A Randomised Placebo Controlled Trial of the Effectiveness of Early MEtformin in Addition to Usual Care in the Reduction of Gestational Diabetes Mellitus Effects (EMERGE)
Phase: PHASE3
Conditions: Gestational Diabetes
Sponsor: National University of Ireland, Galway, Ireland

 
 
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Title page 
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A Randomised Placebo Controlled Trial of the effectiveness of Early MEtformin in Addition to Usual 
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Care in the Reduction of Gestational Diabetes Mellitus Effects (EMERGE) 
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Protocol Version no.:  
 
6.0 
 
 
 
Date:02-May- 2019 
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Test Drug:  
 
 
Metformin 
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Clinical Phase:   
 
III 
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EudraCT number: 
 
2016-001644-19 
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Sponsor Number:  
 
NUIG-2016-01 
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Principal Investigator:   
Prof. Fidelma Dunne 
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School of Medicine 
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Clinical Science Institute 
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National University of Ireland, Galway 
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Galway, Ireland 
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Fidelma.Dunne@nuigalway.ie 
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Co-ordinating Centre:   
HRB Clinical Research Facility Galway 
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National University of Ireland Galway 
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University Hospital Galway 
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Newcastle Road 
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Galway, Ireland 
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(091) 495 964 
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Sponsor:  
 
 
Prof. Lokesh Joshi  
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(Vice President of Research) 
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National University of Ireland Galway 
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University Road 
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Galway 
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(091) 495 678 
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The study will be conducted in compliance with the protocol, International Conference on 
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Harmonization – Good Clinical Practice (ICH-GCP) and any applicable regulatory requirements. 
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Confidential 
This document contains confidential information that must not be disclosed to anyone other than the 
sponsor, the investigative team, regulatory authorities, and members of the research ethics 
committee. 

 
 
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1. SPONSOR PROTOCOL AGREEMENT PAGE 
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I, the undersigned, am responsible for the overall conduct of the trial and agree to the content of the 
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final clinical trial protocol, as presented. 
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Signed 
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__________________________________ 
 
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Sponsor Representative 
 
 
Date 
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2. INVESTIGATOR PROTOCOL AGREEMENTS  
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2.1. Chief Investigator Agreement 
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I, the undersigned, agree to the content of the final clinical trial protocol, as presented. 
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Signed 
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_______________________________  
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Chief Investigator 
 
 
 
