuscular 
Volume 
(MCV)
Neutrophils
Hemoglobin
Mean 
Corpuscular 
Hemoglobin 
(MCH)
Lymphocytes
Hematocrit
Monocytes
Eosinophils
Basophils
Clinical 
Chemistry 1
Blood Urea 
Nitrogen 
(BUN)
Potassium
Aspartate 
aminotransferase 
(AST) (SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
Alanine 
aminotransferase 
(ALT) (SGPT)
Total Protein
Glucose 
Calcium
Alkaline phosphatise
Albumin
Other 
Screening 
Tests
HIV
Hepatitis B (HBsAg)
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
55
Hepatitis C (Hep C antibody)
Follicle Stimulating Hormone (FSH) and estradiol (as needed in women 
of suspected non-child bearing potential only)
Alcohol and drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines)
Serum or urine hCG Pregnancy test (Group 2 only) 2
NOTES :
1.
Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up 
Assessments after liver stopping or monitoring event are given in Section 12.2 and
Appendix 2
2.
Local urine testing will be standard for the protocol unless serum testing is required 
by local regulation or ethics committee.
All laboratory tests with values that are considered clinically significantly abnormal 
during participation in the study should be repeated until the values return to normal or 
baseline.  If such values do not return to normal within a period judged reasonable by the 
investigator, the etiology should be identified and the sponsor notified.
7.4.
Pharmacokinetics
7.4.1.
Blood Sample Collection
Blood samples for pharmacokinetic (PK) analysis of oxytocin will be collected at the 
time points indicated in Section 7.1, Time and Events Table.  The actual date and time of 
each blood sample collection will be recorded.  The timing of PK samples may be altered 
and/or PK samples may be obtained at additional time points to ensure thorough PK 
monitoring.  
At each time point, 4 mL of blood will be collected into K2 or K3 
Ethylenediaminetetraacetic acid (EDTA) tubes and stored on ice for up to 2 hours prior to 
centrifugation in a refrigerated centrifuge. Further details regarding collection/shipping 
procedures are provided in the SRM
7.4.2.
Sample Analysis
Plasma analysis will be performed under the control of PTS-DMPK, GlaxoSmithKline, 
the details of which will be included in the SRM. Concentrations of oxytocin will be 
determined in plasma samples using the currently approved bioanalytical methodology.
Raw data will be archived at the bioanalytical site (detailed in the SRM).
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
56
7.5.
Biomarkers
7.5.1.
Pharmacodynamic Markers
Pre and post-delivery full blood counts will be collected from Group 1 subjects to assess 
for a change in haemoglobin levels.
7.5.2.
Immunogenicity
Blood samples will be taken at the time points specified in the Time and Events Table 
(Section 7.1) to assess the immunogenicity of oxytocin.
Pre- and post-dose samples will be retained in the event that further immunologic tests 
are deemed necessary to support observations of unexpected anaphylaxis/
hypersensitivity, and / or a PK profile for IH oxytocin in any Dosing Session which is 
regarded by the GSK Study Team to be reasonably attributable to circulating anti-
oxytocin antibodies.
Details of the collection / shipping procedures are provided in the SRM.
8.
DATA MANAGEMENT

For this study subject data will be entered into GSK defined CRFs, transmitted 
electronically to GSK or designee and combined with data provided from other 
sources in a validated data system.  

Management of clinical data will be performed in accordance with applicable 
GSK standards and data cleaning procedures to ensure the integrity of the data, 
e.g., removing errors and inconsistencies in the data.

Adverse events and concomitant medications terms will be coded using MedDRA 
(Medical Dictionary for Regulatory Activities) and an internal validated 
medication dictionary, GSKDrug.  

CRFs (including queries and audit trails) will be retained by GSK, and copies will 
be sent to the investigator to maintain as the investigator copy.  Subject initials 
will not be collected or transmitted to GSK according to GSK policy.
9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
9.1.
Hypotheses
The primary objective of this study is to characterize the pharmacokinetics of 400 mcg IH 
oxytocin and 10 I.U. IM oxytocin in women in TSL.
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
57
No formal hypotheses will be tested, however, the following comparisons are of interest,
within Group 1, (IH vs. IM) and between Group 1 and Group 2 (IH oxytocin comparison 
in TSL vs. non-pregnant women on oral contraception) and between Cohorts A and B in 
Group 2 (IH and IV oxytocin comparison in non-pregnant women in the presence and 
absence of oral contraceptive). For each PK endpoint of interest, point estimates and 
corresponding two-sided 90% confidence intervals will be constructed for the ratio of the 
geometric mean of the test treatment to the geometric mean of the reference treatment, 
μ(test)/μ(reference) to provide the range of plausible values for the comparisons of 
interest. 
9.2.
Sample Size Considerations
A sufficient number of subjects will be enrolled to ensure approximately 20 evaluable 
subjects (10 in each of the IM and IH groups) complete all dosing and critical 
assessments in Group 1, as well as 5 subjects in each cohort in Group 2. Whilst sample 
size is based on feasibility, precision calculation was also done to approximate the 
estimate of the expected half width of 90% CI around point estimate for the main 
comparison of interest (IH oxytocin to 10 I.U. IM oxytocin in women in TSL) using a t-
test. 
Table 5 illustrates the associated 90% CIs for the mean treatment ratios, assuming 
between subject SDs of 0.424 and 0.601 (SDs are based on log transformed data) for 
AUC (0-3h) and CP10 respectively, for the comparisons of interest detailed in Section 
9.1. Calculations are based on a symmetric two-tailed procedure on the loge scale and a 
type I error rate of 10%. These values represent estimates of the between-subject 
variability observed in the FTIH study 201558 [GlaxoSmithKline Document Number 
2016N277949_00].
Table 5
Estimated 90% Confidence Intervals for Treatment Ratios
N
Parameter
Between
Subject 
Standard 
Deviation 
(SD)
Estimated 
Treatment 
Ratio
Precision
Expected 
90% CI
10
AUC(0-3h)
0.424
(CVb=44.35%)
1
38.30%
(0.72, 1.38)
10
Cp10
0.601 
(Cvb=65.96%)
1
58.20%
(0.63,1.58)
The precision estimates are deemed acceptable to assess the study objectives at this stage
of development.
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
58
9.2.1.
Sample Size Sensitivity
Considering the variability of AUC(0-3h) and Cp10, Table 6 shows the scenarios for 
different sample size and the precision estimates for IH vs. IM in Group 1.
Table 6
Estimated 90% Confidence Intervals for Treatment Ratios for Sample 
Size Sensitivity
%CVb
N
Precision
Assuming ratio 1, the 
confidence interval
44.35%
5
61.90%
(0.61, 1.61)
15
29.80%
(0.77,1.29)
65.96%
5
98.00%
(0.50, 1.98)
15
44.80%
(0.69, 1.44)
20
37.40%
(0.72,1.37)
85.35%*
5
131.90%
(0.43, 2.31)
10
75.90%
(0.56, 1.75)
15
57.60%
(0.63, 1.57)
20
48.00%
(0.67, 1.48)
* 85.35%  was the largest between subject CV for AUC(0-10) observed for FTIH study 201558 
[GlaxoSmithKline Document Number:2016N277949_00]
9.2.2.
Sample Size Re-estimation or Adjustment
No formal sample size re-estimation is planned for this study. However, if the variability 
is high (for example approaching 85%) then the sample size for Group 1 may be 
increased to a maximum of 10 additional subjects per treatment arm (IH and IM only).
9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations
Enrolled Population

Defined as all subjects who were enrolled for the trial 
irrespective of whether they were randomized or not and 
for whom a record exist on the study database. This 
population will be used for summarizing screening failure 
reasons.
All Subjects Population

Comprise of subjects who receive at least one dose of 
study medication. This population will be used for the 
study population and safety displays.
Pharmacokinetic 
Population

Subjects in the ‘All Subjects’ population for whom a 
pharmacokinetic sample was obtained and analysed.  PK 
population will be the population for reporting PK data.
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
59
9.3.2.
Interim Analysis
No formal interim analysis is planned. However, PK samples will be analysed and 
preliminary PK parameters derived following completion of 5 women on each of the 
following treatments: 400 mcg IH and 10 I.U. IM to women in TSL (Group 1) and 
400 mcg IH to non-pregnant women on the combined  oral contraceptive (Group 2 
Cohort A).  Based on the PK profiles the dose of IH oxytocin to be administered to 
women in TSL will either remain at 400 mcg or be increased (to 600 mcg) (See Section 
6.4.1). This decision will be made by the study team in collaboration with the Principal 
Investigator.
9.4.
Key Elements of Analysis Plan
9.4.1.
Primary Analyses
9.4.1.1.
Safety Analysis
Safety data will be presented in tabular and/or graphical format and summarized 
descriptively according to GSK’s Integrated Data Standards Library (IDSL) standards.
9.4.1.2.
Pharmacokinetic Analysis
Pharmacokinetics analysis will be the responsibility of the Clinical Pharmacokinetics 
Modeling & Simulation department within GlaxoSmithKline.  Plasma oxytocin
concentration-time data will be analyzed by non-compartmental methods with 
WinNonlin V6.3 or greater.  Calculations will be based on the actual sampling times 
recorded during the study. 
From the plasma concentration-time data, the following pharmacokinetic parameters will 
be determined, as data permit: maximum observed plasma concentration (Cmax), time to 
Cmax (tmax), area under the plasma concentration-time curve [AUC(0-3h) and AUC(0-
∞)], the last observed quantifiable concentration (Clast), time of the last quantifiable 
concentration (tlast), Cp10, Cp20, Cp30 (observed plasma concentrations at 10, 20 and 
30minutes post-dose, respectively), plasma clearance (CL; IV only), volume of
distribution (V; IV only) and apparent terminal phase half-life (t1/2).  Other PK 
parameters may also be determined.
Pharmacokinetic data will be presented in graphical and/or tabular form and will be
summarized descriptively. All pharmacokinetic data will be stored in the Archives, 
GlaxoSmithKline Pharmaceuticals, R&D. 
If appropriate, a population PK analysis may also be conducted, in addition the oxytocin 
plasma concentration-time data may be merged with historical data and analysed as part 
of a population PK meta-analysis.
9.4.2.
Secondary Analyses
Statistical analyses of the PK parameter data will be performed by, or under direct 
auspices of Clinical Statistics, QSci.
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
60
9.4.2.1.
Pharmacokinetic Analysis
For evaluating pharmacokinetic treatment comparisons within Group 1 IH vs. IM, point 
estimates and corresponding two-sided 90% confidence intervals will be computed using 
a mixed effect model. Loge-transformed PK parameters will be analysed using the model 
with a fixed effect term for treatment and a random effect term for subject.
Further details of analysis and reporting of PK data will be given in the Reporting 
Analysis Plan (RAP).
9.4.3.
Exploratory Analyses
9.4.3.1.
Pharmacokinetic Analysis
For evaluating pharmacokinetic treatment comparisons between Group 1 and Group 2 
(IH oxytocin comparison in TSL vs. non-pregnant women on the combined oral 
contraceptive), and within Group 2 between Cohorts A and B (IH and IV oxytocin 
comparison in non-pregnant women in the presence and absence of oral contraceptive),
point estimates and corresponding two-sided 90% confidence intervals will be computed 
using a mixed effect model. Loge-transformed PK parameters will be analysed using the 
model with a fixed effect term for treatment and a random effect term for subject.
Further details of analysis and reporting of PK data will be given in the Reporting 
Analysis Plan (RAP).
9.4.3.2.
Device Acceptability Questionnaire
In Group 1, subject satisfaction with device, including instructions and ease of use, will 
be assessed. The questionnaire is located in Section 12.7
10.
STUDY GOVERNANCE CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and the guiding principles of the current 
version of the Declaration of Helsinki.  This includes, but is not limited to, the following:
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
61

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable

Obtaining signed informed consent

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol 
deviations to IRB/IEC)

GSK will provide full details of the above procedures, either verbally, in writing, 
or both.

Signed informed consent must be obtained for each subject prior to participation 
in the study

The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.  

Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.  

Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities.  In this situation, 
written approval of the clinical protocol should state that approval of optional 
assessments is being deferred and the study, with the exception of the optional 
assessments, can be initiated.
10.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK monitors will contact the site prior to the start of the study to review with the 
site staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and GSK requirements.  

When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the CRF will 
serve as the source document.

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRFs <or> entered in the eCRFs that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study; also current medical 
records must be available.
GSK will monitor the study and site activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
62

Study is conducted in accordance with the currently approved protocol and any 
other study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents.
10.4.
Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK 
may conduct a quality assurance assessment and/or audit of the site records, and 
the regulatory agencies may conduct a regulatory inspection at any time during or 
after completion of the study. 

In the event of an assessment, audit or inspection, the investigator (and institution) 
must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all 
relevant documents and to allocate their time and the time of their staff to discuss 
the conduct of the study, any findings/relevant issues and to implement any 
corrective and/or preventative actions to address any findings/issues identified.
10.5.
Study and Site Closure

Upon completion or premature discontinuation of the study, the GSK monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and GSK Standard 
Operating Procedures.

GSK reserves the right to temporarily suspend or prematurely discontinue this 
study at any time for reasons including, but not limited to, safety or ethical issues 
or severe non-compliance. For multicenter studies, this can occur at one or more 
or at all sites.  

If GSK determines such action is needed, GSK will discuss the reasons for taking 
such action with the investigator or the head of the medical institution (where 
applicable).  When feasible, GSK will provide advance notification to the 
investigator or the head of the medical institution, where applicable, of the 
impending action.

If the study is suspended or prematurely discontinued for safety reasons, GSK will
promptly inform all investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study. GSK will also promptly 
inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action.  

If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation.
10.6.
Records Retention

Following closure of the study, the investigator or the head of the medical 
institution (where applicable) must maintain all site study records (except for 
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
63
those required by local regulations to be maintained elsewhere), in a safe and 
secure location.  

The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review 
in conjunction with assessment of the facility, supporting systems, and relevant 
site staff.  

Where permitted by local laws/regulations or institutional policy, some or all of 
these records can be maintained in a format other than hard copy (e.g., microfiche, 
scanned, electronic); however, caution needs to be exercised before such action is 
taken.  

The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, 
including re-generating a hard copy, if required.  Furthermore, the investigator 
must ensure there is an acceptable back-up of these reproductions and that an 
acceptable quality control process exists for making these reproductions.

GSK will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements.  The minimum retention time 
will meet the strictest standard applicable to that site for the study, as dictated by 
any institutional requirements or local laws or regulations, GSK 
standards/procedures, and/or institutional requirements. 

The investigator must notify GSK of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of 
ownership of the records in the event the investigator is no longer associated with
the site.
10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy.
A manuscript will be progressed for publication in the scientific literature if the results 
provide important scientific or medical knowledge.
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
64
11.
REFERENCES
Costantine MM. Physiologic and pharmacokinetic changes in pregnancy. Frontiers in
Pharmacology. 2014. Volume 5. Article 65: 1-5. 
GlaxoSmithKline Document Number 2015N234711_01. Study ID 201558. Clinical 
Pharmacology Study Protocol. A single centre, single blind study to investigate the 
safety, tolerability and pharmacokinetics of single doses of oxytocin (GR121619) 
administered via an inhaled route in healthy female volunteers. 16-NOV-2015.
GlaxoSmithKline Document Number 2015N239682_00. Study ID 201248 – Clinical
Pharmacology Study Report. An enabling study to compare the inhalation profiles of 
women in the third stage of labour to those of non-pregnant female volunteers and to 
explore whether there are any  differences which could impact the delivery of an inhaled 
medicinal product, 16-OCT-2016.
GlaxoSmithKline Document Number 2015N240749_01. GR121619 Investigator's 
Brochure, AUG-2015.  
GlaxoSmithKline Document Number 2016N277949_00. Study ID 201558 – Clinical 
Study Report.. 30-JUN-2016.
Khan KS, Wojdyla D, Say L, Gülmezoglu AM, Van Look PF. WHO analysis of causes 
of maternal death: a systematic review. Lancet. 2006;367(9516):1066-74.
Mousa HA, Blum J, Abou El Senoun G, Shakur H, Alfirevic Z. Treatment for primary 
postpartum haemorrhage. Cochrane Database of Systematic Reviews. 2014, Issue 2. Art. 
No.: CD003249. DOI: 10.1002/14651858.CD003249.pub3.
Prankerd RJ, Nguyen T, Ibrahim JP, et al. Pulmonary Delivery of an Ultra-Fine Oxytocin 
Dry Powder Formulation: Potential for Treatment of Postpartum Haemorrhage in 
Developing Countries. 2013; PLoS One. Vol 8: 12: Article e82965
Syntocinon Summary of Product Characteristics, Novartis, 2014
Thornton S, Davison JM, Baylis PH. Effect of human pregnancy on metabolic clearance 
rate of oxytocin. American Physiological Society. 1990. 0363-6119: R21-R24.
Thornton S, Davison JM, Baylis PH. Plasma oxytocin during third stage of labour: 
comparison of natural and active management.BMJ. 1988. Volume 297:167-169.
WHO Model List of Essential Medicines 18th list (April 2013). Available at: 
http://www.who.int/medicines/publications/essentialmedicines/en/. Accessed May 26, 
2015.
WHO Model List of Essential Medicines for Children 4th list (April 2013). Available at: 
http://www.who.int/medicines/publications/essentialmedicines/en/. Accessed May 26, 
2015.
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
65
WHO, UNICEF, UNFPA. The World Bank World Health Organization (WHO) Press. 
Trends in Maternal Mortality: 1990 to 2008: Estimates Developed by WHO, UNICEF, 
UNFPA and The World Bank. Geneva: WHO, 2010.
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
66
12.
APPENDICES
12.1.
Appendix 1
Abbreviations and Trademarks
Abbreviations
ADAs
Anti drug antibodies
AE
Adverse Event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase (SGPT)
ANP
Atrial natriuretic peptide
AST
Aspartate aminotransferase (SGOT)
AUC
Area under concentration-time curve
AUC(0-3)
Area under the concentration-time curve from time zero 
(pre-dose) to three hours
AUC(0-∞)
Area under the concentration-time curve from time zero to 
infinity
BMI
Body mass index
BP
Blood pressure
BUN
Blood urea nitrogen
C
Centigrade
Ca2+
Intracellular calcium
CI
Confidence Interval
CL
Plasma clearance
Clast
last observed quantifiable concentration
Cmax
Maximum observed plasma concentration
COC
Combined oral contraceptive
CONSORT
Consolidated Standards of Reporting Trials
COPD
Chronic obstructive pulmonary disease
Cp10
Observed plasma concentrations at 10 minutes post-dose
Cp20
Observed plasma concentrations at 20 minutes post-dose
Cp30
Observed plasma concentrations at 30 minutes post-dose
CPK
Creatinine phosphokinase
CRF
Case report form
CVS
Cardiovascular system
DMPK
Drug Metabolism and Pharmacokinetics
DPI
Dry powder inhaler
ECG
Electrocardiogram
EDTA
Ethylenediaminetetraacetic acid
FDA
Food and Drug Administration
FEV1.0
Forced expiratory volume at 1 minute
FRP
Females of Reproductive Potential
FSH
Follicle Stimulating Hormone
FTIH
First time in human
g
Gram
GCP
Good Clinical Practice
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
67
GSK
GlaxoSmithKline
h/hr
Hour(s)
HBsAg
Hepatitis B surface antigen
hCG
Human chorionic gonadotropin
HCP
Health care professional
HIV
Human Immunodeficiency Virus
HPLC
High Performance Liquid Chromatography
HR
Heart rate
I.U.
International units
IB
Investigators Brochure
ICH
International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for 
Human Use
IDSL
Integrated Data Standards Library
IEC
Independent Ethics Committee
IgG
Immunoglobulin G
IgM
Immunoglobulin M
IH
Inhaled
IL
Interleukin
IM
Intramuscular
INR
International normalized ratio
IP
Investigational product
IRB
Institutional Review Board
IV
Intravenous
Kg
kilogram
LDH
Lactate dehydrogenase
m
Meter
mcg
Micrograms
MCH
Mean Corpuscular Hemoglobin
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
ml
Millilitre
mmHg
Millimeter of mercury
MSDS
Material Safety Data Sheet
Msec
Milliseconds
MW
Molecular weight
OTR
Oxytocin receptor
PGF
Prostaglandin F
PI
Principal Investigator
PK
Pharmacokinetics
PPH
Post-partum haemorrhage
QTc
Corrected QT interval
QTcF
QT duration corrected for heart rate by Fridericia’s formula
RAP
Reporting and Analysis plan
RBC
Red blood cells
SAE
Serious Adverse Event
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
68
SD
Standard deviation
SMC
Smooth muscle cells
SPC
Summary of product characteristics
SpO2
Peripheral capillary oxygen saturation
SRM
Study reference manual
T&E
Time and event
t1/2
Terminal phase half-life
TB
Tuberculosis
tmax
Time to Cmax
TSL
Third stage of labour
UK
United Kingdom
ULN
Upper Limit of Normal
V
Vassopresin
VOD
Volume of distribution
WBC
White blood cells
WHO
World Health Organization
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
ROTACAPS
Syntocinon
ROTAHALER
Uniject
WinNonlin
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
69
12.2.
Appendix 2
Liver Safety Required Actions and Follow up 
Assessments
Phase I Liver chemistry stopping criteria have been designed to assure subject safety and 
to evaluate liver event etiology (in alignment with the Food and Drug Administration
[FDA] premarketing clinical liver safety guidance).
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Phase I liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria – Liver Stopping Event
ALT-absolute
ALT≥3xULN
If  ALT≥3xULN  AND bilirubin1,2 2xULN (>35% direct bilirubin) or  INR >1.5, 
Report as an SAE.
See additional Actions and Follow Up Assessments listed below
Required Actions and Follow up Assessments following Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue study treatment 

Report the event to GSK within 24 hours

Complete the liver event CRF, and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries 
resolve, stabilise, or return to within baseline 
(see MONITORING below)
MONITORING:
If ALT≥3xULN AND bilirubin 2xULN  or INR 
>1.5

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24 
hrs

Monitor subjects twice weekly until liver 
chemistries resolve, stabilise or return to 
within baseline

A specialist or hepatology consultation is 

Viral hepatitis serology3

Blood sample for pharmacokinetic (PK) 
analysis, obtained within 4h of the last 
dose4

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on 
the concomitant medications report form 
including acetaminophen, herbal remedies, 
other over the counter medications.

Record alcohol use on the liver event 
alcohol intake case report form
If ALT≥3xULN AND bilirubin 2xULN  or 
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
70
recommended
If ALT≥3xULN AND bilirubin < 2xULN  and 
INR ≤1.5:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24-
72 hrs

Monitor subjects weekly until liver 
chemistries resolve, stabilize or return to 
within baseline
INR >1.5:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG or gamma 
globulins).

Serum acetaminophen adduct High 
Performance Liquid Chromatography
(HPLC) assay (quantifies potential 
acetaminophen contribution to liver injury 
in subjects with definite or likely 
acetaminophen use in the preceding week 
[James, 2009]. NOTE: not required in 
China.

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured, which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); International normalized ratio (INR) measurement is not required 
and the threshold value stated will not apply to subjects receiving anticoagulants
3.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody
4.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
71
12.3.
Appendix 3
Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.3.1.
Definition of Adverse Events
Adverse Event Definition:

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.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae).

The signs and symptoms and/or clinical sequelae resulting from lack of efficacy will 
be reported if they fulfil the definition of an AE or SAE.  Also, "lack of efficacy" or 
"failure of expected pharmacological action" also constitutes an AE or SAE.
Events NOT meeting definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 
condition.
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
72

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
12.3.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
a.
Results in death
b.
Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c.
Requires hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting.  Complications that occur during hospitalization are 
AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d.
Results in disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
73
and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday 
life functions but do not constitute a substantial disruption
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition.  These should also be considered 
serious.

Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse
g.
Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** > 1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick.  If fractionation is unavailable and ALT 3xULN 
and total bilirubin 2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.
12.3.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
74

Deep venous thrombosis/pulmonary embolism

Revascularization
12.3.4.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the CRF

It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to GSK in lieu of completion of the GSK, AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK.  In this instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to 
submission of to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.
12.3.5.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. - an AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
75
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled 
out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of his/her assessment.

For each AE/SAE the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK.  However, it is very important 
that the investigator always make an assessment of causality for every event 
prior to the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.

The investigator is obligated to assist.  This may include additional laboratory tests 
or investigations, histopathological examinations or consultation with other health 
care professionals.

If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide GSK with a copy of any post-mortem findings, 
including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
76
12.3.6.
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data collection 
tool

If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and fax it to the Medical Monitor

Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.

The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of 
the SAE.

After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) will be taken off-line to prevent the entry of new data or changes to 
existing data

If a site receives a report of a new SAE from a study subject or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, the site can report this information on a paper SAE form or to the Medical 
Monitor or the SAE coordinator by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
77
12.4.
Appendix 4
Definition of and Procedures for 
Documenting Medical Device Incidents
12.4.1.
Definitions of a Medical Device Incident
The detection and documentation procedures described in this protocol apply to all GSK 
medical devices provided for use in the study (see Section for the list of GSK medical 
devices).
Medical Device Incident Definition:

Incident – Any malfunction or deterioration in the characteristics and/or performance 
of a device, as well as any inadequacy in the labeling or the instructions for use 
which, directly or indirectly, might lead to or might have led to the death of a 
patient/user/other persons or to a serious deterioration in their state of health.

Not all incidents lead to death or serious deterioration in health.  The non-occurrence 
of such a result might have been due to other fortunate circumstances or to the 
intervention of health care personnel.
It is sufficient that:

an incident associated with a device happened and

the incident was such that, if it occurred again, might lead to death or a serious 
deterioration in health.
A serious deterioration in state of health can include:

life-threatening illness

permanent impairment of body function or permanent damage to a body structure

a condition necessitating medical or surgical intervention to prevent one of the above 

fetal distress, fetal death or any congenital abnormality or birth defects
Examples of incidents

a patient, user, care giver or professional is injured as a result of a medical device 
failure or its misuse

a patient’s treatment is interrupted or compromised by a medical device failure

misdiagnosis due to medical device failure leads to inappropriate treatment

a patient’s health deteriorates due to medical device failure
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
78
12.4.2.
Documenting Medical Device Incidents
Medical Device Incident Documenting:

Any medical device incident occurring during the study will be documented in the 
subject’s medical records, in accordance with the investigator’s normal clinical 
practice, and on the appropriate form.

For incidents fulfilling the definition of an AE or an SAE, the appropriate AE/SAE 
CRF page will be completed as described in Appendix 3.

The form will be completed as thoroughly as possible and signed by the investigator 
before transmittal to GSK.

It is very important that the investigator provides his/her assessment of causality to 
the medical device provided by GSK at the time of the initial report, and describes 
any corrective or remedial actions taken to prevent recurrence of the incident.

A remedial action is any action other than routine maintenance or servicing of a 
device where such action is necessary to prevent recurrence of an incident. This 
includes any amendment to the design to prevent recurrence.
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
79
12.5.
Appendix 5
List of Acceptable Methods for Avoiding 
Pregnancy in FRP and Collection of Pregnancy Information
12.5.1.
Group 2, Cohort B Only: List of Acceptable Non-hormonal
Methods for Avoiding Pregnancy in Females of Reproductive 
Potential (FRP)
The list does not apply to FRP with same sex partners or for subjects 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.
1.
Nonhormonal Intrauterine device or 
2.
Male condom combined with vaginal spermicide
3.
Male partner sterilization with documentation of azoospermia prior to the female 
subject's entry into the study, and this male is the sole partner for that subject 
[Hatcher, 2011]. The documentation on male sterility can come from the site 
personnel’s: review of subject’s medical records, medical examination and/or semen 
analysis, or medical history interview provided by her or her partner.
These allowed 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 these methods of contraception.
12.5.2.
Collection of Pregnancy Information
Group 2 Only

Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study

Information will be recorded on the appropriate form and submitted to GSK within 2 
weeks of learning of a subject's pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on mother and infant, which will be 
forwarded to GSK.  Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date. 

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
80

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK 
as described in Section 12.3. While the investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.
Any female subject who becomes pregnant while participating 

will discontinue study medication or be withdrawn from the study.
12.5.3.
References
Bolton TJ, Randall K, Yentis SM. Effect of the Confidential Enquiries into Maternal 
Deaths on the use of Syntocinon at Caesarean section in the UK. Anaesthesia 2003(58-
3):277-9.
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, Policar MS, 
editors. Contraceptive Technology. 20th edition. Atlanta, Georgia: Ardent Media, Inc., 
2011: 50. Table 3-2.
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
81
12.6.
Appendix 6
Country Specific Requirements
No country-specific requirements exist.
 
2019N402257_00


2016N281575_00
CONFIDENTIAL
205920
82
12.7.
Appendix 7
Device Acceptability Questionnaire
Device Acceptability Questionnaire
Please answer the following questions regarding your use of the ROTAHALER inhaler
for oxytocin.
1. Did you feel confident you had received the medicine?
Yes
No
Neutral
Decline to answer
2. Did you find the inhaler easy to use?
Yes
No
Neutral
Decline to answer
3. Did you prefer to have your medicine from an inhaler instead of an injection?
Yes
No
Neutral
Decline to answer
4. Do you feel using this inhaler is an acceptable way to administer the medicine?
Yes
No
Neutral
Decline to answer
Thank you for answering these questions.
 
2019N402257_00

SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
205920
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan (for Group 1 reporting) for 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.
Compound Number 
:
GR121619
Effective Date 
:
08-MAY-2019
Description:

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 205920.

This RAP is intended to describe the Group 1 analyses required for the study. 

This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverable for Group 1.
Author(s):
Author
Date
Lead
NA
Senior Statistician (FPD, Biostatistics)
Co-Author
Statistics Director (FPD, Biostatistics)
Copyright 2019 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
2019N402257_00
PPD
PPD


CONFIDENTIAL
The GlaxoSmithKline group of companies
205920
2
RAP Team Review Confirmations (Method: E-mail)
Approver
Date
12-APR-2019
Clinical Development Manager, RD PCPS CPSSO
17-APR-2019
Head, RD Respiratory HUP 2
15-APR-2019
Manager, Clinical Pharmacology, CPMS
23-APR-2019
Manager Data Management, CPSSO Data Management 
Respiratory
Medical Director, SERM, CMO GCSP SERM US
12-APR-2019
29-APR2019
Principal Programmer/Analyst, RD PCPS Qsci Clinical Statistics 
9B2
Clinical Statistics and Clinical Programming Line Approvals
(Method: Pharma TMF eSignature)
Approver
Date
08-MAY-2019
Biostatistics and Programming Manager (Infectious Diseases), 
Biostatistics India
On behalf of 
 (Line Manager, FPD, Biostatistics India) 
08-MAY-2019
Programming Manager (FPD) , RD PCPS Qsci Clinical Statistics 
9B
 
2019N402257_00
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


CONFIDENTIAL
205920
3
TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................5
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................5
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................5
2.2.
Study Objective(s) and Endpoint(s)...............................................................6
2.3.
Study Design ................................................................................................9
2.4.
Statistical Hypotheses / Statistical Analyses ...............................................10
3.
PLANNED ANALYSES: GROUP 1.........................................................................11
3.1.
Interim Analyses: Group 1 ..........................................................................11
3.2.
Final Analyses ............................................................................................11
4.
ANALYSIS POPULATIONS ...................................................................................12
4.1.
Protocol Deviations.....................................................................................12
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................13
5.1.
Study Treatment & Sub-group Display Descriptors: Group 1 ......................13
5.2.
Baseline Definitions ....................................................................................13
5.3.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................14
6.
STUDY POPULATION ANALYSES: GROUP 1......................................................15
6.1.
Overview of Planned Study Population Analyses........................................15
7.
SAFETY ANALYSES: GROUP 1............................................................................16
7.1.
Adverse Events Analyses ...........................................................................16
7.2.
Clinical Laboratory Analyses.......................................................................16
7.3.
Other Safety Analyses ................................................................................16
8.
PHARMACOKINETIC ANALYSES : GROUP 1......................................................17
8.1.
Primary Pharmacokinetic Analyses : Group 1.............................................17
8.1.1.
Endpoint / Variables : Group 1.....................................................17
8.1.1.1.
Drug Concentration Measures : Group 1 ....................17
8.1.1.2.
Derived Pharmacokinetic Parameters: Group 1..........17
8.1.2.
Summary Measure: Group 1........................................................18
8.1.3.
Population of Interest : Group 1 ...................................................18
8.2.
POPULATION PHARMACOKINETIC (POPPK) ANALYSES ......................18
8.3.
Secondary Pharmacokinetic Analyses: Group 1 .........................................18
8.3.1.
Endpoint / Variables : Group 1.....................................................18
8.4.
Exploratory Pharmacodynamic Analyses: Group 1 .....................................19
8.4.1.
Endpoint / Variables: Group 1......................................................19
8.4.2.
Summary Measure: Group 1........................................................19
8.4.3.
Population of Interest: Group 1 ....................................................19
9.
REFERENCES.......................................................................................................20
10. APPENDICES........................................................................................................21
 
2019N402257_00


CONFIDENTIAL
205920
4
10.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................21
10.2.
Appendix 2: Schedule of Activities ..............................................................22
10.2.1.
Protocol Defined Schedule of Events : Group 1...........................22
10.2.1.1.
Time & Events General Overview...............................22
10.2.1.2.
Time & Events  - Main Phase Procedures ..................23
10.3.
Appendix 3: Assessment Windows .............................................................24
10.4.
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................25
10.4.1.
Study Phases ..............................................................................25
10.4.1.1.
Study Phases for Concomitant Medication .................25
10.4.2.
Treatment Emergent Flag for Adverse Events .............................26
10.5.
Appendix 5: Data Display Standards & Handling Conventions....................27
10.5.1.
Reporting Process .......................................................................27
10.5.2.
Reporting Standards....................................................................27
10.5.3.
Reporting Standards for Pharmacokinetic....................................29
10.6.
Appendix 6: Derived and Transformed Data ...............................................30
10.6.1.
General........................................................................................30
10.6.2.
Study Population..........................................................................30
10.6.3
Safety ..........................................................................................31
10.7.
Appendix 7: Reporting Standards for Missing Data.....................................32
10.7.1.
Premature Withdrawals................................................................32
10.7.2.
Handling of Missing Data.............................................................32
10.7.2.1.
Handling of Missing and Partial Dates ........................32
10.8.
Appendix 8: Values of Potential Clinical Importance ...................................33
10.8.1.
Laboratory Values........................................................................33
10.8.2.
Vital Signs....................................................................................34
10.9.
Appendix 9: Abbreviations & Trade Marks ..................................................35
10.9.1.
Abbreviations...............................................................................35
10.9.2.
Trademarks .................................................................................36
10.10. Appendix 10: List of Data Displays..............................................................37
10.10.1. Data Display Numbering..............................................................37
10.10.2. Mock Example Shell Referencing ................................................37
10.10.3. Deliverables.................................................................................37
10.10.4. Study Population Tables..............................................................38
10.10.5. Pharmacokinetic Tables...............................................................39
10.10.6. Pharmacokinetic Figures .............................................................40
10.10.7. Safety Tables...............................................................................41
10.10.8. Safety Figure ...............................................................................43
10.10.9. ICH Listings .................................................................................44
10.10.10.Non-ICH Listings..........................................................................45
10.11. Appendix 11: Mock Shell ............................................................................46
 
2019N402257_00


CONFIDENTIAL
205920
5
1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses of 
Group 1 to be included in the Clinical Study Report for Protocol:
Revision Chronology:
2016N281575_00
2016-AUG-22
Original
2016N281575_01
2016-OCT-10
Section 6.2: Inclusion of information on CE marking.
2016N281575_02
2018-JAN-04
Update to PK collection procedures and implementation of in-
stream PK data analysis.
Update to location of Secondary Medical Monitor contact 
information.
2016N281575_03
2018-MAY-30
Modification to informal interim and Group 2 analysis plans.
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
Changes from the originally planned statistical analysis specified in the protocol are 
outlined in Table 1.
Table 1
Changes to Protocol Defined Analysis Plan
Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes

To compare pharmacokinetics of 
IH oxytocin to 10 I.U. IM 
oxytocin in women in TSL.