Date 
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2.2 Site Investigator Agreement 
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I, the undersigned, am responsible for the conduct of the trial at this site and agree to the following: 
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I understand and will conduct the trial according to the protocol, any approved protocol amendments, 
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ICH GCP and all applicable regulatory authority requirements and national laws. 
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I will not deviate from the protocol without prior written approval from the HPRA and the Ethics 
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Committee, except where necessary to prevent any immediate danger to the participant. 
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I have sufficient time to properly conduct and complete the trial within the agreed trial period, and I 
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have available an adequate number of qualified staff and adequate facilities for the foreseen duration 
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of the trial to conduct the trial properly and safely. I will ensure that any staff at my site(s) who are 
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involved in the trial conduct are adequately trained regarding the protocol and their responsibilities.   
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Signed 
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_________________________________ 
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Principal Investigator     
                          Date 
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Table of Contents 
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162 
1. 
SPONSOR PROTOCOL AGREEMENT PAGE 
2 
163 
2. 
INVESTIGATOR PROTOCOL AGREEMENTS 
3 
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2.1 
Chief Investigator Agreement 
3 
165 
2.2 
Site Investigator Agreement 
4 
166 
3. 
DOCUMENT HISTORY 
8 
167 
4. 
SYNOPSIS 
16 
168 
5. 
ABBREVIATIONS 
19 
169 
6. 
INTRODUCTION 
22 
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6.1 
BACKGROUND INFORMATION 
22 
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6.1.1 
What is Gestational Diabetes Mellitus? 
22 
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6.1.2 
How common is Gestational Diabetes Mellitus? 
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6.1.3 
Why is Gestational Diabetes Mellitus Clinically Important in the Short Term? 
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6.1.4 
Why is Gestational Diabetes Mellitus Clinically Important in the Long Term? 
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6.1.5 
Does Treating GDM Improve Clinical Outcomes? 
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6.1.6 
Limitations of Insulin Therapy 
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6.1.7 
Metformin use for GDM 
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6.2 
RATIONALE FOR THE STUDY 
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7. 
STUDY OBJECTIVES 
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7.1 
Primary objective 
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7.2. 
Secondary objectives 
26 
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7.3. 
Primary and secondary outcome measures 
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7.3.1 
Primary Outcome Measure 
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7.3.2 
Secondary Outcome Measures 
27 
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8. 
TRIAL DESIGN 
27 
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8.1. 
Design Summary 
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8.1.1 
Treatment Group 
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8.1.2 
Placebo Group 
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8.1.3 
Usual Care 
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8.2. 
Selection of Study Population 
29 
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8.2.1 
Population 
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8.2.2 
Inclusion Criteria 
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8.2.3 
Exclusion Criteria 
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8.3. 
Study Visits and procedures 
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8.3.1 
Screening and Randomisation Visit and Procedures 
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8.3.2 
Prenatal Visit and Procedures 
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8.3.3 
Delivery Visit 
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8.3.4 
Phone Visit (Visit 1 Post-Partum) 
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8.3.5 
12 Week Post-Partum Visit (Visit 2 Post-Partum) 
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8.4 
Description of Study Procedures 
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8.4.1 
Informed Consent 
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8.4.2 
Medical History 
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8.4.3 
Physical Assessments 
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8.4.4 
OGTT 
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8.4.5 
Laboratory Tests 
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8.4.6 
Bio-banking 
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8.4.7 
Glucometer data 
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8.4.8 
Study Drug Accountability 
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8.4.9 
Neonatal Measurements 
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8.5 
Randomisation 
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8.6 
Blinding 
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8.6.1 
Emergency Unblinding 
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8.7 
Definition of end-of-trial 
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8.7.1 
Premature termination of the study 
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8.8 
Discontinuation/withdrawal of participants from study treatment 
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9. 
TREATMENT OF TRIAL PARTICIPANTS 
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9.1 
Description of study treatments 
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9.1.1 
Usual Care 
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9.1.2 
Treatment Group 
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9.1.3 
Placebo Group 
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9.1.4 
Requirement for Insulin 
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9.2 
Formulation, packaging, and handling 
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9.3 
Storage of study treatments(s) 
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9.4 
Accountability of the study treatment(s) 
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9.5 
Assessment of compliance 
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9.5.1 
Missed Dose 
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9.6 
Overdose of study treatment 
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9.7 
Prior and concomitant therapy 
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9.7.1 
Permitted Medications/Non- Investigational Medicinal Products 
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9.7.2 
Prohibited Medications 
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9.7.3 
Cautionary Medications 
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10. 
SAFETY REPORTING 
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10.1 
Definitions 
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10.1.1 
Adverse event (AE) 
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10.1.2 
Adverse reaction (AR) 
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10.1.3 
Serious adverse event (SAE) 
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10.1.4 
Severe adverse events 
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10.1.5 
Suspected unexpected serious adverse reactions 
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10.2 
Evaluations of AEs and SAEs 
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10.2.1 
Assessment of seriousness 
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10.2.2 
Assessment of casuality 
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10.2.3 
Assessment of severity 
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10.2.4 
Assessment of expectedness 
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10.3 
Reporting Responsibilities of the investigator 
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10.3.1 
Adverse Events/Serious Adverse Events 
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10.3.2 
Timelines for reporting 
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10.3.3 
Safety Reporting for Non-IMP 
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10.4 
Reporting responsibilities of the sponsor 
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10.4.1 
Regulatory Authorities 
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10.4.2 
Safety Reports 
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10.4.3 
Annual Reports 
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10.4.4 
Safety reports for non-IMP 
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10.5 
Data safety monitoring board (DSMB) 
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10.6 
Trial Steering and Advisory Group 
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11. 
STATISTICS 
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11.1 
General Considerations 
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11.2 
Determination of sample size 
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11.3 
Analysis Sets 
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11.3.1 
Intention-to-Treat Analysis Set 
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11.3.2 
Safety Analysis Set 
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11.4 
Demographic and baseline disease characteristics 
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11.5 
Effectiveness Analysis 
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11.5.1 
Primary Effectivness Outcomes 
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11.5.2 
Secondary Effectiveness Outcomes 
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11.5.3 
Health Economic Outcomes 
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11.6 
The level of statistical significance 
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11.7 
Procedure for accounting for missing, unused and spurious data 
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11.8 
Health economic analysis 
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12. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
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13. 
DATA HANDLING AND RECORD KEEPING 
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13.1 
Data collection, source documents and case report forms (CRF): 
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13.2 
Data reporting 
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14. 
RETENTION OF ESSENTIAL DOCUMENTS 
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15. 
REGULATIONS, ETHICS, COMPLIANCE AND GOVERNANCE 
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15.1 
Sponsorship 
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15.2 
Indemnity 
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15.3 
Finance 
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15.4 
Regulatory and Ethical Approvals 
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15.5 
Audits and Inspections 
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15.6 
Ethical Considerations 
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15.7 
Protocol Compliance 
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15.8 
Patient Confidentiality 
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15.9 
Good Clinical Practice 
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16. 
AUDITS AND INSPECTIONS 
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17. 
ETHICS 
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17.1 
Approvals 
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17.2 
Benefits and risks assessment 
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17.3 
Participant confidentiality 
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18. 
CLINICAL STUDY REPORT AND PUBLICATION POLICY 
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19. 
REFERENCES 
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3. DOCUMENT HISTORY 
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Document Version 
Date of Issue 
 
Summary of Change 
1.0 
5th August 2016 
 
Original version
2.0 
23rd September 2016 
Update to inclusion criteria and exclusion criteria. 
 
3.0 
29th September 2016 
 
Update to Section 9.2.1. Exceptions from 
AE/SAE reporting 
 
Updates to sections 7.3.1 and 7.4.4. have 
been made to reflect the previous changes 
to the exclusion/exclusion criteria made in 
the version 2 protocol 
 
The MA holder has been updated in section 
8.2. to Merck Santé  
 
Section 8.2. has been updated to include 
bottle sizes of 170 tablets 
 
Typographical Corrections 
4.0  
22nd August 2017 
 
Update to section 6.2. Rational for the 
Study, with reference to changes in 
inclusion criteria and typographical error in 
primary outcome timepoint. 
 