To produce summary 
statistics for IH and IM 
Oxytocin

Due to sparse PK 
concentration available for
IM and IH Oxytocin a formal 
statistical analysis 
comparison is not possible;
summary statistics will be 
presented instead.

To characterize the 
pharmacokinetics of single 
doses of IH oxytocin and 10 
International Units (I.U.) IM 
oxytocin in women in TSL.

To produce individual 
plasma concentration-time 
plots and summary 
statistics for PK  
parameters : Maximum 
observed plasma 
concentration (Cmax), 
Observed plasma 
concentrations at 10 
minutes (min) postdose 
(Cp10), Observed plasma 
concentrations at 20 min 
post-dose (Cp20), 
Observed plasma 
concentrations at 30 min 
post-dose (Cp30), Time to 
Cmax (tmax), Area under 

As only sparse PK 
concentration is available 
for IM and IH Oxytocin PK
parameters will be derived 
wherever data permit. 
Terminal Phase half-life 
(t1/2) will not be calculated.
AUC(0-3h) will not be 
calculated instead AUC(0-t) 
and time of last quantifiable
concentration will be 
computed.
 
2019N402257_00


CONFIDENTIAL
205920
6
Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes
concentration-time curve 
from time zero to the time 
of the last quantifiable 
concentration (AUC(0-t)),as 
data permit. Terminal 
Phase half-life (t1/2) will not 
be calculated

To compare pharmacokinetics of 
IH oxytocin between Group 1 
and Group 2

No statistical comparison 
will be done

As only sparse PK 
concentration is available
for IH Oxytocin in Group 1 
as compared to Group 2, a 
statistical comparison will  
not be reported.

All Subjects Population

All Subjects population 
label changed to Safety 
population.

To be compliant with the 
new RAP template

Enrolled Population (Defined as 
all subjects who were enrolled 
for the trial irrespective of 
whether they were randomized 
or not and for whom a record 
exists on the study database. 
This population will be used for 
summarizing screening failure
reasons.

All participants who passed 
screening and entered the 
study including randomized 
participants and run in 
failures 
Note: Screening failures (who 
never passed screening even if 
rescreened) and participants 
screened but never enrolled into 
the study (Reserve, Not Used) 
are excluded from the Enrolled 
population as they did not enter 
the study.

To be compliant with the 
new RAP template
2.2.
Study Objective(s) and Endpoint(s)
Group 1 – Women in Third Stage of Labour (TSL)op
Objectives
Endpoints
Primary Objectives
Primary Endpoints

To characterize the pharmacokinetics 
of single doses of IH oxytocin and 10 
International Units (I.U.) IM oxytocin in
       women in TSL.

Plasma concentration time profile for IH
oxytocin and 10 I.U. IM oxytocin.

PK parameters: Maximum observed plasma
concentration (Cmax), Observed plasma concentrations 
at 10 minutes (min) postdose (Cp10), Observed plasma 
concentrations at 20 min post-dose (Cp20), Observed 
plasma concentrations at 30 min post-dose (Cp30), Time 
to Cmax (tmax), Area under concentration-time curve 
(AUC), and Terminal phase half-life (t1/2) will be 
calculated as data permit.
Secondary Objectives
Secondary Endpoints

To evaluate the safety and tolerability 
of inhaled oxytocin.

General safety parameters: adverse events (AE); 
absolute values and changes over time of vital signs 
(blood pressure, heart rate, respiratory rate, temperature).
 
2019N402257_00


CONFIDENTIAL
205920
7
Objectives
Endpoints

To compare pharmacokinetics of IH 
oxytocin to 10 I.U. IM oxytocin in 
women in TSL.

Cmax, Cp10, Cp20, Cp30, Area under the concentration-
time curve from time zero (pre-dose) to three hours (h) 
(AUC[0-3h]) will be compared as data permit.
Exploratory Objectives
Exploratory Endpoints

Pharmacodynamic effect of IH 
oxytocin and 10 I.U. IM oxytocin in 
women in TSL.

Pre and post-delivery haemoglobin

Participant feedback regarding ease 
of use, instructions, and perceived 
ability of patients to use the 
ROTAHALER.

Questionnaire results from participants.
Group 2 – Non-pregnant, non-lactating females of child bearing potential
Objectives
Endpoints
Primary Objectives
Primary Endpoints

To evaluate the safety and tolerability 
of IH and IV Oxytocin

General safety parameters: adverse events; absolute 
values and changes over time of vital signs (blood 
pressure, heart rate) and 12-lead electrocardiogram 
(ECG) parameters (PR, QRS, QT, Corrected QT interval 
[QTc] intervals) from pre-dose values.

Specific respiratory safety parameters: adverse 
respiratory events as monitored by spirometry including 
Forced expiratory volume at 1 minute (FEV1.0), 
respiratory rate, and pulse oximetry.

To characterize the pharmacokinetics 
of single doses of IH oxytocin and 5 
I.U. IV oxytocin.

Plasma concentration time profile for IH oxytocin and 5
I.U. IV oxytocin.

PK parameters: Cmax, Cp10, Cp20, Cp30, tmax, AUC, 
Plasma clearance (CL), volume of distribution and t1/2 
will be calculated as data permit.
Exploratory Objectives
Exploratory Endpoints

To evaluate endogenous plasma 
oxytocin concentrations in non-
pregnant females in the presence and 
absence of the combined oral 
contraceptive.

Pre-dose plasma concentrations of
oxytocin.

To compare the IH pharmacokinetics 
of oxytocin between Cohort A 
(subjects on combined oral 
contraceptive) and Cohort B (subjects 
using a non-hormonal form of 
contraception).

Cp10, Cp20, Cp30, Cmax, AUC(0-3h), Area under the 
concentration time curve from time zero to infinity 
(AUC[0-∞]) and t1/2, will be compared as data permit.

To compare the IV pharmacokinetics 
of oxytocin between Cohort A and 
Cohort B.

Cmax, AUC, t1/2, CL and Volume of distribution (VOD) 
will be compared as data permit.
 
2019N402257_00


CONFIDENTIAL
205920
8
Groups 1 and 2 – Women in TSL and Non-pregnant, non-lactating females of child bearing potential
Objectives
Endpoints
Primary Objectives
Primary Endpoints

To compare pharmacokinetics of IH 
oxytocin between Group 1 and Group 
2

Cp10, Cp20, Cp30, Cmax, AUC(0-3h)  AUC(0-∞), and 
t1/2 will be compared as data permit.
 
2019N402257_00


CONFIDENTIAL
205920
9
2.3.
Study Design
Overview of Study Design and Key Features
Group 1 – Women in TSL
Group 2 – Non-pregnant, non-lactating females of child bearing potential
Design
Features

Group 1: This is an open-label, randomized, single dose study enrolling women in the 
third stage of labour who will receive either IH or IM oxytocin 

Group 2: This is an open-label, randomized, two dosing, cross over study enrolling 
healthy, non-pregnant, non-lactating female subjects of childbearing potential who will 
receive IH oxytocin at one dosing session and IV oxytocin at the other dosing session.  
It will be divided into two cohorts: 
Cohort A will enrol women on a combined oral contraceptive. 
Cohort B will enrol women who are not using a hormonal form of contraceptive.  
Dosing

Group 1: Subjects will receive 400 mcg IH oxytocin or 10 I.U. IM oxytocin in one 
dosing session. Follow Up 1 within approximately 24 hours post dose. Follow Up 2 at 
least 7 days and no greater than 14 days after study drug administration.

Total duration: Screening after 18th week of pregnancy (i.e. within 168 days of 1 
dosing session) + follow up of 7 - 14 days = approximately 183 days

Group 2: Subjects will receive 400 mcg IH oxytocin and 5 I.U.  IV oxytocin in two
dosing sessions. Follow Up will take place at least 7 days and no greater than 21 days 
after last study drug administration.

Total duration: Screening within 28 days of dosing session 1 + 2 dosing sessions with 
a maximum of 14 days between dosing + follow-up of 7 – 21 days = 64 days
Time & 
Events

[Refer to Appendix 2: Schedule of Activities]
Treatment 
Assignment

Group 1: Subjects will be randomised to receive one of the following study 
treatments:
A: 400 mcg IH oxytocin
B: 10 I.U. IM oxytocin

Group 2: Subjects will receive both of the following study treatments over the course 
 
2019N402257_00


CONFIDENTIAL
205920
10
Overview of Study Design and Key Features
of two dosing sessions:
C: 400 mcg IH oxytocin
D: 5 I.U. IV oxytocin
Interim 
Analysis

No formal Interim Analysis are planned, however, PK samples will be analysed and 
preliminary PK parameters derived following completion of approximately 5 women on 
each treatment group: 400 mcg IH and 10 I.U. IM to women in TSL (Group 1) and 400 
mcg IH to non-pregnant women on the combined oral contraceptive (Group 2 Cohort 
A), in order to assess if dose escalation is required.
2.4.
Statistical Hypotheses / Statistical Analyses
No formal hypotheses will be tested. 
For IH and IM oxytocin, summary statistics will be produced separately for IH Oxytocin 
and IM Oxytocin. Due to sparse PK concentrations, it is not possible to include a formal 
statistical analysis to compare IH and IM Oxytocin. PK parameters will be derived as 
data permit. Individual plots, listings and summary tables will be produced for available 
PK concentration data. Only listings and summary tables will be produced for PK 
Parameter data.
 
2019N402257_00


CONFIDENTIAL
205920
11
3.
PLANNED ANALYSES: GROUP 1
3.1.
Interim Analyses: Group 1
No formal Interim Analysis are planned, however, PK samples will be analysed and 
preliminary PK parameters derived following completion of approximately 5 women on 
each treatment group: 400 mcg IH and 10 I.U. IM to women in TSL (Group 1) and 400 
mcg IH to non-pregnant women on the combined oral contraceptive (Group 2 Cohort A), 
in order to assess if dose escalation is required.
Due to sparse PK concentration-time data available following administration of IH and 
IM oxytocin to women in TSL, only concentration time plots were presented at the 
interim analysis. The Study has been terminated early due the unanticipated inability to 
be able to quantify plasma oxytocin using a selective and sensitive (LLQ 2pg/mL) 
analytical assay due to low oxytocin concentrations (<2pg/mL) in the majority of samples 
collected from women in Third Stage Labour (TSL), following either IM or IH 
administration. Therefore, the Primary objective of the study to characterise the PK of 
single doses of IH and IM oxytocin in women in TSL, cannot be met, and the study is 
being terminated
3.2.
Final Analyses
The final planned primary analyses for Group 1 will be performed after the completion of 
the following sequential steps:
1.
All participants who had enrolled into the study prior to the termination of the study 
as defined in the protocol will be part of final analysis.
2.
All required database cleaning activities have been completed for group 1 and final 
database release (DBR) and database freeze (DBF) for group 1 has been declared by 
Data Management.
3.
All criteria for unblinding the randomization codes for group 1 have been met. 
4.
Randomization codes for group 1 have been distributed according to RandAll NG
procedures.
 
2019N402257_00


CONFIDENTIAL
205920
12
4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
Screened

All participants who were screened for eligibility

Screen Failures
Enrolled

All participants who passed screening and entered the 
study including randomized participants and run in 
failures 
Note: Screening failures (who never passed screening even if 
rescreened) and participants screened but never enrolled into 
the study (Reserve, Not Used) are excluded from the Enrolled 
population as they did not enter the study.

Study Population
Safety

Comprise of subjects who receive at least one dose of 
study medication. This population will be used for the 
study population and safety displays.
Note: This population will be based on the treatment the 
participants actually received

Study Population

Safety
Pharmacokinetic
(PK)

Subjects in the ‘Safety’ population for whom a 
pharmacokinetic sample was obtained and analysed. PK 
population will be the population for reporting PK data.

PK
Refer to Appendix 10: List of Data Displays which details the population used for each display.
4.1.
Protocol Deviations
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan.
o Data will be reviewed prior to freezing the database to ensure all important 
deviations are captured and categorised on the protocol deviations dataset. 
o The SI dataset will include all protocol deviations; the analysis dataset will 
include only important protocol deviations. The analysis dataset will be used for 
the listing of important protocol deviations.
o The study endpoints will be reported using the populations detailed in Section 4 of 
this document regardless of whether the participants deviate from the protocol.
o A separate listing of all inclusion/exclusion criteria deviations will also be 
provided. This listing will be based on data as recorded on the inclusion/exclusion 
page of the eCRF.
 
2019N402257_00


CONFIDENTIAL
205920
13
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS
5.1.
Study Treatment & Sub-group Display Descriptors: Group 1
Treatment Group Descriptions
RandAll NG
Data Displays for Reporting
Code
Description
Description
Order in TLF
A
400 mcg IH oxytocin
400 mcg IH
1
B
10 I.U. IM oxytocin
17 mcg IM
2
The treatment dosage will be included in the footnotes for the respective tables/listings. If 
treatment codes have been displayed in the tables/listings the treatment descriptions 
should be included as footnotes.
5.2.
Baseline Definitions
For all endpoints (except as noted in baseline definitions) the baseline value will be the 
latest pre-dose assessment with a non-missing value. If time is not collected, Day 1 
assessments are assumed to be taken prior to first dose and used as baseline. Unscheduled 
visits will not be used for baseline calculation
 
2019N402257_00


CONFIDENTIAL
205920
14
Baseline definitions for Group 1
Parameter
Study Assessments Considered as Baseline
Baseline Used in 
Data Display
Screening
Day -1
Day 1 (Pre-Dose)
Safety
Vital Signs (blood 
pressure, heart rate, 
temperature, 
respiratory rate)
X
X
X
Day 1
LAB
X
Screening
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing.
5.3.
Other Considerations for Data Analyses and Data Handling 
Conventions
Other considerations for data analyses and data handling conventions are outlined in the 
appendices:
Section
Component
10.3
Appendix 3: Assessment Windows
10.4
Appendix 4: Study Phases and Treatment Emergent Adverse Events
10.5
Appendix 5: Data Display Standards & Handling Conventions
10.6
Appendix 6: Derived and Transformed Data
10.7
Appendix 7: Reporting Standards for Missing Data
10.8
Appendix 8: Values of Potential Clinical Importance
 
2019N402257_00


CONFIDENTIAL
205920
15
6.
STUDY POPULATION ANALYSES: GROUP 1
6.1.
Overview of Planned Study Population Analyses
The study population analyses will be based on the Safety & Enrolled population, with 
screen failures as an exception. 
Study population analyses including analyses of subject’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
and exposure and treatment compliance will be based on GSK Core Data Standards.  
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK data standards and statistical principles.
 
2019N402257_00


CONFIDENTIAL
205920
16
7.
SAFETY ANALYSES: GROUP 1
The safety analyses will be based on the Safety population, unless otherwise specified.
7.1.
Adverse Events Analyses
Adverse events analyses including the analysis of adverse events (AEs), Serious (SAEs)
and other significant AEs will be based on GSK Core Data Standards. The details of the 
planned displays are provided in Appendix 10: List of Data Displays.
7.2.
Clinical Laboratory Analyses
Laboratory evaluations including the analyses of Chemistry laboratory tests, Hematology 
laboratory tests, Urinalysis, and liver function tests will be based on GSK Core Data 
Standards. The details of the planned displays are in Appendix 10: List of Data Displays.
7.3.
Other Safety Analyses
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, unless otherwise specified. The details of the 
planned displays are presented in Appendix 10: List of Data Displays.
 
2019N402257_00


CONFIDENTIAL
205920
17
8.
PHARMACOKINETIC ANALYSES : GROUP 1
8.1.
Primary Pharmacokinetic Analyses : Group 1
8.1.1.
Endpoint / Variables : Group 1
•
Plasma concentration time profile for IH oxytocin and 10 I.U. IM oxytocin.
•
PK parameters: Maximum observed plasma concentration (Cmax), Observed 
plasma concentrations at 10 minutes (min) postdose (Cp10), Observed plasma 
concentrations at 20 min post-dose (Cp20), Observed plasma concentrations at 30 min 
post-dose (Cp30), Time to Cmax (tmax), Area under concentration-time curve (AUC(0-
t)), and time of last quantifiable concentration will be calculated as data permit.
8.1.1.1.
Drug Concentration Measures : Group 1
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 10.5.2
and Section 10.5.3 Reporting Standards for Pharmacokinetic)
8.1.1.2.
Derived Pharmacokinetic Parameters: Group 1
Pharmacokinetic parameters will be calculated by standard non-compartmental analysis 
according to current working practices and GSK procedures using the currently supported 
version of WinNonlin. All calculations of non-compartmental parameters will be based 
on actual sampling times. Pharmacokinetic parameters listed will be determined from the 
plasma concentration-time data, as data permits.
Treatment
Parameter
Parameter Description
IH/IM
Cmax
Maximum observed concentration, determined directly from the 
concentration-time data.
IH/IM
Cp10
Quantified concentration in PK sample collected at 10 minutes (nominal 
time) post-dose, determined directly from the concentration-time data.
IH/IM
Cp20
Quantified concentration in PK sample collected at 20 minutes (nominal 
time) post-dose, determined directly from the concentration-time data.
IH/IM
Cp30
Quantified concentration in PK sample collected at 30 minutes (nominal 
time) post-dose, determined directly from the concentration-time data.
IH/IM
tmax
Time to reach Cmax, determined directly from the concentration-time 
data.
IH/IM
AUC(0-t)
Area under the concentration-time curve from time zero to the time of the 
last quantifiable concentration (C(t)) will be calculated using the linear 
trapezoidal rule for each incremental trapezoid and the log trapezoidal 
rule for each decremental trapezoid.
IH/IM
tlast
Time of last quantifiable concentration
At least 2 quantifiable (3 including time 0 where NQ values at time zero will be set to 0) 
values per profile are required to calculate the AUC(0-t). For profiles with less than 2 
quantifiable values, AUC(0-t) will be coded with NC in the PKPar file.
 
2019N402257_00


CONFIDENTIAL
205920
18
8.1.2.
Summary Measure: Group 1
Pharmacokinetic concentration data will be presented in graphical and/or tabular form 
and will be summarized descriptively by IH oxytocin and IM Oxytocin.
The conversion factor to normalise IM doses is 1 IU = 1.7 mcg oxytocin  
As a large number of PK parameter values will be reported as Non Calculable (NC: PK 
parameter cannot be derived due to the presence of non-quantifiable data) then the PK 
parameter will be summarised by following measures

number of subjects with non-missing observations, n, (includes those reported as
NC)

number of subjects for whom parameter cannot be derived because of NQ
concentrations, n*, (reported as NC)

median, minimum and maximum
In addition a frequency table of the number of subjects with all concentrations NQ and
the number of subjects with one, or 2 or more measurable concentrations will be 
produced.
8.1.3.
Population of Interest : Group 1
The primary pharmacokinetic analyses will be based on the Pharmacokinetic population, 
unless otherwise specified.
8.2.
POPULATION PHARMACOKINETIC (POPPK) 
ANALYSES
PK samples will be analysed periodically throughout the study duration to enable 
development of a preliminary population PK model. If appropriate, a population PK 
analysis may also be conducted on the final data. In addition the oxytocin plasma 
concentration-time data may be merged with historical data and analysed as part of a 
population PK meta-analysis. The timeline for these analyses will be independent of the 
analysis described in this RAP. To support this analysis a NONMEM-specific data file 
will be generated, the specifications of which are provided in POP PK RAP appendix.
8.3.
Secondary Pharmacokinetic Analyses: Group 1
8.3.1.
Endpoint / Variables : Group 1
• Cmax, Cp10, Cp20, Cp30, Area under the concentration-time curve from time zero 
(pre-dose) to three hours (h) (AUC[0-3h]) will be compared as data permit.
Due to sparse PK concentrations, it is not possible to include a formal statistical analysis
to compare IH and IM Oxytocin therefore no statistical analysis will be performed. 
 
2019N402257_00


CONFIDENTIAL
205920
19
8.4.
Exploratory Pharmacodynamic Analyses: Group 1
8.4.1.
Endpoint / Variables: Group 1
•
Pre and post-delivery haemoglobin
•
Questionnaire results from participants
8.4.2.
Summary Measure: Group 1
Pre and post-delivery Haemoglobin will be summarized and listed along with other 
haematology parameters. A box plot will be produced for pre and post-delivery 
haemoglobin. 
A listing and a summary table will be produced for the questionnaire results from the 
Rotahaler.
8.4.3.
Population of Interest: Group 1
The exploratory analyses will be based on the Safety population, unless otherwise 
specified.
 
2019N402257_00


CONFIDENTIAL
205920
20
9.
REFERENCES
GlaxoSmithKline Document Number 2016N281575_03: A randomized, open-label study 
to characterize the pharmacokinetics of IH 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. (amendment no.3 – 30-May-2018)
 
2019N402257_00


CONFIDENTIAL
205920
21
10.
APPENDICES
10.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population
This section is not applicable as Per Protocol Population is not defined for this study.
 
2019N402257_00


CONFIDENTIAL
205920
22
10.2.
Appendix 2: Schedule of Activities
10.2.1.
Protocol Defined Schedule of Events : Group 1
10.2.1.1.
Time & Events General Overview
1. Only required if done as part of routine care. Additional study-specific laboratory 
assessments not required.
2. Includes blood pressure, heart rate, temperature, respiratory rate
3. Only to be used when randomized to IH oxytocin
4. To be completed after 18th week of pregnancy (based on estimated date of delivery).
 
2019N402257_00


CONFIDENTIAL
205920
23
10.2.1.2.
Time & Events  - Main Phase Procedures
1. Includes blood pressure, heart rate, temperature, respiratory rate
2. Predose PK sample to be taken immediately prior to administration of study treatment
3. Only to be administered when randomized to IH oxytocin
 
2019N402257_00


CONFIDENTIAL
205920
24
10.3.
Appendix 3: Assessment Windows
No assessment windows will be applied.
 
2019N402257_00


CONFIDENTIAL
205920
25
10.4.
Appendix 4: Study Phases and Treatment Emergent 
Adverse Events
10.4.1.
Study Phases
Assessments and events will be classified according to the time of occurrence relative to 
study treatment.
Study Phase
Definition
Pre-Treatment 
Date < Study Treatment Start Date
On-Treatment
Study Treatment Start Date ≤ Date ≤ Study Treatment Stop Date +1
Post-Treatment
Date > Study Treatment Stop Date +1
10.4.1.1.
Study Phases for Concomitant Medication
Study Phase
Definition
Prior
If medication end date is not missing and is prior to 18th week of pregnancy.
Concomitant
Any medication that is not a prior
NOTES: 

Please refer to Appendix 7: Reporting Standards for Missing Data for handling of missing and partial dates for 
concomitant medication. Use the rules in this table if concomitant medication date is completely missing.
 
2019N402257_00


CONFIDENTIAL
205920
26
10.4.2.
Treatment Emergent Flag for Adverse Events
Flag
Definition
Treatment 
Emergent

If AE onset date is on or after treatment start date & on or before treatment stop 
date. 

Study Treatment Start Date ≤ AE Start Date ≤ Study Treatment Stop Date +1.
NOTES: 

If the study treatment stop date is missing, then the AE will be considered to be On-Treatment.

Time of study treatment dosing and start/stop time of AEs should be considered, if collected.
 
2019N402257_00


CONFIDENTIAL
205920
27
10.5.
Appendix 5: Data Display Standards & Handling 
Conventions
10.5.1.
Reporting Process
Software

The currently supported versions of SAS software 9.4 will be used.
Reporting Area
HARP Server
: UK1SALX00175
HARP Compound (Group 1 Dry Run)
: /arenv/arprod/gr121619/mid205920/final_03
HARP Compound (Group 1 Final)
/arenv/arprod/gr121619/mid205920/final_04
Analysis Datasets 

Analysis datasets will be created according to Legacy GSK A&R dataset
Generation of RTF Files

RTF files will be generated for summary tables
10.5.2.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx):

4.03 to 4.23: General Principles

5.01 to 5.08: Principles Related to Data Listings

6.01 to 6.11: Principles Related to Summary Tables

7.01 to 7.13: Principles Related to Graphics 
Formats

All data will be reported according to the actual treatment the subject received unless otherwise stated.

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for reporting of 
data based on the raw data collected, unless otherwise stated.

Numeric data will be reported at the precision collected on the eCRF.

The reported precision from non eCRF sources will follow the IDSL statistical principles but may be
adjusted to a clinically interpretable number of DP’s.
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses:

Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled visit days 
on the analyses and interpretation of the results will be assessed as appropriate.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the subject’s listings. 
Unscheduled Visits

Unscheduled visits will not be included in summary tables and/or figures.

All unscheduled visits will be included in listings.
 
2019N402257_00


CONFIDENTIAL
205920
28
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Reporting of Pharmacokinetic Concentration Data
Descriptive Summary 
Statistics
Refer to IDSL Statistical Principle 6.06.1
Assign zero to NQ values (Refer to GUI_51487 for further details)
Reporting of Pharmacokinetic Parameters
Summary table
Summary table will be produced as described in Section 8.1.2
Listing
All PK Parameters that are collected will be listed
Reporting of No treatment
If in a situation where a subject has received no treatment, then the subject will be included only in 
Screened and enrolled population.
Graphical Displays
Refer to IDSL Statistical Principals 7.01 to 7.13.
All figures will use coloured lines
 
2019N402257_00


CONFIDENTIAL
205920
29
10.5.3.
Reporting Standards for Pharmacokinetic
Pharmacokinetic Concentration Data
PC Windows Non-
Linear (WNL) File
WNL file will be produced for PK parameters.
Note: Concentration values will be imputed as per GUI_51487
Descriptive Summary 
Statistics, Graphical 
Displays and Listings
Refer to IDSL PK Display Standards.
Refer to IDSL Statistical Principle 6.06.1.
Note: Concentration values will be imputed as per GUI_51487 for descriptive 
summary statistics/analysis and summarized graphical displays only. 
NONMEM/Pop PK 
File
Pop-PK file (CSV format) for the POP-PK analysis by Clinical Pharmacology 
Modelling and Simulation function will be created according to the data specification 
detailed in Section 9.1 Data Specification of the Pop-PK RAP (RAP-IVF116828-
201558-205920-PopPK, located in Cabinets/Study File/GR121619/_Project/Meta 
Analysis/ RAP-IVF116828-201558-205920-PopPK)
Pharmacokinetic Parameter Derivation
PK Parameter to be 
Derived by 
Programmer
The following PK parameters will be derived by the Programmer: Cp10, Cp20 and 
Cp30 
 
2019N402257_00


CONFIDENTIAL
205920
30
10.6.
Appendix 6: Derived and Transformed Data
10.6.1.
General
Multiple Measurements at One Analysis Time Point

Mean of the measurements will be calculated and used in any derivation of summary statistics but if 
listed, all data will be presented.

Participants having both High and Low values for Normal Ranges at any post-baseline visit for safety 
parameters will be counted in both the High and Low categories of “Any visit post-baseline” row of 
related summary tables. This will also be applicable to relevant Potential Clinical Importance summary 
tables.
Study Day

Calculated as the number of days from First Dose Date:

Ref Date = Missing              → Study Day = Missing 

Ref Date < First Dose Date → Study Day = Ref Date – First Dose Date

Ref Data ≥ First Dose Date → Study Day = Ref Date – (First Dose Date) + 1    
10.6.2.
Study Population
Demographics
Age

GSK standard IDSL algorithms will be used for calculating age.

Randomization date will be used as reference date to calculate age
Body Mass Index (BMI)

Calculated as Weight (kg) / [Height (m)2
Extent of Exposure

Number of days of exposure to study drug will be calculated based on the formula:  
Duration of Exposure in Days = Treatment Stop Date – (Treatment Start Date) + 1

Participants who were randomized but did not report a treatment start date will be categorised as 
having zero days of exposure. If there are any treatment breaks during the study, exposure data will be 
adjusted accordingly.
 
2019N402257_00


CONFIDENTIAL
205920
31
10.6.3
Safety
ECG Parameters
RR Interval

IF RR interval (msec) is not provided directly, then RR can be derived as :
    [1] If QTcB is machine read & QTcF is not provided, then :
                       RR = [(QT/QTcB)^(2) ]*1000
    [2] If QTcF is machine read and QTcB is not provided, then: 
                       RR = [(QT/QTcF)^(3) ]*1000

If ECGs are manually read, the RR value preceding the measurement QT interval should be collected 
values THEN do not derive.
Corrected QT Intervals

When not entered directly in the eCRF, corrected QT intervals using Bazett’s (QTcB) and Fredericia’s 
(QTcF) formulas will be calculated, in msec, depending on the availability of other measurements.

IF RR interval (msec) is provided or calculated then missing QTcB and/or QTcF will be derived as :
Laboratory Parameters

If a laboratory value which is expected to have a numeric value for summary purposes, has a non-
detectable level reported in the database, where the numeric value is missing, but typically a character 
value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than x in the comment field) is 
present, the number of significant digits in the observed values will be used to determine how much to 
add or subtract in order to impute the corresponding numeric value. 
o
Example 1: 2 Decimal Points = ‘< x’ becomes x – 0.01
o
Example 2: 1 Decimal Point = ‘> x’ becomes x + 0.1
o
Example 3: 0 Decimal Points = ‘< x’ becomes x – 1    
 
2019N402257_00


CONFIDENTIAL
205920
32
10.7.
Appendix 7: Reporting Standards for Missing Data
10.7.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion (i.e. as specified in the protocol) was defined as who has 
completed all phases of the study including the follow-up visit(s).

Withdrawn subjects may be replaced in the study.

All available data from participants who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, unless 
otherwise specified.
10.7.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank fields on 
the collection instrument:
o
These data will be indicated by the use of a “blank” in subject listing displays. 
Unless all data for a specific visit are missing in which case the data is excluded 
from the table. 
o
Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such.
Outliers

Any participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
10.7.2.1.
Handling of Missing and Partial Dates
Element
Reporting Detail
General

Partial dates will be displayed as captured in subject listing displays.
Adverse Events

The eCRF does not allow for the possibility of partial dates. The eCRF and the 
site need to enter the full date or if not known, they would be required to 
complete an item level comment bubble to specify why the date is unknown. 
This would also be documented in the Data Quality Release Report by DM.

Completely missing start or end dates will remain missing, with no imputation 
applied. Consequently, time to onset and duration of such events will be missing
Concomitant 
Medications/Medical 
History

Partial dates for any concomitant medications recorded in the CRF will be 
imputed using the following convention:
o
If the partial date is a start date, a '01' will be used for the day and 'Jan' will 
be used for the month
o
If the partial date is a stop date, a '28/29/30/31' will be used for the day 
(dependent on the month and year) and 'Dec' will be used for the month.

The recorded partial date will be displayed in listings.
 
2019N402257_00


CONFIDENTIAL
205920
33
10.8.
Appendix 8: Values of Potential Clinical Importance
10.8.1.
Laboratory Values
Haematology
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Hematocrit 
Ratio of 
1
Female
0.3
0.54
∆from BL
Haemoglobin
g/L
Female
80
180
∆from BL
Lymphocytes 
x109/ L
0.8
Neutrophil Count 
x109/ L
1.5
Platelet Count 
x109/ L
100
550
While Blood Cell Count (WBC)
x109/ L
3
22
Liver Function
Test Analyte
Units
Category
Clinical Concern Range
ALT/SGPT 
U/L
High
3x ULN
AST/SGOT 
U/L
High
3x ULN
AlkPhos 
U/L
High
3x ULN
T Bilirubin 
µmol/L
High
1.5xULN
T. Bilirubin + ALT
µmol/L
High
1.5xULN T. Bilirubin
+
2x ULN ALT
U/L
 
2019N402257_00


CONFIDENTIAL
205920
34
10.8.2.
Vital Signs
Vital Sign Parameter
(Absolute)
Units
Clinical Concern Range
Lower
Upper
Systolic Blood Pressure
mmHg
< 85
> 160
Diastolic Blood Pressure
mmHg
< 45
> 100
Heart Rate
bpm
< 40
> 110
 
2019N402257_00


CONFIDENTIAL
205920
35
10.9.
Appendix 9: Abbreviations & Trade Marks
10.9.1.
Abbreviations
Abbreviation
Description
AE
Adverse Event
AIC
Akaike's Information Criteria
A&R
Analysis and Reporting 
CI
Confidence Interval
CPMS
Clinical Pharmacology Modelling & Simulation
COC
Combined Oral Contraceptive
non-COC
non-Combined Oral Contraceptive 
CPSSO
Clinical Pharmacology Science & Study Operations
CS
Clinical Statistics
CSR
Clinical Study Report
CTR
Clinical Trial Register
CVb / CVw
Coefficient of Variation (Between) / Coefficient of Variation (Within)
DBF
Database Freeze
DBR
Database Release
DOB
Date of Birth
DP
Decimal Places
eCRF
Electronic Case Record Form
ECG
Electrocardiogram
EMA
European Medicines Agency
F
Inhaled Bioavailability
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Clinical Results Disclosure Requirements
FEV1.0
Forced expiratory volume at 1 minute
FPD
Future Pipelines Discovery
GSK
GlaxoSmithKline
IA
Interim Analysis
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee 
IDSL
Integrated Data Standards Library
IH
Inhaled
IM
Intramuscular
IMMS
International Modules Management System
IP
Investigational Product
I.U.
International units
IV
Intravenous
MMRM
Mixed Model Repeated Measures
PCI
Potential Clinical Importance 
PCPS
Projects, Clinical Platforms and Sciences
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan
PK
Pharmacokinetic
 
2019N402257_00


CONFIDENTIAL
205920
36
Abbreviation
Description
PP
Per Protocol
PopPK
Population PK
QC
Quality Control
QTcF
Frederica’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
RAP
Reporting & Analysis Plan
SAC
Statistical Analysis Complete
SAE
Serious Adverse Event
SPDS
Statistics, Programming and Data Sciences
SOP
Standard Operation Procedure
TA
Therapeutic Area
TFL
Tables, Figures & Listings 
TSL
Third stage of labour
10.9.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
ROTAHALER
WinNonlin
 
2019N402257_00


CONFIDENTIAL
205920
37
10.10.
Appendix 10: List of Data Displays
10.10.1.
Data Display Numbering
All displays (Tables, Figures & Listings) will use the term 'Subjects'. The following 
numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.7-1.12
N/A
Pharmacokinetic
2.6-2.8
2.8
Safety
3.17-3.28
3.1
Section
Listings
ICH Listings
35-50
Other Listings
51-53
10.10.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in Appendix 11: Example Mock Shells for Data Displays.
Section
Figure
Table
Listing
Safety
SAFE_FN
SAFE_TN
SAFE_LN
Pharmacokinetic
N/A
PK_TN
NA
NOTES: 

Non-Standard displays are indicated in the ‘IDSL /  Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’
10.10.3.
Deliverables
Delivery [Priority] [1]
Description
DR [1]
Prior to DBR. Dry Run for Study Pop, Safety displays 
SAC
Final Statistical Analysis Complete
NOTES: 
1.
Indicates priority (i.e. order) in which displays will be generated for the reporting effort
 
2019N402257_00


CONFIDENTIAL
205920
38
10.10.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.7.
Safety
ES1
Summary of Subject Disposition for the Subject Conclusion 
Record
ICH E3, FDAAA, EudraCT
DR [1], SAC
1.8.
Enrolled
NS1
Summary of Number of Subjects Enrolled by Country and Site 
ID
EudraCT/Clinical Operations
DR [1], SAC
Population Analysed
1.9.
Screened
SP1
Summary of Study Populations 
DR [1], SAC
Demographic and Baseline Characteristics
1.10.
Safety
DM1
Summary of Demographic Characteristics
ICH E3, FDAAA, EudraCT
DR [1], SAC
1.11.
Enrolled
DM11
Summary of Age Ranges
EudraCT
DR [1], SAC
1.12.
Safety
DM5
Summary of Race and Racial Combinations
ICH E3, FDA, FDAAA, EudraCT
DR [1], SAC
 
 
 