Update to wording in section 7.1. Primary 
Objective 
 
Timepoints of assessments have been 
removed in section 7.2. Secondary 
Objectives  
 
Clarification provided on primary outcome 
measure section 7.3.1. 
 
Update to section 8.1.3. Usual Care to 
include a trained delegate 
 
Update to 8.2. Selection of Study 
Population, inclusion and exclusion criteria  
 
Update to 8.3.1. to reflect changes in 
inclusion criteria. 
 
Timepoints for study drug accountability, 
bio-banking, laboratory tests, updated in 
section 8.3.2. Prenatal Visits and 
Procedures. Study visit windows also 
removed. 
 
Update to Figure 2 Schedule of Events to 
reflect changes in timepoints in section 
8.3.2. 
 
Section 8.3.4. 4 weeks post-partum visit 
updated to Visit 1 post-partum with updates 
to figure 2  
 
Section 8.3.5. 12 weeks post-partum visit  
with updates to figure 2 updated to Visit 2 
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 
Section 8.4.1. updated to reflect changes in 
biobanking timepoints.  
 
Updates to section 8.4.5. Laboratory Tests 
 
Update to 8.4.6. Biobanking, to include a 
maternal biobanking sample at Visit 7 (week 
12) 
 
Type of glucometer used and quantity of 
data downloaded, and use of data updated 
in section 8.4.7. Glucometer Data. 
 
Timepoints for study drug accountability 
updated in section  8.4.8. Study Drug 
Accountability 
 
Update to 9.1.1. Usualcare to include a 
trained delegate. 
 
Storage temperature updated in section 9.3. 
Storage of Study Treatment(s) to below 
30°C 
 
Medication supplied by the contracted 
packaging provider updated in section 9.4. 
Accountability of Study Treatments  
 
Section 9.5. Assessment of Compliance 
updated to reflect change in timepoints for 
study drug accountability. 
 
Update to section 9.7. Prior and 
Concomitant Therapy to include exceptions 
from con med recording. 
 
Updates to Section 9.7.3. Cautionary 
medications  
 
Update to section 10.2.1 Exceptions from 
SAE reporting. 
 
Email address to report SAE’s to the 
sponsor removed in section  10.3.1 Adverse 
Events/Serious Adverse Events as reporting 
will be via the eCRF. 
 
Section 11.6 Level of Statistical Significance 
updated to include 95% confidence Intervals 
 
Section 15.2 Indemity updated to include 
information from section 18. Section 18 
removed. 
 
Update to 15.7. Protocol Complaince 
 
Removal of  sections 17.1 and 17.2 as the 
information was contained within section 15 
 
Typographical Corrections throughout 
5.0 
27th November 2017 
 
Update to Table of contents page 10 
 
Typographical corrections in section 4.0 
“Synopsis” and section 8.4.6 “Biobanking”. 
 
Updates to figure 1 to include addition of  
box for baby procedures at 4 week post 
partum visit and 12 week post partum visit 
to align with text in section 8.3.4. “Phone 
Visit (Visit 1 Post-Partum)” and section 8.3.5 

 
 
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“12 Week Post-Partum Visit (Visit 2 Post-
Partum)”. 
 
Updates to section 8.3.3. Delivery Visit 
include removal of height, weight and BMI 
measurements at the delivery visit 
 
Update to figure 2 include: 
a) Addition of text “weeks post 
randomisation”  
b) Addition of status of baby and 
neonatal measurements at 12 week 
post partum visit to align with text in 
section 8.3.5 “12 Week Postpartum 
Visit” 
 
Updates to section 8.4.5. Laboratory Tests 
include: 
a) Addition of visit window for 12 week 
post partum visit “+/- 4 weeks”. 
b) addition of urea, creatine, alanine 
aminotransferase (ALT), and 
aspartate transaminase (AST) at the 
randomisation visit as per the 
requirements of protocol version 
3.0. 
 
Update to section 8.4.7 “Glucometer Data” 
to clarify data will be reviewed at each “on-
site” visit. 
 
Update to section 8.4.9. Neonatal 
Measurements to include ‘weight’ 
 
Update to section 15.1. “Sponsorship” to 
change “Principal Investigator” to “Chief 
Investigator”. 
6.0 
02-May- 2019 
 
Update to Table of contents page 5 and to 
the footer throughout the protocol 
 
Updates to formatting and spacing have 
been made throughout the protocol  
 
The abbreviation of GDPR has been added 
to the list of abbreviations in section 5 
 
Update to sections 4 “synopsis” and section 
8.2.3. “exclusion criteria” ,and to all further 
references made throughout the protocol to 
study exclusion criteria: “Known foetal 
anomaly” which was the previous exclusion 
criteria has since been updated to “major 
congenital malformations or an abnormality 
deemed unsuitable for metformin by the 
site PI or attending consultant” to define 
congenital anomalies  which are a study 
exclusion criteria 
 
Update to sections 4 “synopsis”, sections 
8.1.2 and 8.3.4 and to all further references 
made throughout the protocol to the 4 week 

 
 
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post partum visit: 
The visit window for the 4 week post partum 
visit has since been updated from +/- 5 days 
to +/- 7 days.  
 
Update made to section 4 ”Synopsis” to 
remove reference to Cork University 
Hospital as a trial site. Portiuncula 
University Hospital and Mayo University 
Hospital have since been added to this 
section. 
 