2019N402257_00


CONFIDENTIAL
205920
39
10.10.5.
Pharmacokinetic Tables
Pharmacokinetic Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
PK Concentration Data
2.6.
PK
pkct1
Summary of Plasma Concentration-time Data
Page by subjects before study restart, 
subjects after restart and all subjects 
together. 
SAC
2.7.
PK
PK_T1
Summary of Derived Plasma Pharmacokinetic Parameters
(untransformed data)
Page by subjects before study restart, 
subjects after restart and all subjects 
together. This will be an overall 
summary and will not be displayed by 
timepoints.
SAC
2.8. 
PK
PK_T2
Summary of Number and Percentage of Subjects with 
Measurable Concentrations
Page by subjects before study restart, 
subjects after restart and all subjects 
together. This will be an overall 
summary and will not be displayed by 
timepoints.
SAC
 
 
 
2019N402257_00


CONFIDENTIAL
205920
40
10.10.6.
Pharmacokinetic Figures
Pharmacokinetic Figures
No.
Population
IDSL /  
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Individual Concentration Plots
2.8.
PK
pkcf6
Individual Subject Plasma Concentration-time Plot (Linear and 
Semi-log) by Treatment
By Treatment, Page by subjects 
before study restart, subjects after 
restart and all subjects together
SAC
 
 
 
2019N402257_00


CONFIDENTIAL
205920
41
10.10.7.
Safety Tables
Safety: Tables
No.
Population
IDSL /
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events (AEs)
3.17.
Safety
AE1
Summary of All Adverse Events by System Organ Class and 
Preferred Term
DR [1], SAC
3.18.
Safety
AE1
Summary of Drug-Related Adverse Events
DR [1], SAC
3.19.
Safety
AE1
Summary of Non-Serious Adverse Events
DR [1], SAC
3.20.
Safety
AE15
Summary of Common (>1 Subject) Non-serious Adverse 
Events by System Organ Class and Preferred Term (Number of 
Subjects and Occurrences)
FDAAA, EudraCT
DR [1], SAC
Serious and Other Significant Adverse Events
3.21.
Safety
AE16
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Subjects and Occurrences)
FDAAA, EudraCT
DR [1], SAC
3.22.
Safety
AE1
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Drug or Withdrawal from Study
DR [1], SAC
 
 
 
2019N402257_00


CONFIDENTIAL
205920
42
Safety: Tables
No.
Population
IDSL /
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Laboratory: Hematology
3.23.
Safety
LB1
Summary of Haematology Values
DR [1], SAC
3.24.
Safety
LB1
Summary of Haematology Changes from Baseline
DR [1], SAC
Vital Signs
3.25.
Safety
VS1
Summary of Vital Signs
DR [1], SAC
3.26.
Safety
VS1
Summary of Change from Baseline for Vital Signs
DR [1], SAC
3.27.
Safety
VS7
Summary of Vital Sign Results Relative to Potential Clinical 
Importance (PCI) Criteria Post-Baseline Relative to Baseline
DR [1], SAC
Exploratory : Questionnaire Results
3.28.
Safety
SAFE_T1
Summary of Device Acceptability Questionnaire for Rotahaler 
Inhaler
DR[1], SAC
 
 
 
2019N402257_00


CONFIDENTIAL
205920
43
10.10.8.
Safety Figure
Safety: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events
3.1.
Safety
  LB10
Safety Summary Plot of Pre and Post-Delivery Haemaglobin 
IDSL
Include the timepoints in the x-axis 
and values in the y-axis
DR[1], SAC
 
 
 
2019N402257_00


CONFIDENTIAL
205920
44
10.10.9.
ICH Listings
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
35.     Screened
ES7
Listing of Reasons for Screening Failure
DR [1], SAC
36.
Safety
ES2
Listing of Reasons for Withdrawal
DR [1], SAC
37.
Safety
TA1
Listing of Randomised and Actual Treatments
DR [1], SAC
Protocol Deviations
38.
Safety
DV2
Listing of Important Protocol Deviations 
DR [1], SAC
39.
Safety
IE3
Listing of Participants with Inclusion/Exclusion Criteria 
Deviations
DR [1], SAC
Populations Analysed
40.
Enrolled
SP3
Listing of Participants Excluded from Analysis Population
DR [1], SAC
Demographic and Baseline Characteristics
41.
Safety
DM2
Listing of Demographic Characteristics
DR [1], SAC
42.
Safety
DM9
Listing of Race
DR [1], SAC
Prior and Concomitant Medications
43.
Safety
CM3
Listing of Concomitant Medications
DR [1], SAC
Exposure and Treatment Compliance
44.
Safety
        EX3
Listing of Exposure Data
DR [1], SAC
Adverse Events
45.
Safety
AE8
Listing of All Adverse Events
DR [1], SAC
46.
Safety
AE7
Listing of Subject Numbers for Individual Adverse Events
DR [1], SAC 
 
 
 
2019N402257_00


CONFIDENTIAL
205920
45
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Serious and Other Significant Adverse Events
47.
Safety
AE8
Listing of  Serious Adverse Events
DR [1], SAC
48.
Safety
AE8
Listing of Adverse Events Leading to Withdrawal from Study
DR [1], SAC
All Laboratory
49.
Safety 
LB5
Listing of All Hematology Data
All PCI criteria will be flagged
DR [1], SAC
Vital Signs
50.
Safety
VS4
Listing of All Vital Signs Data
All PCI criteria will be flagged
DR [1], SAC
10.10.10.
Non-ICH Listings
Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Safety
51.
Safety 
SAFE_L1
Listing of Device Acceptability Questionnaire for Rotahaler 
Inhaler
DR [1], SAC
PK Concentration
52.
PK
PK07
Listing of Plasma Pharmacokinetic Concentration-Time Data
SAC
53.
PK
PK13
Listing of Derived Plasma Pharmacokinetic
Parameters
SAC
 
 
 
2019N402257_00


CONFIDENTIAL
205920
46
10.11.
Appendix 11: Mock Shell
Example: SAFE_T1
Protocol: 205920                                                                                 Page 1 of 2
Population: Safety
                                                 Table x.xx
                  Summary of Device Acceptability Questionnaire for Rotahaler Inhaler
                                                                    Total
                                                                    (N=XX)          
                ----------------------------------------------------------------------------
                Feel Confident Received the Medicine
                  n                                                  xx             
                  Yes 
xx (xx%)
                  No 
xx (xx%)
  Neutral    
        xx (xx%)
                 Decline to Answer
xx (xx%)
                               
                
                Find This Inhaler Easy to Use
                  n                                                  xx             
                  Yes 
xx (xx%)
                  No 
xx (xx%)
  Neutral    
        xx (xx%)
                 Decline to Answer
xx (xx%)
                Prefer Inhaler Instead of Injection
                  n                                                  xx             
                  Yes
xx (xx%)
                  No 
xx (xx%)
  Neutral    
        xx (xx%)
                 Decline to Answer
xx (xx%)
 
 
 
2019N402257_00


CONFIDENTIAL
205920
47
Example: SAFE_T1
Protocol: 205920                                                                                 Page 2 of 2
Population: Safety
                                                 Table x.xx
                  Summary of Device Acceptability Questionnaire for Rotahaler Inhaler
                                                                    Total
                                                                    (N=XX)          
                ----------------------------------------------------------------------------
               This Inhaler Acceptable to Administer
                  n                                                  xx             
                  Yes 
xx (xx%)
                  No 
xx (xx%)
  Neutral    
        xx (xx%)
                 Decline to Answer
xx (xx%)
 
 
 
2019N402257_00


CONFIDENTIAL
205920
48
Example 
: SAFE_L1
Page 1 of n
Protocol
: GR121619
Population
: Safety
                                                                                       
Listing SAFE_T1
Listing of Device Acceptability Questionnaire for Rotahaler Inhaler
        
Site Id./
Subj Id.   Visit            Date                   Question                         Response
  ------------------------------------------------------------------------------------------------------------
  Xxxx/
    PERIOD 1 GRP1    
         Feel Confident Received the Medicine       Yes                   
            
                                    
                 Find This Inhaler Easy to Use              Yes
                                                   Prefer Inhaler Instead of Injection       Yes
                                                   This Inhaler Acceptable to Administer      Yes
  Xxxx/
    PERIOD 1 GRP1    
         Feel Confident Received the Medicine       Neutral                   
            
                                    
                 Find This Inhaler Easy to Use              Yes
                                                   Prefer Inhaler Instead of Injection       Yes
                                                   This Inhaler Acceptable to Administer      Yes
                                                                     
                                                                
 
 
 
2019N402257_00
PPD
PPD
PPD
PPD


CONFIDENTIAL
205920
49
Example: PK_T1
     Page 1 of xx
Population: Pharmacokinetic {Group}
Table x.x
Summary of Derived [Analyte] [Matrix] Pharmacokinetic Parameters {by Group}
Parameter
Treatment
N
n
n*
Median
Range
AUC(0-t) (units)
400mcg
24
24
xxxx.xx
NC
NC to NC
24
xxxx.xx
xxxx.xx
NC to xx
17mg
24
24
xxxx.xx
xxxx.xx
xxxx.x
23
xxxx.xx
xxxx.xx
xxxx.x
Cmax (units)
400mcg
24
24
xxxx.xx
xxxx.xx
xxxx.x
23
xxxx.xx
xxxx.xx
xxxx.x
17mg
24
24
xxxx.xx
xxxx.xx
xxxx.x
21
xxxx.xx
xxxx.xx
xxxx.x
NC = non calculable due to NQ concentrations
NA = not applicable due to insufficient data to derive summary measure
n = Number of subjects with non-missing observations (including imputed NC values)
n* = Number of subjects for whom parameter cannot be derived because of NQ concentrations
Note: for Cmax and AUC, NCs were imputed prior to derivation of summary statistics; No NC values were
imputed for tmax.
Cmax imputed with ½ LLQ (5 pg/mL)
AUC(0-t) imputed with ½ lowest observed AUC(0-t) (5.45 pg.h/mL)
 
 
 
2019N402257_00


CONFIDENTIAL
205920
50
Example: PK_T2
     Page 1 of xx
Population: Pharmacokinetic 
Table x.x
Summary of Number and Percentage of Subjects with Measurable
Concentrations
n=Number of subjects with non-missing observations (including NC values)
Treatment 
(mcg)
N
n
Number of measurable Concentrations in the Concentration-time Profile
0
1
2
3
>/=4 but <7
400
8
8
2(25%)
2 (25%)
1 (12.5 %)
1 (12.5%)
2 (25%)
17
7
7
5 (71%)
0 (0%)
0 (0%)
0 (0%)
2 (29%)
 
 
 
2019N402257_00


CONFIDENTIAL
The GlaxoSmithKline group of companies
205920
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan (for Group 2 reporting) for 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.
Compound Number 
:
GR121619
Effective Date 
:
16-JAN-2019
Description:

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 205920.

This RAP is intended to describe the Group 2 analyses required for the study. 

This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverable for Group 2.
RAP Author(s):
Approver
Date
Approval Method
N/A
N/A
Associate Statistician (FPD, SPDS India)
09-JAN-2019
e-signature
Statistics Director (FPD, SPDS)
Copyright 2019 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
 
 
51
2019N402257_00
PPD
PPD


CONFIDENTIAL
The GlaxoSmithKline group of companies
205920
2
RAP Team Approvals:
Approver
Date
Approval Method
09-JAN-2019
e-signature
Clinical Development Manager, RD PCPS 
CPSSO
09-JAN-2019
e-mail
Head, RD Respiratory HUP 2
09-JAN-2019
e-signature
Manager, Clinical Pharmacology, CPMS
09-JAN-2019
e-signature
Manager Data Management, CPSSO Data 
Management Respiratory
Medical Director, SERM, CMO GCSP SERM 
US
16-JAN-2019
          e-mail
10-JAN-2019
e-signature
Principal Programmer/Analyst, RD PCPS Qsci 
Clinical Statistics 9B2
Clinical Statistics and Clinical Programming Line Approvals:
Approver
Date
Approval Method
09-JAN-2019
e-signature
Biostatistics and Programming Manager, SPDS 
India
09-JAN-2019
e-signature
Programming Manager, RD PCPS Qsci Clinical 
Statistics 9B
 
 
 
52
2019N402257_00
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


CONFIDENTIAL
205920
3
TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................5
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................5
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................5
2.2.
Study Objective(s) and Endpoint(s)...............................................................6
2.3.
Study Design ................................................................................................8
2.4.
Statistical Hypotheses / Statistical Analyses .................................................9
3.
PLANNED ANALYSES: GROUP 2.........................................................................10
3.1.
Interim Analyses: Group 2 ..........................................................................10
3.2.
Final Analyses ............................................................................................10
4.
ANALYSIS POPULATIONS ...................................................................................10
4.1.
Protocol Deviations.....................................................................................11
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................12
5.1.
Study Treatment & Sub-group Display Descriptors: Group 2 ......................12
5.2.
Baseline Definitions ....................................................................................12
5.3.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................13
6.
STUDY POPULATION ANALYSES : GROUP 2.....................................................14
6.1.
Overview of Planned Study Population Analyses........................................14
7.
SAFETY ANALYSES : GROUP 2...........................................................................15
7.1.
Adverse Events Analyses ...........................................................................15
7.2.
Clinical Laboratory Analyses.......................................................................15
7.3.
Other Safety Analyses ................................................................................15
8.
PHARMACOKINETIC ANALYSES : GROUP 2......................................................16
8.1.
Primary Pharmacokinetic Analyses : Group 2.............................................16
8.1.1.
Endpoint / Variables : Group 2.....................................................16
8.1.1.1.
Drug Concentration Measures : Group 2 ....................16
8.1.1.2.
Derived Pharmacokinetic Parameters: Group 2..........16
8.1.2.
Summary Measure: Group 2........................................................17
8.1.3.
Population of Interest : Group 2 ...................................................18
8.2.
POPULATION PHARMACOKINETIC (POPPK) ANALYSES ......................18
8.3.
Exploratory Pharmacokinetic Analyses: Group 2 ........................................18
8.3.1.
Endpoint / Variables : Group 2.....................................................18
8.3.2.
Summary Measure: Group 2........................................................18
8.3.3.
Population of Interest: Group 2 ....................................................18
8.3.4.
Statistical Analyses / Methods: Group 2.......................................19
8.3.4.1.
Statistical Methodology Specification..........................19
9.
REFERENCES.......................................................................................................21
10. APPENDICES........................................................................................................22
 
 
 
53
2019N402257_00


CONFIDENTIAL
205920
4
10.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................22
10.2.
Appendix 2: Schedule of Activities ..............................................................23
10.2.1.
Protocol Defined Schedule of Events : Group 2 ...........................23
10.2.1.1.
Time & Events General Overview...............................23
10.2.1.2.
Time & Events  - Main Phase Procedures ..................24
10.3.
Appendix 3: Assessment Windows .............................................................25
10.4.
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................26
10.4.1.
Study Phases ..............................................................................26
10.4.1.1.
Study Phases for Concomitant Medication .................26
10.4.2.
Treatment Emergent Flag for Adverse Events .............................27
10.5.
Appendix 5: Data Display Standards & Handling Conventions....................28
10.5.1.
Reporting Process .......................................................................28
10.5.2.
Reporting Standards....................................................................28
10.5.3.
Reporting Standards for Pharmacokinetic....................................30
10.6.
Appendix 6: Derived and Transformed Data ...............................................31
10.6.1.
General........................................................................................31
10.6.2.
Study Population..........................................................................31
10.6.3
Safety ..........................................................................................32
10.7.
Appendix 7: Reporting Standards for Missing Data.....................................33
10.7.1.
Premature Withdrawals................................................................33
10.7.2.
Handling of Missing Data.............................................................33
10.7.2.1.
Handling of Missing and Partial Dates ........................33
10.8.
Appendix 8: Values of Potential Clinical Importance ...................................34
10.8.1.
Laboratory Values........................................................................34
10.8.2.
ECG.............................................................................................35
10.8.3.
Vital Signs....................................................................................35
10.9.
Appendix 11: Abbreviations & Trade Marks ................................................36
10.9.1.
Abbreviations...............................................................................36
10.9.2.
Trademarks .................................................................................37
10.10. Appendix 12: List of Data Displays..............................................................38
10.10.1. Data Display Numbering..............................................................38
10.10.2. Mock Example Shell Referencing ................................................38
10.10.3. Deliverables.................................................................................38
10.10.4. Study Population Tables..............................................................39
10.10.5. Pharmacokinetic Tables...............................................................40
10.10.6. Pharmacokinetic Figures .............................................................41
10.10.7. Safety Tables...............................................................................42
10.10.8. ICH Listings .................................................................................44
10.10.9. Non-ICH Listings..........................................................................46
10.11. Appendix 13: Example Mock Shells for Data Displays ................................47
 
 
 
54
2019N402257_00


CONFIDENTIAL
205920
5
1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses of 
Group 2 to be included in the Clinical Study Report for Protocol:
Revision Chronology:
2016N281575_00
2016-AUG-22
Original
2016N281575_01
2016-OCT-10
Section 6.2: Inclusion of information on CE marking.
2016N281575_02
2018-JAN-04
Update to PK collection procedures and implementation of in-
stream PK data analysis.
Update to location of Secondary Medical Monitor contact 
information.
2016N281575_03
30-MAY-2018
Modification to informal interim and Group 2 analysis plans.
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
Changes from the originally planned statistical analysis specified in the protocol are 
outlined in Table 1.
Table 1
Changes to Protocol Defined Analysis Plan
Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes

To compare the IV
pharmacokinetics of oxytocin 
between Cohort A and Cohort B. 

To produce summary 
statistics for IV Bolus and 
IV infusion by Cohort

Some participants, received 
IV Bolus dose and some 
participants received IV 
infusion dose. As the 
number of participants that 
received IV bolus and IV 
infusion are too small to 
allow for a formal stats 
analysis comparison, 
summary statistics will be 
presented instead.

All Subjects Population

All Subjects population 
label changed to Safety 
population.

To be compliant with the 
new RAP template

Enrolled Population (Defined as 
all subjects who were enrolled 
for the trial irrespective of 
whether they were randomized 
or not and for whom a record 
exists on the study database. 
This population will be used for 
summarizing screening failure
reasons.

All participants who passed 
screening and entered the 
study including randomized 
participants and run in 
failures 
Note: Screening failures (who 
never passed screening even if 
rescreened) and participants 
screened but never enrolled into 
the study (Reserve, Not Used) 

To be compliant with the 
new RAP template
 
 
 
55
2019N402257_00


CONFIDENTIAL
205920
6
Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes
are excluded from the Enrolled 
population as they did not enter 
the study.
2.2.
Study Objective(s) and Endpoint(s)
Group 1 – Women in Third Stage of Labour (TSL)
Objectives
Endpoints
Primary Objectives
Primary Endpoints

To characterize the pharmacokinetics 
of single doses of IH oxytocin and 10 
International Units (I.U.) IM oxytocin in
       women in TSL.

Plasma concentration time profile for IH
oxytocin and 10 I.U. IM oxytocin.

PK parameters: Maximum observed plasma
concentration (Cmax), Observed plasma concentrations 
at 10 minutes (min) postdose (Cp10), Observed plasma 
concentrations at 20 min post-dose (Cp20), Observed 
plasma concentrations at 30 min post-dose (Cp30), Time 
to Cmax (tmax), Area under concentration-time curve 
(AUC), and Terminal phase half-life (t1/2) will be 
calculated as data permit.
Secondary Objectives
Secondary Endpoints

To evaluate the safety and tolerability 
of inhaled oxytocin.

General safety parameters: adverse events (AE); 
absolute values and changes over time of vital signs 
(blood pressure, heart rate, respiratory rate, temperature).

To compare pharmacokinetics of IH 
oxytocin to 10 I.U. IM oxytocin in 
women in TSL.

Cmax, Cp10, Cp20, Cp30, Area under the concentration-
time curve from time zero (pre-dose) to three hours (h) 
(AUC[0-3h]) will be compared as data permit.
Exploratory Objectives
Exploratory Endpoints

Pharmacodynamic effect of IH 
oxytocin and 10 I.U. IM oxytocin in 
women in TSL.

Pre and post-delivery haemoglobin

Participant feedback regarding ease 
of use, instructions, and perceived 
ability of patients to use the 
ROTAHALER.

Questionnaire results from participants.
Group 2 – Non-pregnant, non-lactating females of child bearing potential
Objectives
Endpoints
Primary Objectives
Primary Endpoints

To evaluate the safety and tolerability 
of IH and IV Oxytocin

General safety parameters: adverse events; absolute 
values and changes over time of vital signs (blood 
pressure, heart rate) and 12-lead electrocardiogram 
(ECG) parameters (PR, QRS, QT, Corrected QT interval 
[QTc] intervals) from pre-dose values.

Specific respiratory safety parameters: adverse 
respiratory events as monitored by spirometry including 
Forced expiratory volume at 1 minute (FEV1.0), 
respiratory rate, and pulse oximetry.

To characterize the pharmacokinetics 

Plasma concentration time profile for IH oxytocin and 5 
 
 
 
56
2019N402257_00


CONFIDENTIAL
205920
7
Objectives
Endpoints
of single doses of IH oxytocin and 5 
I.U. IV oxytocin.
I.U. IV oxytocin.

PK parameters: Cmax, Cp10, Cp20, Cp30, tmax, AUC, 
Plasma clearance (CL), volume of distribution and t1/2 
will be calculated as data permit.
Exploratory Objectives
Exploratory Endpoints

To evaluate endogenous plasma 
oxytocin concentrations in non-
pregnant females in the presence and 
absence of the combined oral 
contraceptive.

Pre-dose plasma concentrations of
oxytocin.

To compare the IH pharmacokinetics 
of oxytocin between Cohort A 
(subjects on combined oral 
contraceptive) and Cohort B (subjects 
using a non-hormonal form of 
contraception).

Cp10, Cp20, Cp30, Cmax, AUC(0-3h), Area under the 
concentration time curve from time zero to infinity 
(AUC[0-∞]) and t1/2, will be compared as data permit.

To compare the IV pharmacokinetics 
of oxytocin between Cohort A and 
Cohort B.

Cmax, AUC, t1/2, CL and Volume of distribution (VOD) 
will be compared as data permit.
Groups 1 and 2 – Women in TSL and Non-pregnant, non-lactating females of child bearing potential
Objectives
Endpoints
Primary Objectives
Primary Endpoints

To compare pharmacokinetics of IH 
oxytocin between Group 1 and Group 
2

Cp10, Cp20, Cp30, AUC(0-3h) Cmax, AUC(0-3h)  
AUC(0-∞), and t1/2 will be compared as data permit.
 
 
 
57
2019N402257_00


CONFIDENTIAL
205920
8
2.3.
Study Design
Overview of Study Design and Key Features
Group 1 – Women in TSL
Group 2 – Non-pregnant, non-lactating females of child bearing potential
Design
Features

Group 1: This is an open-label, randomized, single dose study enrolling women in the 
third stage of labour who will receive either IH or IM oxytocin 

Group 2: This is an open-label, randomized, two dosing, cross over study enrolling 
healthy, non-pregnant, non-lactating female subjects of childbearing potential who will 
receive IH oxytocin at one dosing session and IV oxytocin at the other dosing session.  
It will be divided into two cohorts: 
Cohort A will enrol women on a combined oral contraceptive. 
Cohort B will enrol women who are not using a hormonal form of contraceptive.  
Dosing

Group 1: Subjects will receive 400 mcg IH oxytocin or 10 I.U. IM oxytocin in one 
dosing session. Follow Up 1 within approximately 24 hours post dose. Follow Up 2 at 
least 7 days and no greater than 14 days after study drug administration.

Total duration: Screening after 18th week of pregnancy (i.e. within 168 days of 1 
dosing session) + follow up of 7 - 14 days = approximately 183 days

Group 2: Subjects will receive 400 mcg IH oxytocin and 5 I.U.  IV oxytocin in two
dosing sessions. Follow Up will take place at least 7 days and no greater than 21 days 
after last study drug administration.

Total duration: Screening within 28 days of dosing session 1 + 2 dosing sessions with 
a maximum of 14 days between dosing + follow-up of 7 – 21 days = 64 days
Time & 
Events

[Refer to Appendix 2: Schedule of Activities]
Treatment 
Assignment

Group 1: Subjects will be randomised to receive one of the following study 
treatments:
A: 400 mcg IH oxytocin
B: 10 I.U. IM oxytocin

Group 2: Subjects will receive both of the following study treatments over the course 
 
 
 
58
2019N402257_00


CONFIDENTIAL
205920
9
Overview of Study Design and Key Features
of two dosing sessions:
C: 400 mcg IH oxytocin
D: 5 I.U. IV oxytocin
Interim 
Analysis

No formal Interim Analysis are planned, however, PK samples will be analysed and 
preliminary PK parameters derived following completion of approximately 5 women on 
each treatment group: 400 mcg IH and 10 I.U. IM to women in TSL (Group 1) and 400 
mcg IH to non-pregnant women on the combined oral contraceptive (Group 2 Cohort 
A), in order to assess if dose escalation is required.
2.4.
Statistical Hypotheses / Statistical Analyses
No formal hypotheses will be tested, however, the following comparison is of interest:
•
Cohort A (inhaled oxytocin) vs Cohort B(inhaled oxytocin)
For each PK endpoint of interest, point estimates and corresponding two-sided 90% 
confidence intervals will be constructed for the ratio of the geometric mean of the test 
treatment to the geometric mean of the reference treatment, μ(test)/μ(reference) to 
provide the range of plausible values for the comparisons of interest.
For IV oxytocin, summary statistics will be produced separately for IV Bolus Oxytocin 
and IV Infusion Oxytocin. Due to small participant numbers, a formal statistical analysis 
to compare Cohort A vs Cohort B is not possible for IV Bolus or for IV infusion.
 
 
 
59
2019N402257_00


CONFIDENTIAL
205920
10
3.
PLANNED ANALYSES: GROUP 2
3.1.
Interim Analyses: Group 2 
No formal Interim Analysis are planned, however, PK samples will be analysed and 
preliminary PK parameters derived following completion of approximately 5 women on 
each treatment group: 400 mcg IH and 10 I.U. IM to women in TSL (Group 1) and 400 
mcg IH to non-pregnant women on the combined oral contraceptive (Group 2 Cohort A), 
in order to assess if dose escalation is required.
3.2.
Final Analyses
An analysis of Group 2 (non-pregnant volunteers) will be performed once Group 2 has 
completed to allow for full reporting of non-pregnant volunteer data prior to completion 
of Group 1.
The final planned primary analyses for Group 2 will be performed after the completion of 
the following sequential steps:
1.
All participants in group 2 have completed the study as defined in the protocol 
2.
All required database cleaning activities have been completed for group 2 and final 
database release (DBR) and database freeze (DBF) for group 2 has been declared by 
Data Management.
3.
All criteria for unblinding the randomization codes for group 2 have been met. 
4.
Randomization codes for group 2 have been distributed according to RandAll NG
procedures.
4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
Screened

All participants who were screened for eligibility

Screen Failures
Enrolled

All participants who passed screening and entered the 
study including randomized participants and run in 
failures 
Note: Screening failures (who never passed screening even if 
rescreened) and participants screened but never enrolled into 
the study (Reserve, Not Used) are excluded from the Enrolled 
population as they did not enter the study.

Study Population
Safety

Comprise of subjects who receive at least one dose of 
study medication. This population will be used for the 
study population and safety displays.
Note: This population will be based on the treatment the 
participants actually received

Study Population

Safety
Pharmacokinetic
(PK)

Subjects in the ‘Safety’ population for whom a 
pharmacokinetic sample was obtained and analysed. PK 
population will be the population for reporting PK data.

PK
Refer to Appendix 12: List of Data Displays which details the population used for each display.
 
 
 
60
2019N402257_00


CONFIDENTIAL
205920
11
4.1.
Protocol Deviations
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan.
o Data will be reviewed prior to freezing the database to ensure all important 
deviations are captured and categorised on the protocol deviations dataset. 
o The SI dataset will include all protocol deviations; the analysis dataset will 
include only important protocol deviations. The analysis dataset will be used for 
the listing of important protocol deviations.
o The study endpoints will be reported using the populations detailed in Section 4 of 
this document regardless of whether the participants deviate from the protocol.
o A separate listing of all inclusion/exclusion criteria deviations will also be 
provided. This listing will be based on data as recorded on the inclusion/exclusion 
page of the eCRF.
 
 
 
61
2019N402257_00


CONFIDENTIAL
205920
12
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
5.1.
Study Treatment & Sub-group Display Descriptors: Group 2
Treatment Group Descriptions
RandAll NG
Data Displays for Reporting
Code
Description
Description
Order in TLF
C
400 mcg IH oxytocin
400 mcg IH
1
D1
5 I.U. IV oxytocin
8.5 mcg IV bolus
2
D2
5 I.U. IV oxytocin
8.5 mcg IV Infusion
3
Treatment comparisons will be displayed as follows using the descriptors as specified:
1.
IH Oxytocin (COC) vs IH Oxytocin (non-COC) 
If the duration of IV oxytocin dose administered is less than or equal to 2min then the IV 
dose administered is an IV Bolus dose. If the duration of IV oxytocin dose administered 
is greater than 2 min then the IV dose administered is an IV Infusion dose. The 
tables/listings that would display the statistics should display IV oxytocin administered as 
IV Bolus Oxytocin and IV Infusion Oxytocin. Subjects assigned to treatment code D and 
received the IV via bolus will be labelled as D1 and those who received IV via infusion 
will be labelled as D2.
The treatment dosage will be included in the footnotes for the respective tables/listings. If 
treatment codes have been displayed in the tables/listings the treatment descriptions 
should be included as footnotes. COC refers to Combined Oral Contraceptive and non-
COC refers to non-Combined Oral Contraceptive.
5.2.
Baseline Definitions
For all endpoints (except as noted in baseline definitions) the baseline value will be the 
latest pre-dose assessment with a non-missing value. If time is not collected, Day 1 
assessments are assumed to be taken prior to first dose and used as baseline.
 
 
 
62
2019N402257_00


CONFIDENTIAL
205920
13
Baseline definitions for Group 2
Parameter
Study Assessments Considered as Baseline
Baseline Used in 
Data Display
Screening
Day -1
Day 1 (Pre-Dose)
Safety
Vital Signs (pressure, 
heart rate, 
temperature, 
respiratory rate)
X
X
X
Day 1
LAB
X
X
X
Day 1
ECG
X
X
X
Day 1
FEV1
X
X
X
Day 1
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing.
5.3.
Other Considerations for Data Analyses and Data Handling 
Conventions
Other considerations for data analyses and data handling conventions are outlined in the 
appendices:
Section
Component
10.3
Appendix 3: Assessment Windows
10.4
Appendix 4: Study Phases and Treatment Emergent Adverse Events
10.5
Appendix 5: Data Display Standards & Handling Conventions
10.6
Appendix 6: Derived and Transformed Data
10.7
Appendix 7: Reporting Standards for Missing Data
10.8
Appendix 8: Values of Potential Clinical Importance
 
 
 
63
2019N402257_00


CONFIDENTIAL
205920
14
6.
STUDY POPULATION ANALYSES : GROUP 2
6.1.
Overview of Planned Study Population Analyses
The study population analyses will be based on the Safety & Enrolled population, with 
screen failures as an exception. The study population displays will be produced page 
wise, grouped by cohorts A and B
Study population analyses including analyses of subject’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
and exposure and treatment compliance will be based on GSK Core Data Standards.  
Details of the planned displays are provided in Appendix 12: List of Data Displays and 
will be based on GSK data standards and statistical principles.
 
 
 
64
2019N402257_00


CONFIDENTIAL
205920
15
7.
SAFETY ANALYSES : GROUP 2
The safety analyses will be based on the Safety population, unless otherwise specified.
7.1.
Adverse Events Analyses
Adverse events analyses including the analysis of adverse events (AEs), Serious (SAEs)
and other significant AEs will be based on GSK Core Data Standards. The details of the 
planned displays are provided in Appendix 12: List of Data Displays.
7.2.
Clinical Laboratory Analyses
Laboratory evaluations including the analyses of Chemistry laboratory tests, Hematology 
laboratory tests, Urinalysis, and liver function tests will be based on GSK Core Data 
Standards. The details of the planned displays are in Appendix 12: List of Data Displays.
7.3.
Other Safety Analyses
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, unless otherwise specified. The details of the 
planned displays are presented in Appendix 12: List of Data Displays.
 
 
 
65
2019N402257_00


CONFIDENTIAL
205920
16
8.
PHARMACOKINETIC ANALYSES : GROUP 2
8.1.
Primary Pharmacokinetic Analyses : Group 2
8.1.1.
Endpoint / Variables : Group 2
•
Plasma concentration time profile for IH oxytocin and 5 I.U. IV oxytocin.
•
PK parameters: Cmax, Cp10, Cp20, Cp30, tmax, AUC(including AUC(0-t), 
AUC(0-inf) and AUC(0-3h)), Plasma clearance (CL), volume of distribution and t1/2 will 
be calculated as data permit
8.1.1.1.
Drug Concentration Measures : Group 2
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 10.5.3.
Reporting Standards for Pharmacokinetic)
8.1.1.2.
Derived Pharmacokinetic Parameters: Group 2
Pharmacokinetic parameters will be calculated by standard non-compartmental analysis 
according to current working practices and GSK procedures using the currently supported 
version of WinNonlin. All calculations of non-compartmental parameters will be based 
on actual sampling times. Pharmacokinetic parameters listed will be determined from the 
plasma concentration-time data, as data permits.
Treatment
Parameter
Parameter Description
IH/IV
Cmax
Maximum observed concentration, determined directly from the 
concentration-time data.
IH/IV
Pre - dose
Quantified concentration in PK sample collected at predose, determined 
directly from the concentration-time data.
IH
Cp10
Quantified concentration in PK sample collected at 10 minutes (nominal 
time) post-dose, determined directly from the concentration-time data.
IH
Cp20
Quantified concentration in PK sample collected at 20 minutes (nominal 
time) post-dose, determined directly from the concentration-time data.
IH
Cp30
Quantified concentration in PK sample collected at 30 minutes (nominal 
time) post-dose, determined directly from the concentration-time data.
IH/IV
tmax
Time to reach Cmax, determined directly from the concentration-time 
data.
IH/IV
AUC(0-t)
Area under the concentration-time curve from time zero to the time of the 
last quantifiable concentration (C(t)) will be calculated using the linear 
trapezoidal rule for each incremental trapezoid and the log trapezoidal 
rule for each decremental trapezoid.
IH/IV
AUC (0-inf)
Area under the concentration-time curve extrapolated to infinity will be 
calculated as: AUC = AUC(0-t) + C(t) / lambda_z
IH/IV
AUC(0-3h)
Area under the concentration-time curve from time zero to 3 h post-dose
IV
Plasma clearance 
(CL)
Plasma clearance (a volume per time, i.e. a flow) expresses the overall 
ability of the body to eliminate a drug by scaling the drug elimination rate 
(amount per time) by the corresponding plasma concentration level.
 