The words “subject” and “women” used 
throughout the protocol when referring to 
trial participants has since been replaced to 
simply “participant”. 
 
Definition of “Neonatal hypoglycaemia” has 
been expanded in section 7.3.2 
 
Section 8.1 “Design Summary” has been 
updated to clarify that participants are 
followed up until 12 weeks post partum (+/- 
4 weeks). The reference to the number of 
trial sites has since been updated to state 
that the trial will take place in upto 3 trial 
sites. 
 
Section 8.1.2 “Placebo Group” has been 
updated to include the visit windows for the 
4 week and the 12 week post partum study 
visits.  
 
Updates to figure 1 include:  
o 
“Usual care received” to be 
obtained at randomisation and the 
week 4 visit has been added 
o 
“EQ5D-5L” and “medical 
resources” to be obtained at the 
randomisation visit has been added 
o 
Return of study drug every 4 weeks 
has been added  
o 
“Physical measurements” and “vital 
signs” have since been moved from 
the “2 weekly post randomisation” 
box to the box containing additional 
procedures to be undertaken 
during the prenatal treatment study 
phase, as per the protocol update 
o 
The maternal bio-banking sample 
at randomisation and week 12 post 
randomisation has been removed 
from figure 1, as this substudy has 
been removed from the main 
protocol  
o 
“Adverse events” has been added 
to the 4 week and 12 week post 
partum visits scheduled for the 

 
 
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mother, as per the schedule of 
visits and procedures. “Adverse 
events” has also been added to the 
delivery, 4 week and 12 week post 
partum visits for the baby. 
o 
Addition of statement of “in person 
visits only” when referring to 
glucometer data download during 
the 2 weekly post randomisation 
study visits. 
o 
Addition of “last routine HbA1c” and 
“gastrointestinal events” to the box 
outlining the study procedures at 
the fortnightly post randomisation 
study visits 
o 
Removal of “laboratory samples” 
from the box containing the delivery 
procedures for the mother, which 
were removed in protocol version 
4.0 
o 
Removal of “cord blood bio-
banking” from the box outlining the 
study procedures for the baby at 
the delivery visit, as this has been 
removed from the main study 
protocol 
o 
Removal of “height and weight” 
from the box outlining the study 
procedures for the baby at the 12 
week post-partum study visit 
o 
“Vital signs” has been added to the 
box outlining the schedule of 
events at the 12 week post partum 
visit in the mother, as per the the 
protocol 
 
Updates have been made to section 8.3.1 
“Screening and Randomisation Visit and 
Procedures”. The previous sentence of “all 
con meds including herbal and vitamin 
supplements” has been removed when 
referring to the review of concomitant 
medications during this visit. The bio-
banking component of the study has since 
been removed from the main study protocol 
into a sub-study protocol,which is 
acknowleded in the amended text.  
 
Updates made to section 8.3.2  “prenatal 
visit and procedures”. Removed the 
requirement to obtain physical 
measurements and vital signs every 2 
weeks, and instead specified these 
measurements are to be obtained at the 32 

 
 
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week (+/- 1 week) and 38 week (+/- 1 
week) gestation visits. Removed the 
requirement to obtain the maternal blood 
sample for bio-banking at gestational week 
38 (+/- 1 week). A sentence was also 
added to the “glucometer data download” 
procedure, to acknowledge that this applies 
for in person visits only. Sentence was 
added to state “visits that do not require an 
in person physical measurement, laboratory 
assessment or drug dispensation can be 
completed over the telephone”.  
 
A sentence has been added to bullet point 
number 3 “adverse events” in section 8.3.3 
“Delivery visit” to clarify that adverse events 
are to be collected for both the mother and 
baby 
 
The collection of “adverse events” in both 
the mother and baby for the schedule of 
procedures at the week 4 and the week 12 
post partum visits have been added to  
sections 8.3.4 and section 8.3.5, as per the 
protocol 
 
Removed requirement to collect “height and 
weight of baby” from section 8.3.5 “12 week 
Post-Partum Visit”. 
 
Updates to Figure 2 include: 
o 
New column for “additional Visit(s)” 
which may occur pre-natally has 
been added  
o 
Additional superscripts have been 
added to certain procedures, which 
has updated previous letters as a 
result. These additional 
superscripts were added to clarify 
further when procedures are 
required. Additional footnotes have 
been added at the end of figure 2 
as a result.  
o 
Reference to obtain neonatal 
measurements at the 12 week post 
partum visit has been removed 
o 
The figure has been updated to 
account for the return of study drug 
every 4 weeks during pre-natal 
study visits 
o 
The bio-banking sample which was 
previously listed as a study 
procedure at the week 12 post 
randomisation visit has been 
removed, as this substudy is being 
removed from the main protocol 

 
 
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o 
“Adverse Events” has been added 
to the list of neonatal procedures at 
the delivery, 4 week post partum 
and 12 week post partum visits for 
clarity  
 
The reference to obtaining additional 
consent for the maternal biobanking 
samples and the cord blood samples in 
section 8.4.1 “Informed consent” has been 
removed, as this will no longer form part of 
the main protocol study procedures 
 
Section 8.4.2 “Medical history” has been 
updated to clarify the relevant required 
medical conditions to be documented at the 
screening visit 
 
Section 8.4.5 “laboratory tests” has been 
updated. The word “fasting” has been 
removed from both the insulin and c-
peptide laboratory assessments performed 
at the randomisation visit, as these 
particular assessments do not require the 
participant to be fasting.   
 