 
 
66
2019N402257_00


CONFIDENTIAL
205920
17
Treatment
Parameter
Parameter Description
IV
VOD
Volume of distribution of a drug gives information on its distribution in the 
body. Calculated as VD=Total amount of blood in the body/Drug blood 
plasma concentration.
IH/IV
t1/2
Apparent terminal half-life will be calculated as: t½ = ln2 / Lambda_z
(NOTE: Lambda_z is the terminal phase rate constant).
IH/IV
Clast
Last observed quantifiable concentration
IH/IV
tlast
Time of the last observed quantifiable concentration
IH/IV
Lambda_z
The first order rate constant associated with the terminal (log-linear) 
portion of the concentration-time curve.
IH/IV
Lambda_z_lower
First time point used in computing Lambda_z.
IH/IV
Lambda_z_upper
Last time point used in computing Lambda_z.
IH/IV
#pts
Number of points used in computing Lambda_z.
IH/IV
r-squared
R-squared of Lambda_z computation.
IH/IV
AUC(0-inf)/D
AUC(0-inf) corrected for dose
NOTES:

Additional parameters may be included as required.
The absolute bioavailability (F) will be derived for each subject using the formula 
outlined below. If dose normalised AUC(0-∞) cannot be determined this will be 
substituted with dose normalised AUC(0-t) for that profile.  All PK parameters (including 
the derived inhaled bioavailability, F) will be listed and summarised.  
The conversion factor to normalise IV doses is 1 IU = 1.7 mcg oxytocin  
8.1.2.
Summary Measure: Group 2
Pharmacokinetic data will be presented in graphical and/or tabular form and will be 
summarized descriptively by IH oxytocin , IV Bolus Oxytocin, IV Infusion Oxytocin for 
each Cohort (Cohort A  and Cohort B). In addition data for the derived absolute 
bioavailability, F will also be summarised by cohort.
For each of the parameters the following summary statistics will be calculated 
• Untransformed Data: N, n, arithmetic mean, 90% confidence interval (CI) for the
arithmetic mean, standard deviation (SD), median, minimum, maximum.
• Loge-transformed Data: Geometric mean, 90% CI for the geometric mean, standard 
deviation (SD) of loge-transformed data and %CVb.
For tmax, and t½ the summary statistics specified for untransformed data above will be
 
 
 
67
2019N402257_00


CONFIDENTIAL
205920
18
generated.
8.1.3.
Population of Interest : Group 2
The primary pharmacokinetic analyses will be based on the Pharmacokinetic population, 
unless otherwise specified.
8.2.
POPULATION PHARMACOKINETIC (POPPK) 
ANALYSES
PK samples will be analysed periodically throughout the study duration to enable 
development of a preliminary population PK model. If appropriate, a population PK 
analysis may also be conducted on the final data. In addition the oxytocin plasma 
concentration-time data may be merged with historical data and analysed as part of a 
population PK meta-analysis. The timeline for these analyses will be independent of the 
analysis described in this RAP. To support this analysis a NONMEM-specific data file 
will be generated, the specifications of which are provided in POP PK RAP appendix.
8.3.
Exploratory Pharmacokinetic Analyses: Group 2
8.3.1.
Endpoint / Variables : Group 2
• Pre-dose plasma concentrations of oxytocin.
• For IH formulation: - Cp10, Cp20, Cp30, Cmax, Tmax, AUC(0-3h), Area under the 
concentration time curve from time zero to infinity (AUC[0-∞]) and t1/2, will be 
compared as data permit.
•
For IV formulation: - Cmax, AUC(0-inf), AUC(0-3h), t1/2, CL and Volume of 
distribution (VOD) will be compared as data permit.
8.3.2.
Summary Measure: Group 2
Descriptive Statistics will be produced for Pre-dose plasma concentrations of oxytocin.  
Pharmacokinetic data will be presented in graphical and/or tabular form and will be 
summarized descriptively by cohort
As the number of subjects required to statistically compare IV Bolus Oxytocin and IV 
Infusion Oxytocin between Cohort A and Cohort B is not sufficient, only summary 
statistics will be produced for IV Bolus Oxytocin and IV Infusion oxytocin. The Inhaled 
oxytocin will be statistically compared between Cohort A and Cohort B as described in 
Section 8.3.4
8.3.3.
Population of Interest: Group 2
The exploratory pharmacokinetic analyses will be based on the Pharmacokinetic 
population, unless otherwise specified
 
 
 
68
2019N402257_00


CONFIDENTIAL
205920
19
8.3.4.
Statistical Analyses / Methods: Group 2
Details of the planned displays are provided in Appendix 12: List of Data Displays and 
will be based on GSK Data Standards and statistical principles.
The following pharmacokinetic statistical analyses will only be performed, if sufficient
data is available (i.e. if subjects have well defined plasma profiles). Pharmacokinetic
analysis will be the responsibility of the Clinical Pharmacology Modelling and
Simulation Department, (CPMS) and Statistical analyses of the pharmacokinetic
parameter data will be the responsibility of Clinical Statistics (CS).
To compare the IH pharmacokinetics of oxytocin between Cohort A (subjects on 
combined oral contraceptive) and Cohort B (subjects using a non-hormonal form of 
contraception), point estimates and corresponding two-sided 90% confidence intervals 
will be computed for Cp10, Cp20, Cp30, Cmax, Tmax, AUC(0-3h), Area under the 
concentration-time curve from time zero to infinity (AUC[0-∞]) and t1/2.
Data will be loge-transformed prior to analysis using a mixed effect model with a fixed 
effect term for cohort and a random effect term for subject, with the exception of T1/2 
and Tmax which will be analysed non-parametrically using Mann Whitney test.
8.3.4.1.
Statistical Methodology Specification
Endpoint / Variables

For IH: - Cp10, Cp20, Cp30, AUC(0-3h), Cmax, Area under the concentration time curve from 
time zero to infinity (AUC[0-∞]) will be compared as data permit.
Note: These endpoints will be log transformed for analysis.
Model Specification

Mixed Effect model will be used to analyze the data.
Endpoint: log transformed PK parameter
Fixed effect: Cohort (COC/Non-COC)
Random effect: Subject

The Kenward and Roger method for approximating the denominator degrees of freedom and 
correcting for bias in the estimated variance-covariance of the fixed effects will be used.

An unstructured covariance structure for the G matrix will be used.

In the event that this model fails to converge, alternative covariance structures may be 
considered such as VC or CS.

Akaike’s Information Criteria (AIC) will be used to assist with the selection of covariance 
structure.
 
 
 
69
2019N402257_00


CONFIDENTIAL
205920
20
Model Checking & Diagnostics

For the Mixed Model, model assumptions will be checked, and appropriate adjustments may 
be applied based on the data.

Distributional assumptions underlying the model used for analysis will be examined by 
obtaining a normal probability plot of the residuals and a plot of the residuals versus the fitted 
values (i.e. checking the normality assumption and constant variance assumption of the model 
respectively) to gain confidence that the model assumptions are reasonable.

If there are any departures from the distributional assumptions, alternative transformations, 
such as data squared or square root of data, will be explored.

Non-parametric analyses will be conducted if the normality assumption does not hold.
Model Results Presentation

Point estimates and corresponding two-sided 90% confidence intervals for the comparison of 
interest that is Cohort A (COC) vs Cohort B (non-COC) for IH Oxytocin. These will then be 
back-transformed to provide point estimates and corresponding 90% confidence intervals for 
the geometric mean ratios (COC/Non-COC)
Endpoint / Variables

t1/2 , Tmax
Note: This endpoint will not be log transformed for analysis
Model Specification

Mann-Whitney test

The test will be performed for IH oxytocin only
Model Results Presentation

Point estimate and 90% confidence interval for the median difference COC-non COC
 
 
 
70
2019N402257_00


CONFIDENTIAL
205920
21
9.
REFERENCES
GlaxoSmithKline Document Number 2016N281575_03 (amendment no.3 – 30-May-
2018): A randomized, open-label study to characterize the pharmacokinetics of IH 
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.
 
 
 
71
2019N402257_00


CONFIDENTIAL
205920
22
10.
APPENDICES
10.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population
This section is not applicable as Per Protocol Population is not defined for this study.
 
 
 
72
2019N402257_00


CONFIDENTIAL
205920
23
10.2.
Appendix 2: Schedule of Activities
10.2.1.
Protocol Defined Schedule of Events : Group 2
10.2.1.1.
Time & Events General Overview
1. Smokerlyzer at PI/designee discretion if smoking history in question.
2. If test otherwise performed within 3 months prior to first dose of study treatment, 
repeat testing at screening is not required.
3. Includes blood pressure, heart rate, temperature, respiratory rate, and SpO2.
4. Performed in triplicate.
5. To be completed within 28 days of randomization.
 
 
 
73
2019N402257_00


CONFIDENTIAL
205920
24
10.2.1.2.
Time & Events  - Main Phase Procedures
1. Smokerlyzer at Principal Investigator (PI)/designee discretion if smoking history in 
question.
2. Includes blood pressure, heart rate, temperature, respiratory rate, and SpO2
3. FEV 1.0 will be performed in triplicate at each time point. Record all three values on 
source document, and record best effort in eCRF.
4. Discharge at PI discretion, no sooner than 4-hours post-dose.
5. 3 pre-dose samples: approximately 1 hr pre-dose, 30 minutes pre-dose, and 15 minutes 
pre-dose
 
 
 
74
2019N402257_00


CONFIDENTIAL
205920
25
10.3.
Appendix 3: Assessment Windows
No assessment windows will be applied.
 
 
 
75
2019N402257_00


CONFIDENTIAL
205920
26
10.4.
Appendix 4: Study Phases and Treatment Emergent 
Adverse Events
10.4.1.
Study Phases
Assessments and events will be classified according to the time of occurrence relative to 
study treatment.
Study Phase
Definition
Pre-Treatment 
Date ≤ Study Treatment Start Date
On-Treatment
Study Treatment Start Date ≤Date ≤ Study Treatment Stop Date
Post-Treatment
Date > Study Treatment Stop Date 
10.4.1.1.
Study Phases for Concomitant Medication
Study Phase
Definition
Prior
If medication end date is not missing and is before 28 days prior to screening visit
Concomitant
Any medication that is not a prior
NOTES: 

Please refer to Appendix 7: Reporting Standards for Missing Data for handling of missing and partial dates for 
concomitant medication. Use the rules in this table if concomitant medication date is completely missing.
 
 
 
76
2019N402257_00


CONFIDENTIAL
205920
27
10.4.2.
Treatment Emergent Flag for Adverse Events
Flag
Definition
Treatment 
Emergent

Any AE’s occurring after Period 1 dosing and before Period 2 dosing (predose), 
will be considered as Period 1 AE’s. Any AE’s occurring after Period 2 dosing will 
be considered as Period 2 AE’s.

For studies with greater than one treatment period (e.g., crossover study), if AE 
onset is during one period and worsens during a later period it would be counted 
in both periods. 
NOTES: 

If the study treatment stop date is missing, then the AE will be considered to be On-Treatment.

Time of study treatment dosing and start/stop time of AEs should be considered, if collected.
 
 
 
77
2019N402257_00


CONFIDENTIAL
205920
28
10.5.
Appendix 5: Data Display Standards & Handling 
Conventions
10.5.1.
Reporting Process
Software

The currently supported versions of SAS software 9.4 will be used.
Reporting Area
HARP Server
: UK1SALX00175
HARP Compound
: /arenv/arprod/gr121619/mid205920/final_01
Analysis Datasets 

Analysis datasets will be created according to Legacy GSK A&R dataset
Generation of RTF Files

RTF files will be generated for summary tables
10.5.2.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx):

4.03 to 4.23: General Principles

5.01 to 5.08: Principles Related to Data Listings

6.01 to 6.11: Principles Related to Summary Tables

7.01 to 7.13: Principles Related to Graphics 
Formats

All data will be reported according to the actual treatment the subject received unless otherwise stated.

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for reporting of 
data based on the raw data collected, unless otherwise stated.

Numeric data will be reported at the precision collected on the eCRF.

The reported precision from non eCRF sources will follow the IDSL statistical principles but may be
adjusted to a clinically interpretable number of DP’s.
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses:

Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled visit days 
on the analyses and interpretation of the results will be assessed as appropriate.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the subject’s listings. 
Unscheduled Visits

Unscheduled visits will not be included in summary tables and/or figures.

All unscheduled visits will be included in listings.
 
 
 
78
2019N402257_00


CONFIDENTIAL
205920
29
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Reporting of Pharmacokinetic Concentration Data
Descriptive Summary 
Statistics
Refer to IDSL Statistical Principle 6.06.1
Assign zero to NQ values (Refer to GUI_51487 for further details)
Reporting of Pharmacokinetic Parameters
Descriptive Summary 
Statistics.                      
(Loge Transformed)  
N, n, geometric mean, 90% CI of geometric mean, standard deviation (SD) of 
logged data and between geometric coefficient of variation (CVb (%)) will be 
reported.
CVb (%) = √ (exp(SD2) - 1) * 100 [NOTE: SD = SD of loge transformed    data]
Following steps can be used to calculate 90% CI for PK parameters:
Standard Error = [(Geometric Stdev-1)/Sqrt(N)],
Margin of Error = [Standard Error * 1.645], and
CI = [Geometric Mean Margin of Error]
Parameters Not 
Being Loge 
Transformed  
Tmax, and t1/2 
Summary Tables
The following PK parameters will not be summarised: tlast, Lambda_z, 
Lambda_z_lower, Lambda_z_upper, #pts and
r-squared .
The following PK parameters will not be log-transformed: Tmax. t1/2
All other parameters will be summarised as log-transformed and non-log-
transformed data as described in Section 8.1.2.
Listings
Include PK Parameters Cmax, Clast, tmax, tlast, AUC(0-3h), AUC(0-t), AUC (0-∞) 
),Cp(10), Cp(20), Cp(30) , t1/2, Clearance (IV only), Volume of distribution (IV only), 
F (Inhaled Bioavailability) Lambda_z, Lambda_z_lower, Lambda_z_upper, #pts and 
r-squared  as data permit
Reporting of Partial Dose / No treatment
If in a situation where a subject has received partial dose or a subject has received no treatment in a 
particular period, then they will be handled as given below:
Enrolled, Screened 
Population
Safety, PK 
Population
Listings, individual PK figures, Study Population tables 
without period treatment information 
Include
Include
Summary PK figures, Safety and PK tables with 
treatment information 
Include
Exclude
Graphical Displays
Refer to IDSL Statistical Principals 7.01 to 7.13.
 
 
 
79
2019N402257_00


CONFIDENTIAL
205920
30
10.5.3.
Reporting Standards for Pharmacokinetic
Pharmacokinetic Concentration Data
PC Windows Non-
Linear (WNL) File
PC WNL file (CSV format) for the non compartmental analysis by Clinical 
Pharmacology Modelling and Simulation function will be created according to IDSL 
Standards.
Note: Concentration values will be imputed as per GUI_51487
Descriptive Summary 
Statistics, Graphical 
Displays and Listings
Refer to IDSL PK Display Standards.
Refer to IDSL Statistical Principle 6.06.1.
Note: Concentration values will be imputed as per GUI_51487 for descriptive 
summary statistics/analysis and summarized graphical displays only. 
NONMEM/Pop PK 
File
Pop-PK file (CSV format) for the POP-PK analysis by Clinical Pharmacology 
Modelling and Simulation function will be created according to the data specification 
detailed in Section 9.1 Data Specification of the Pop-PK RAP (RAP-IVF116828-
201558-205920-PopPK, located in Cabinets/Study File/GR121619/_Project/Meta 
Analysis/ RAP-IVF116828-201558-205920-PopPK)
Pharmacokinetic Parameter Derivation
PK Parameter to be 
Derived by 
Programmer
The following PK parameters will be derived by the Programmer: Cp10, Cp20 and 
Cp30 and pre-dose
Pharmacokinetic Parameter Data
Is NQ impacted PK 
Parameters Rule 
Being Followed
Yes, refer to Standards for Handling NQ Impacted PK Parameters
Descriptive Summary 
Statistics, Graphical 
Displays and Listings
Refer to IDSL PK Display Standards.
Refer to Standards for the Transfer and Reporting of PK Data using HARP
 
 
 
80
2019N402257_00


CONFIDENTIAL
205920
31
10.6.
Appendix 6: Derived and Transformed Data
10.6.1.
General
Multiple Measurements at One Analysis Time Point

Mean of the measurements will be calculated and used in any derivation of summary statistics but if 
listed, all data will be presented.

Participants having both High and Low values for Normal Ranges at any post-baseline visit for safety 
parameters will be counted in both the High and Low categories of “Any visit post-baseline” row of 
related summary tables. This will also be applicable to relevant Potential Clinical Importance summary 
tables.
Study Day

Calculated as the number of days from First Dose Date:

Ref Date = Missing              → Study Day = Missing 

Ref Date < First Dose Date → Study Day = Ref Date – First Dose Date

Ref Data ≥ First Dose Date → Study Day = Ref Date – (First Dose Date) + 1    
10.6.2.
Study Population
Demographics
Age

GSK standard IDSL algorithms will be used for calculating age.

Randomization date will be used as reference date to calculate age
Body Mass Index (BMI)

Calculated as Weight (kg) / [Height (m)2
Extent of Exposure

Number of days of exposure to study drug will be calculated based on the formula:  
Duration of Exposure in Days = Treatment Stop Date – (Treatment Start Date) + 1

Participants who were randomized but did not report a treatment start date will be categorised as 
having zero days of exposure. 

The cumulative dose will be based on the formula:
Cumulative Dose = Sum of (Number of Days x Total Daily Dose)

If there are any treatment breaks during the study, exposure data will be adjusted accordingly.
 
 
 
81
2019N402257_00


CONFIDENTIAL
205920
32
10.6.3
Safety
ECG Parameters
RR Interval

IF RR interval (msec) is not provided directly, then RR can be derived as :
    [1] If QTcB is machine read & QTcF is not provided, then :
                       RR = [(QT/QTcB)^(2) ]*1000
    [2] If QTcF is machine read and QTcB is not provided, then: 
                       RR = [(QT/QTcF)^(3) ]*1000

If ECGs are manually read, the RR value preceding the measurement QT interval should be collected 
values THEN do not derive.
Corrected QT Intervals

When not entered directly in the eCRF, corrected QT intervals using Bazett’s (QTcB) and Fredericia’s 
(QTcF) formulas will be calculated, in msec, depending on the availability of other measurements.

IF RR interval (msec) is provided or calculated then missing QTcB and/or QTcF will be derived as :
 
 
 
82
2019N402257_00


CONFIDENTIAL
205920
33
10.7.
Appendix 7: Reporting Standards for Missing Data
10.7.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion (i.e. as specified in the protocol) was defined as who has 
completed all phases of the study including the follow-up visit(s).

Withdrawn subjects may be replaced in the study.

All available data from participants who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, unless 
otherwise specified.
10.7.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank fields on 
the collection instrument:
o
These data will be indicated by the use of a “blank” in subject listing displays. 
Unless all data for a specific visit are missing in which case the data is excluded 
from the table. 
o
Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such.
Outliers

Any participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
10.7.2.1.
Handling of Missing and Partial Dates
Element
Reporting Detail
General

Partial dates will be displayed as captured in subject listing displays.
Adverse Events

The eCRF does not allow for the possibility of partial dates. The eCRF and the 
site need to enter the full date or if not known, they would be required to 
complete an item level comment bubble to specify why the date is unknown. 
This would also be documented in the Data Quality Release Report by DM.

Completely missing start or end dates will remain missing, with no imputation 
applied. Consequently, time to onset and duration of such events will be missing
Concomitant 
Medications/Medical 
History

Partial dates for any concomitant medications recorded in the CRF will be 
imputed using the following convention:
o
If the partial date is a start date, a '01' will be used for the day and 'Jan' will 
be used for the month
o
If the partial date is a stop date, a '28/29/30/31' will be used for the day 
(dependent on the month and year) and 'Dec' will be used for the month.

The recorded partial date will be displayed in listings.
 
 
 
83
2019N402257_00


CONFIDENTIAL
205920
34
10.8.
Appendix 8: Values of Potential Clinical Importance
10.8.1.
Laboratory Values
Haematology
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Hematocrit 
Ratio of 
1
Male
0.54
Female
0.54
∆from BL
↓0.075
Haemoglobin
g/L
Male
180
Female
180
∆from BL
↓25
Lymphocytes 
x109/ L
0.8
Neutrophil Count 
x109/ L
1.5
Platelet Count 
x109/ L
100
550
While Blood Cell Count (WBC)
x109/ L
3
20
Clinical Chemistry
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Albumin 
g/L
30
Calcium
mmol/L
2
2.75
Creatinine
umol/L
∆from BL
↑ 44.2
Glucose
mmol/L
3
9
Magnesium
mmol/L
0.5
1.23
Phosphorus
mmol/L
0.80
1.60
Potassium
mmol/L
3
5.5
Sodium
mmol/L
130
150
Total CO2
mmol/L
18.0
32.0
Liver Function
Test Analyte
Units
Category
Clinical Concern Range
ALT/SGPT 
U/L
High
2x ULN
AST/SGOT 
U/L
High
2x ULN
AlkPhos 
U/L
High
2x ULN
T Bilirubin 
µmol/L
High
1.5xULN
T. Bilirubin + ALT
µmol/L
High
1.5xULN T. Bilirubin
+
2x ULN ALT
U/L
 
 
 
84
2019N402257_00


CONFIDENTIAL
205920
35
10.8.2.
ECG
ECG Parameter
Units
Clinical Concern Range
Lower
Upper
Absolute
Absolute QTc Interval
msec
> 450
Absolute PR Interval
msec
< 110
> 220
Absolute QRS Interval
msec
< 75
>110
10.8.3.
Vital Signs
Vital Sign Parameter
(Absolute)
Units
Clinical Concern Range
Lower
Upper
Systolic Blood Pressure
mmHg
< 85
> 160
Diastolic Blood Pressure
mmHg
< 45
> 100
Heart Rate
bpm
< 40
> 110
 
 
 
85
2019N402257_00


CONFIDENTIAL
205920
36
10.9.
Appendix 11: Abbreviations & Trade Marks
10.9.1.
Abbreviations
Abbreviation
Description
AE
Adverse Event
AIC
Akaike's Information Criteria
A&R
Analysis and Reporting 
CI
Confidence Interval
CPMS
Clinical Pharmacology Modelling & Simulation
COC
Combined Oral Contraceptive
non-COC
non-Combined Oral Contraceptive
CPSSO
Clinical Pharmacology Science & Study Operations
CS
Clinical Statistics
CSR
Clinical Study Report
CTR
Clinical Trial Register
CVb / CVw
Coefficient of Variation (Between) / Coefficient of Variation (Within)
DBF
Database Freeze
DBR
Database Release
DOB
Date of Birth
DP
Decimal Places
eCRF
Electronic Case Record Form
ECG
Electrocardiogram
EMA
European Medicines Agency
F
Inhaled Bioavailability
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Clinical Results Disclosure Requirements
FEV1.0
Forced expiratory volume at 1 minute
FPD
Future Pipelines Discovery
GSK
GlaxoSmithKline
IA
Interim Analysis
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee 
IDSL
Integrated Data Standards Library
IH
Inhaled
IM
Intramuscular
IMMS
International Modules Management System
IP
Investigational Product
I.U.
International units
IV
Intravenous
MMRM
Mixed Model Repeated Measures
PCI
Potential Clinical Importance 
PCPS
Projects, Clinical Platforms and Sciences
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan
 
 
 
86
2019N402257_00


CONFIDENTIAL
205920
37
Abbreviation
Description
PK
Pharmacokinetic
PP
Per Protocol
PopPK
Population PK
QC
Quality Control
QTcF
Frederica’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
RAP
Reporting & Analysis Plan
SAC
Statistical Analysis Complete
SAE
Serious Adverse Event
SPDS
Statistics, Programming and Data Sciences
SOP
Standard Operation Procedure
TA
Therapeutic Area
TFL
Tables, Figures & Listings 
TSL
Third stage of labour
10.9.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
ROTAHALER
WinNonlin
 
 
 
87
2019N402257_00


CONFIDENTIAL
205920
38
10.10.
Appendix 12: List of Data Displays
10.10.1.
Data Display Numbering
All displays (Tables, Figures & Listings) will use the term 'Subjects'. The following 
numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.6
N/A
Pharmacokinetic
2.1 to 2.5
2.1 to 2.7
Safety
3.1 to 3.16
N/A
Section
Listings
ICH Listings
1 to 24
Other Listings
25 to 29
10.10.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in Appendix 13: Example Mock Shells for Data Displays.
Section
Figure
Table
Listing
Pharmacokinetic
N/A
PK_Tn
N/A
NOTES: 

Non-Standard displays are indicated in the ‘IDSL /  Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’
10.10.3.
Deliverables
Delivery [Priority] [1]
Description
DR [1]
Prior to DBR. Dry Run for Study Pop, Safety & PK concentration displays 
(Summary Table and Mean/Median plots)
DR [2]
Post DBF, prior to SAC. Dry Run for displays not part of Dry run [1]
SAC
Final Statistical Analysis Complete
NOTES: 
1.
Indicates priority (i.e. order) in which displays will be generated for the reporting effort
 
 
 
88
2019N402257_00


CONFIDENTIAL
205920
39
10.10.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.1.
Safety
ES1A
Summary of Participant Disposition for the Participant
Conclusion Record
By Cohort
ICH E3, FDAAA, EudraCT
DR [1], SAC
1.2.
Enrolled
NS1
Summary of Number of Subjects Enrolled by Country and Site 
ID
By Cohort
EudraCT/Clinical Operations
DR [1], SAC
Population Analysed
1.3.
Screened
SP1
Summary of Study Populations 
By Cohort
DR [1], SAC
Demographic and Baseline Characteristics
1.4.
Safety
DM3
Summary of Demographic Characteristics
By Cohort
ICH E3, FDAAA, EudraCT
DR [1], SAC
1.5.
Enrolled
DM11
Summary of Age Ranges
By Cohort EudraCT
DR [1], SAC
1.6.
Safety
DM5
Summary of Race and Racial Combinations
By Cohort
ICH E3, FDA, FDAAA, EudraCT
DR [1], SAC
 
 
 
89
2019N402257_00


CONFIDENTIAL
205920
40
10.10.5.
Pharmacokinetic Tables
Pharmacokinetic Tables
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
PK Concentration Data
2.1.
PK
pkct1
Summary of Plasma Concentration-time Data
By Cohort
DR [1], SAC
PK Derived Parameters
2.2.
PK
pkpt1
Summary of Derived Plasma Pharmacokinetic Parameters
(untransformed data)
By Cohort
DR [2], SAC
2.3.
PK
pkpt3
Summary of Derived Plasma Pharmacokinetic Parameters (log-
transformed data)
By Cohort
DR [2], SAC
Statistical Analysis Tables
2.4.
PK
PK_T1
Summary of Statistical Analysis of Loge-transformed 
Pharmacokinetic Parameters (IH Formulation)
For Cp10, Cp20, Cp30, Cmax, AUC(0-
3h) and AUC(0-inf) only.
Include treatment dosage in the 
footnote (Refer Section 5.1)
DR [2], SAC
2.5.
PK
PK_T2
Summary of Statistical Analysis of un-transformed 
Pharmacokinetic Parameter (IH Formulation)
For t1/2 and Tmax only
Include treatment dosage in the 
footnote (Refer Section 5.1)
DR [2], SAC
 
 
 
90
2019N402257_00


CONFIDENTIAL
205920
41
10.10.6.
Pharmacokinetic Figures
Pharmacokinetic Figures
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Individual Concentration Plots
2.1.
PK
pkcf1x
Individual Plasma Concentration-time Plot (Linear and Semi-log) 
by Subject
By Cohort, By Subject
DR [2], SAC
2.2.
PK
pkcf6
Individual Subject Plasma Concentration-time Plot (Linear and 
Semi-log) by Treatment
By Cohort, By Treatment
DR [2], SAC
Mean/Median Plots
2.3.
PK
pkcf4
Arithmetic Mean (±SD) Plasma Concentration-time Plot (Linear 
and Semi-log) – Cohort Comparison
Use nominal times in X Axis. By 
treatment. Produce two curves one for 
COC and one for non-COC.
DR [1], SAC
2.4.
PK
pkcf5
Median (range) Plasma Concentration-time Plot (Linear and 
Semi-log) (IH Formulation)– Cohort Comparison
Use nominal times in X Axis, By
treatment
DR [1], SAC
2.5.
PK
pkcf4
Arithmetic Mean (±SD) Plasma Concentration-time Plot (Linear 
and Semi-log) – Treatment Comparison
Use nominal times in X Axis. By Cohort. 
Produce three curves. One each for IH, 
IV Bolus, IV infusion
DR [1], SAC
2.6.
PK
pkcf5
Median (range) Plasma Concentration-time Plot (Linear and 
Semi-log) (IH Formulation)– Treatment Comparison
Use nominal times in X Axis, By Cohort
DR [1], SAC
Comparative plots
2.7.
PK
pkpf3
Comparative Plot of Individual Subject Plasma Pharmacokinetic
Parameter Versus Treatment
For all PK Parameter page by 
Treatment sequence;
By Cohort
DR [2], SAC
 
 
 
91
2019N402257_00


CONFIDENTIAL
205920
42
10.10.7.
Safety Tables
Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events (AEs)
3.1.
Safety
AE1CP
Summary of All Adverse Events by System Organ Class and 
Preferred Term
By Cohort
DR [1], SAC
3.2.
Safety
AE1CP
Summary of Drug-Related Adverse Events
By Cohort
DR [1], SAC
3.3.
Safety
AE1CP
Summary of Non-Serious Adverse Events
By Cohort
DR [1], SAC
3.4.
Safety
AE15
Summary of Common (>1 Subject) Non-serious Adverse Events 
by System Organ Class and Preferred Term (Number of 
Subjects and Occurrences)
By Cohort 
FDAAA, EudraCT
DR [1], SAC
Serious and Other Significant Adverse Events
3.5.
Safety
AE16
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Subjects and Occurrences)
By Cohort
FDAAA, EudraCT
DR [1], SAC
3.6.
Safety
AE1CP
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Drug or Withdrawal from Study
By Cohort
DR [1], SAC
Laboratory: Chemistry 
3.7.
Safety
LB1
Summary of Chemistry Laboratory Values
By Cohort
DR [1], SAC
3.8.
Safety
LB1
Summary of Change from Baseline for Chemistry Laboratory 
Values
By Cohort
DR [1], SAC
 
 
 
92
2019N402257_00


CONFIDENTIAL
205920
43
Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Laboratory: Hematology
3.9.
Safety
LB1
Summary of Haematology Laboratory Values
By Cohort
DR [1], SAC
3.10.
Safety
LB1
Summary of Change from Baseline for Haematology Laboratory 
Values
By Cohort
.
DR [1], SAC
Spirometry
3.11.
Safety
LB1
Summary of Spirometry data
By Cohort.
DR [1], SAC
ECG
3.12.
Safety
EG1
Summary of ECG Findings 
By Cohort
DR [1], SAC
3.13.
Safety
EG2
Summary of ECG Values
By Cohort
DR [1], SAC
Vital Signs
3.14.
Safety
VS1
Summary of Vital Signs
By Cohort
DR [1], SAC
3.15.
Safety
VS1
Summary of Change from Baseline for Vital Signs
By Cohort
DR [1], SAC
3.16.
Safety
VS7
Summary of Vital Sign Results Relative to Potential Clinical 
Importance (PCI) Criteria Post-Baseline Relative to Baseline
By Cohort
DR [1], SAC
 
 
 
93
2019N402257_00


CONFIDENTIAL
205920
44
10.10.8.
ICH Listings
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.
    Screened
ES7
Listing of Reasons for Screening Failures
By Cohort
DR [1], SAC
2.
Safety
ES3
Listing of Reasons for Withdrawal
By Cohort
DR [1], SAC
3.
Safety
TA2
Listing of Randomized and Actual Treatments
By Cohort
DR [1], SAC
Protocol Deviations
4.
Safety
DV2A
Listing of Important Protocol Deviations 
By Cohort
.
DR [1], SAC
5.
Safety
IE4
Listing of Participants with Inclusion/Exclusion Criteria 
Deviations
By Cohort
DR [1], SAC
Populations Analysed
6.
Enrolled
SP3A
Listing of Participants Excluded from Analysis Population
By Cohort
DR [1], SAC
Demographic and Baseline Characteristics
7.
Safety
DM4
Listing of Demographic Characteristics
By Cohort
DR [1], SAC
8.
Safety
DM10
Listing of Race
By Cohort
DR [1], SAC
Prior and Concomitant Medications
9.
Safety
CM5
Listing of Concomitant Medications
By Cohort
DR [1], SAC
Exposure and Treatment Compliance
10.
Safety
        EX4
Listing of Exposure Data
By Cohort
DR [1], SAC
Adverse Events
11.
Safety
AE9 
Listing of All Adverse Events
By Cohort
DR [1], SAC
 
 
 
94
2019N402257_00


CONFIDENTIAL
205920
45
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
12.
Safety
AE7
Listing of Subject Numbers for Individual Adverse Events
By Cohort
DR [1], SAC 
Serious and Other Significant Adverse Events
13.
Safety
AE9
Listing of  Serious Adverse Events
By Cohort
DR [1], SAC
14.
Safety
AE9
Listing of Adverse Events Leading to Withdrawal from Study
By Cohort
DR [1], SAC
All Laboratory
15.
Safety
LB6
Listing of Laboratory Values of Potential Clinical Importance
By Cohort
DR [1], SAC
16.
Safety
LB6
Listing of All Laboratory Data for Subjects with Any Value of 
Potential Clinical Importance 
By Cohort
DR [1], SAC
17.
Safety
LB6
Listing of Hematology Values of Potential Clinical Importance
By Cohort
DR [1], SAC
18.
Safety
LB6
Listing of All Hematology Laboratory Data for Subjects with Any 
Value of Potential Clinical Importance 
By Cohort
DR [1], SAC
19.
Safety
UR2B
Listing of Urinalysis Data
By Cohort
DR [1], SAC
ECG
20.
Safety
EG4
Listing of All ECG Values for Participants with Any Value of 
Potential Clinical Importance
By Cohort
DR [1], SAC
21.
Safety
EG4
Listing of ECG Values of Potential Clinical Importance
By Cohort
DR [1], SAC
22.
Safety
         EG6
Listing of Abnormal ECG Findings
By Cohort
DR [1], SAC
Vital Signs
23.
Safety
VS5
Listing of All Vital Signs Data for Subjects with Any Value of 
Potential Clinical Importance
By Cohort
DR [1], SAC
24.
Safety
VS5
Listing of Vital Signs of Potential Clinical Importance
By Cohort
DR [1], SAC
 
 
 
95
2019N402257_00


CONFIDENTIAL
205920
46
10.10.9.
Non-ICH Listings
Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Safety
25.
Safety
EG4
Listing of Spirometry data
By Cohort
DR [1], SAC 
PK Concentration
26.
PK
PK08
Listing of Plasma Pharmacokinetic Concentration-Time Data
By Cohort
DR [2], SAC
PK Parameter
27.
PK
PK14
Listing of Derived Plasma Pharmacokinetic
Parameters
By Cohort
DR [2], SAC
28.
PK
N/A
Raw SAS output for Summary of Statistical Analysis of Loge-
transformed Pharmacokinetic Parameters for IH formulation
For Cp10, Cp20, Cp30, Cmax, AUC(0-
3h) and AUC(0-inf) only.
Include treatment dosage in the 
footnote (Refer Section 5.1). Include 
footnotes present in the corresponding 
analysis table
DR [2], SAC
29.
PK
N/A
Raw SAS output for Summary of Statistical Analysis of un-
transformed Plasma Pharmacokinetic Parameter for IH 
formulation
For t/2 and Tmax only
Include treatment dosage in the 
footnote (Refer Section 5.1).
Include footnotes present in the 
corresponding analysis table
DR [2], SAC
 
 
 
96
2019N402257_00


CONFIDENTIAL
205920
47
10.11.
Appendix 13: Example Mock Shells for Data Displays
Example 
: PK_T1
Page 1 of n
Protocol
: GR121619
Population
: Pharmacokinetic 
                                                                                       
                            Table PK_T1
Summary of Statistical Analysis of log transformed GR121619 Pharmacokinetic Parameters for IH formulation
        
      
Parameter (units)              Comparison                               Geom.LsMean               
Ratio                    90% 
                                                                                                             ------------------------------                                    Confidence Interval
                                                                                                            n        Test            n       Ref
  --------------------------------------------------------------------------------------------------------
AUC(0-t)(µg.h/mL)    COC vs non-COC         xx   x.xxx   xx x.xxx    x.xxx        (x.xxx,  x.xxx)
Note:1. Mixed Effect Model has been used for the analysis. Cohort (COC/Non-COC is fitted as Fixed Effect. 
Subject is fitted as Random Effect. 
2.
_______________ covariance structure is used
 
 
 
97
2019N402257_00


CONFIDENTIAL
205920
48
Example 
: PK_T2
Page 1 of n
Protocol
: GR121619
Population
: Pharmacokinetic 
                            Table PK_T2
Summary of Statistical Analysis of un-transformed Pharmacokinetic Parameter IH Formulation
        
      
Parameter (units)      Comparison          
              Median               
Diff                   90% 
                                                                                                ------------------------------                                       Confidence Interval
                                                                                                 n        Test            n       Ref
  --------------------------------------------------------------------------------------------------------
T1/2            COC vs non-COC        xx   x.xxx    xx x.xxx     x.xxx    (x.xxx, x.xxx)
Appropriate footnotes to be used
 
 
 
98
2019N402257_00