Section 8.4.6 “Bio-banking” has been 
updated to remove the bio-banking 
component of the study from the main 
study protocol. Participants at all trial sites 
will be invited to partake in the bio-banking 
sub-study preapproved by the research 
ethics committee, as guided by local 
practice patterns and the availability of 
resources (including staff). All further 
references made to the collection of cord-
blood biobanking samples at delivery and 
the maternal bio-banking samples at 
randomisation and week 12 post 
randomisation throughout the protocol have 
been revised accordingly. 
 
Section 8.4.7 “glucometer data” has been 
updated to acknowledge that glucometer 
data will be downloaded at a subsequent in 
person study visit 
 
Section 8.4.8 “study drug accountability” 
has been updated to revise the sentence 
“participants will be deemed compliant if 
they have taken 80% of study medication, 
i.e. 80% of the maximum tolerated dose” to 
‘Non-compliance is defined as less than 
80% drug adherence of the participants 
maximum tolerated dose’. 
 
Section 8.4.9 “Neonatal Measurements” 
has been updated to include the sentence 
“where available, abdominal circumference 

 
 
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and mid-upper arm circumference will be 
taken” 
 
Section 8.8 “Discontinuation/withdrawal of 
participant from study treatment” has been 
amended to clarify the difference between a 
participant discontinuing study medication, 
and a participant withdrawing study consent 
 
Sections 9.3 and 9.4 have been updated to 
remove the previous references to storage 
of treatment in locked cabinets at the 
research pharmacy. The reference to the 
supply of study medication by the 
contracted packaging provider in section 
9.4 has been updated to state that study 
medication will be supplied to the site as 
per the sponsor supply process. The 
reference to the “research nurse” in section 
9.4 has been changed to “research 
delegate” 
 
The list of exempted concomitant 
medications in section 9.7 “prior and 
concomitant therapy” has been updated to 
remove the exemptions d) betamethasone 
12mg for foetal lung maturation and e) 
magnesium sulphate, which were listed in 
protocol version 5.0. New expected 
concomitant medications have since been 
added to the list. These include: (f) routine 
vaccines in the baby (BCG/TB, Diphtheria, 
Tetanus, Pertussis, Haemophilus Influenza 
B (Hib), Polio, Hep B, Pneumococcal 
(PCV), Meningococcal (Men B) (g) 
maternal vaccinations,  (h) Vitamin K 
administration (baby only), (i) Anti D for 
mother, (j) Over-the-counter antenatal 
multivitamins 
 
Additional clarification and definitions in 
relation to safety have been added to 
sections 10.1.1 and 10.1.3  
 
Additional safety event exemptions have 
been added to section 10.2 “Evaluation of 
AEs and SAEs”.  
 
Figure 3 has been introduced to section 
10.2 “Evaluation of AEs and SAEs” 
 
Additional clarification has been added to 
section 10.3.2 to clarify site awareness and 
what is considered a valid SAE report 
 
Section 10.4.1. has been updated to amend 
the information in relation to regulatory 
authorities 
 
An additional sentence has been added to 

 
 
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section 10.4.4 in relation to the safety 
reporting for the non-IMP 
 
Section 11.2 “Determination of sample size” 
has been revised to include relevant 
information from Portiuncula and Mayo 
University Hospitals 
 
Section 14 “Retention of essential 
documents” has been revised to clarify the 
storage of the trial master file and the 
investigator site files. 
 
Section 15.7 “Protocol compliance” has 
been updated to remove references to the 
previous study procedure for reporting 
protocol deviations  
 
Section 17.3 “Participant Confidentiality” 
has been updated to include reference to 
the General Data Protection Regulation 
2018 
 
297 
 
298 
 
299 
 
300 
 
301 
 
302 
 
303 
 
304 
 
305 
 
306 
 
307 
 
308 
 
309 
 
310 
 
311 
4. SYNOPSIS 
312 
Title of study 
A randomised placebo controlled trial of the effectiveness of Early 
MEtformin in addition to usual care in the Reduction of Gestational 
diabetes mellitus Effects (EMERGE) 
 
Name of sponsor 
Prof. Lokesh Joshi  
(Vice President of Research) 
National University of Ireland Galway, 
University Road 
Galway, Ireland 
 
Clinical Study Phase 
III 
 
Objectives 
 
 
 
The overall objective of the EMERGE trial is to determine whether 
metformin + usual care, compared to placebo + usual care (introduced 
at the time of initial diagnosis of GDM), reduces a) the need for insulin 
use, or hyperglycemia (primary outcome measure); b) excessive 

 
 
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maternal weight gain; c) maternal and neonatal morbidities and, d) cost 
of treatment for participants with Gestational Diabetes Mellitus. 
 
Primary Objective: 
The primary objective is to determine if metformin reduces the 
requirement for insulin or the rate of fasting hyperglycaemia (≥ 5.1 
mmol/l)  at gestational weeks 32 or 38. 
 
Secondary Objectives: 
1. To determine if metformin delays the initiation of insulin  
2. To determine if metformin reduces the insulin dose required (and 
dose/kg/week of gestation)  
3. To determine if metformin impacts on maternal body weight, BMI, 
waist circumference, blood glucose status, insulin resistance status 
and metabolic syndrome postpartum ; 
4. To determine if metformin reduces the proportion of infants with 
morbidities; 
5. To determine if metformin in addition to usual care reduces infant 
birth weight when compared to usual care alone 
6. To determine if metformin reduces the proportion of maternal 
morbidities when compared to usual care alone  
7. To determine if metformin in addition to usual care reduces 
excessive maternal gestational weight gain (GWG)  
8. To determine if participants consider metformin a more acceptable 
treatment than insulin  
9. To determine the cost, cost effectiveness, and budget impact of 
metformin in addition to usual care for GDM  
Test Drugs 
 
Name of Active Ingredient 
    
Dose(s) 
 
 
 
Route of administration 
 
Duration of treatment 
Metformin 
 
Metformin 
 
Dose will be titrated up, as tolerated, over a period of 10 days, from a 
starting dose of 500mg once daily to a maximum of 1.5g in the morning 
and 1g in the evening. 
 
Oral 
 
 Until Delivery 
Reference Drugs 
 
Name of Active Ingredient 
    
Dose(s) 
 
 
 
Route of administration 
 
Duration of treatment 
 
Metformin placebo 
 
Not applicable 
 
Dose will be titrated up, as tolerated, over a period of 10 days, from a 
starting dose of 500mg once daily to a maximum of 1.5g in the morning 
and 1g in the evening. 
 
Oral 
 
Until Delivery 
Usual care 
Medical nutritional therapy and exercise advice provided by the 
Diabetes team or trained delegate 

 
 
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Indication 
 
Gestational Diabetes Mellitus  
Trial design 
A phase III, parallel, randomised, double blind, placebo controlled trial  
 
Inclusion criteria 
a) Willing and able to provide written informed consent 
b) Participants aged 18-50  
c) Pregnancy gestation up to 28 weeks (+ 6 days) confirmed by 
positive pregnancy test  
d) Singleton pregnancy as determined by scan 
e) Positive diagnosis of Gestational Diabetes Mellitus on a OGTT 
according to IADPSG criteria if any one of the following are 
achieved: 
i. 
Fasting glucose >/= 5.1mmol/l and <7mmol/l, or 
ii. 
1 hour post glucose load of >/=10mmol/l, or 
iii. 
2 hour post glucose load of >/=8.5 mmol/l and 
<11.1mmo/l 
f) 
Resident in the locality and intending to deliver within the trial 
site 
 
Exclusion criteria 
a) Participants who have an established diagnosis of diabetes 
(Type 1, Type 2, Monogenic or secondary) 
b) Participants with a fasting glucose ≥ 7mmol/l or a 2h value ≥ 
11.1 mmol/l 
c) Multiple pregnancies (twins, triplets etc.) as determined by scan 
d) Known intolerance to metformin 
e) Known contraindication to the use of metformin which include:  
i. 
renal insufficiency (defined as serum creatinine of 
greater than 130 µmol/L or creatinine clearance <60 
ml/min) 
ii. 
moderate to severe liver dysfunction (aspartate 
aminotransferase (AST)  and alanine aminotransferase 
(ALT) greater than 3 times the upper limit of normal)  
iii. 
shock or sepsis, and 
iv. 
previous hypersensitivity to metformin 
f) 
Major congenital malformations or an abnormality deemed 
unsuitable for metformin by the site PI or attending consultant 
g) Known small for gestational age1  
h) Known current gestational hypertension or pre-eclampsia or 
ruptured membranes 
i) 
Particiants who have a history of drug or alcohol use that, in the 
opinion of the investigator, would interfere with adherence to 
study requirements 
j) 
Participants with significant gastrointestinal problems such as 
severe vomiting, Crohn’s disease or colitis which will 
inadvertently affect absorption of the study drug 
k) Participants with congestive heart failure or history of 
congestive heart failure 
l) 
Participants with serious mental illness which would affect 
adherence to study medication or compliance with study 
protocol in the opinion of the investigator 
m) Patients with rare hereditary problems of galactose intolerance, 

 
 
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the Lapp lactase deficiency or glucose-galactose malabsorption 
 
1Small for gestational age (SGA) refers to fetal growth less than the 
10th percentile (RCOG, 2014), or if foetal growth is deemed 
unsatisfactory by the treating obstetrician.  
Type of control 
Placebo 
Number of participants 
550 participants will be randomised across 3 sites (Galway University 
Hospital, Portiuncula University Hospital and Mayo University Hospital) 
Methodology 
 
 
 
The study will comprise 3 periods; 1) screening, 2) treatment, and 3) 
follow up. 
During screening, informed consent will be obtained and evaluations of 
the participant’s eligibility will be performed. At the beginning of the 
treatment period, participants will be randomised up to 28 weeks 
gestation (+ 6 days) in a 1:1 ratio, stratified by BMI and previous GDM 
to receive either metformin or matching placebo, in addition to usual 
care. The treatment period will be until delivery. Participants will be 
followed up at 4 weeks post-partum (+/- 7 days) by telephone, and 12 
weeks postpartum (+/- 4 weeks) in the clinic for maternal and neonatal 
outcomes. 
Statistical methods 
 
 
 
 
 
The primary analysis will be a comparison of the incidence of the 
composite primary outcome of proportion of participants needing insulin 
or fasting blood glucose ≥ 5.1 mmol/l at gestational weeks 32 or 38 
between treatment and control arms, using an exact test for a binomial 
response. A secondary analysis will involve a comparison of the time to 
insulin initiation between the treatment groups, using the log-rank test 
and the proportional hazards model. 
 
Health Economic Analysis 
 
 
The health economic analysis will consist of trial-based economic 
evaluation and will incorporate both cost effectiveness analysis and 
cost utility analysis to compare the alternative treatment strategies: 1) 
metformin in addition to usual care for GDM and 2) usual care for GDM. 
 
313 
 
314 
 
315 
5. ABBREVIATIONS 
316 
 
317 
ACOG  
American Congress of Obstetrics and Gynaecologists 
318 
ADA  
 
American Diabetes Association 
319 
AE 
 
Adverse event 
320 
ALT 
 
Alanine Aminotransferase 
321 
ANOVA  
Analysis of Variance 
322 
APH 
 
Antepartum haemorrhage  
323 
AR 
 
Adverse reaction 
324 
AST 
 
Aspartate Aminotransferase 
325 
b.i.d. 
 
Twice daily 
326 
BCSH  
British Committee for Standards in Haematology  
327 
BMI 
 
Body mass index 
328 
CDMS  
Clinical data management system 
329 
CI 
 
Confidence interval 
330 
CRF 
 
Case report form 
331 
CRFG  
Clinical Research Facility Galway 
332 

 
 
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CT 
 
Clinical trial 
333 
CTA 
 
Clinical trial authorisation 
334 
DNS 
 
Diabetes Nurse Specialist 
335 
DMF 
 
Data management file 
336 
DOB 
 
Date of birth 
337 
DTSQ  
Diabetes Treatment Satisfaction Questionnaire 
338 
DSMB  
Data safety and monitoring board 
339 
DSUR  
Development safety update report 
340 
EBCOG 
European Board and College of Obstetrics and Gynaecology 
341 
e-CRF  
Electronic case report form 
342 
EDC 
 
Electronic data capture 
343 
EDTA  
Ethylenediaminetetraacetic acid 
344 
EQ5D  
Euroqol Five DimensionsMeasurement Tool 
345 
eGFR  
Estimated glomerular filtration rate 
346 
EU  
 
European Union 
347 
FBG 
 
Fasting blood glucose 
348 
FIGO 
 
Federation of International Gynaecological and Obstetric Societies 
349 
GCP 
 
Good Clinical Practice 
350 
GDM 
 
Gestational Diabetes Mellitus 
351 
GDPR  
General Data Protection Regulation 
352 
GMP 
 
Good manufacturing practice 
353 
GWG 
 
Gestational Weight Gain 
354 
GP 
 
General Practitioner 
355 
HbA1c  
Glycated haemoglobin 
356 
Hb 
 
Haemoglobin 
357 
HDL 
 
High density lipoprotein cholesterol 
358 
HDPE  
High density polyethylene 
359 
HEPA   
the Health Economic and Policy Analysis 
360 
HIQA 
 
the Health information and Quality Authority 
361 
HPRA  
Health Products Regulatory Authority 
362 
IB 
 
Investigators brochure 
363 
ICF 
 
Informed consent form 
364 
ICH 
 
International Conference on Harmonisation 
365 
IEC 
 
Independent Ethics Committee 
366 
IFG 
 
Impaired fasting glucose 
367 
IOM 
 
Institute of Medicine 
368 
IUGR 
 
Intrauterine growth restriction 
369 
IMP 
 
Investigational medicinal products 
370 
IMPD 
 
Investigational medicinal product dossier 
371 
ISO 
 
International Organisation for Standardization 
372 
IADPSG 
the International Association of the Diabetes and Pregnancy Study Groups 
373 
LDL 
 
Low density lipoprotein cholesterol 
374 
LGA 
 
Large for gestational age 
375 
MetS 
 
Metabolic Syndrome 
376 
Mmol/l  
millimole per litre 
377 
Ml/min  
millilitre per minute 
378 
MNT 
 
Medical Nutritional Therapy 
379 
NGT 
 
Normal Glucose Tolerance 
380 
NIMP 
 
Non-Investigational Medicinal Product 
381 
NNU 
 
Neonatal unit 
382 
aOR 
 
adjusted odds ratio 
383 
OB 
 
Obese 
384 

 
 
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o.d. 
 
Once daily 
385 
OGTT  
Oral glucose tolerance test 
386 
OR 
 
Odds ratio 
387 
OW 
 
Overweight 
388 
PCOS  
Polycystic ovarian syndrome 
389 
PET 
 
Preeclampsia 
390 
PI 
 
Principal Investigator 
391 
PIH 
 
Pregnancy induced hypertension 
392 
PIL 
 
Patient/participant information leaflet 
393 
PPH 
 
Post-partum haemorrhage  
394 
RCT 
 
Randomised controlled trial 
395 
REC 
 
Research Ethics Committee 
396 
SAE 
 
Serious adverse event 
397 
SAR 
 
Serious adverse reaction 
398 
SmPC  
Summary of product characteristics 
399 
SOP 
 
Standard operating procedure 
400 
SUSAR  
Suspected unexpected serious adverse reaction 
401 
TC 
 
Total cholesterol 
402 
Tg 
 
Triglycerides 
403 
t.i.d. 
 
Three times a day 
404 
TMF 
 
Trial master file 
405 
TSC 
 
Trial steering committee 
406 
QALY  
Quality–adjusted life years 
407 
q.i.d. 
 
Four times a day 
408 
WHO 
 
World Health Organisation 
409 
 
 
410 

 
 
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6. INTRODUCTION 
411 
 
412 
6.1. BACKGROUND INFORMATION 
413 
 
414 
6.1.1. 
What is Gestational Diabetes Mellitus?  
415 
 
416 
Gestational Diabetes Mellitus (GDM) is defined by the World Health Organisation (WHO) as glucose 
417 
intolerance resulting in hyperglycaemia during pregnancy (ADA 2004). There are a number of 
418 
diagnostic criteria from National and International Organisations, which differ by the threshold of 
419 
hyperglycaemia required to diagnose GDM, based on one of the following, i) fasting glucose, ii) 
420 
random glucose and/or iii) oral glucose tolerance test OGTT. The IADPSG and WHO define GDM as 
421 
fasting glucose ≥5.1mmmol/l or 1-hour glucose post-OGTT of ≥10.0mmmol/ or 2-hour glucose post-
422 
OGTT >/= 8.5mmol/l. Other North American guidelines define GDM as fasting glucose of 
423 
≥5.3mmmol/l. The rationale for selecting these cut-points are based on epidemiologic studies 
424 
reporting the association between glycaemia and maternal and foetal outcomes in pregnancy, and 
425 
evidence from clinical trials on the effect of reducing hyperglycaemia on clinical outcomes.  The 
426 
IADPSG criteria have now been accepted by WHO, American Diabetes Association (ADA), Endocrine 
427 
society, Federation of International Gynaecological and Obstetric societies (FIGO), and European 
428 
Board and College of Obstetrics and Gynaecology (EBCOG).   
429 
 
430 
6.1.2. 
How common is Gestational Diabetes Mellitus?  
431 
 
432 
ATLANTIC Diabetes in Pregnancy (Atlantic DIP) was established in 2006 and covers a population of 
433 
500,000 with 11,000 deliveries annually across 5 antenatal centres in Ireland. Women from both 
434 
urban and rural locations are included as are those having both public and private health care. 
435 
Atlantic DIP carries out observational cohort studies and randomised control trials in pregnant women 
436 
with diabetes. One such study was a prospective cohort study to estimate GDM prevalence when 
437 
applying universal screening and IADPSG criteria to a regional population. GDM prevalence was 
438 
found to be 12.4% (O Sullivan 2011). Increasing age, previous GDM, obesity, and family history of 
439 
diabetes are known risk factors. Internationally, GDM prevalence is quoted at 17% with a range of 9-
440 
25% across 15 centres (Sacks 2012).  
441 
 
442 
6.1.3. 
Why is Gestational Diabetes Mellitus Clinically Important in the Short Term? 
443 
 
444 
The association between maternal glycaemia and pregnancy outcome represents a continuum of 
445 
increasing risk of adverse outcomes. In ATLANTIC-DIP, GDM was associated with increased adverse 
446 
maternal and neonatal outcomes (O Sullivan 2011). In particular, maternal hypertensive disorders 
447 
were increased 2 fold (OR1.5 CI 1-2), and delivery by Caesarean section increased by 30% (OR 1.3 
448 
CI 1-1.6). There was a significant increase in macrosomia (birth weight > 4kg) at 23.9% compared to 
449 
17% in women without diabetes (P<0.05) and also in the delivery of LGA babies (>90th centile) at 
450 
22.6% compared to 16.2% in normal glucose tolerant (NGT) women (P<0.01). The admission rate to 
451 
neonatal unit care (NNU) was 26% compared to 9.1% in NGT women (P<0.0001) and the main 
452 
reason for admission was hypoglycaemia at a rate of 2.4% compared to 0.6% in NGT women 
453 
(P<0.0001). Obesity in pregnancy was shown to be a growing problem contributing to GDM but also 
454 
causing significant independent morbidities for the mother and infant (Dennedy 2012). Caesarean 
455 
deliveries increased in overweight (OW) and obese (OB) women significantly with OR of 1.57 (CI 
456 
1.24-1.98) and 2.65 (OR 2.03-3.46) respectively. Hypertensive disorders in pregnancy were also 
457 
greater with an OR of 2.3 (CI 1.55-3.4) and 3.29 (CI 2.14-5.05) in OW and OB women respectively. 
458 
Mean birth weight was 3.46Kg in offspring of normal BMI women rising to 3.56kg and 3.62 kg in OW 
459 
and OB women respectively (P<0.01). Macrosomia occurred in 15.5%, 21.4% and 27.8% of normal 
460 
OW and OB women respectively (P<0.01). The cost of diagnosing and managing GDM in Ireland is 
461 

 
 
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substantial (Gillespie 2013). GDM pregnancies incur an additional cost of circa 30% driven mainly by 
462 
NNU care admissions and delivery by Caesarean section. Obesity is also a significant contributor to 
463 
costs. 
464 
 
465 
6.1.4. 
Why is Gestational Diabetes Mellitus Clinically Important in the Long Term? 
466 
 
467 
Atlantic DIP found persistent glucose abnormalities in 19% of GDM women in the first 6 month’s post-
468 
partum compared with 2.7% in women with NGT in pregnancy (O Reilly 2011). Gestational insulin use 
469 
increased the chance of having persistent post-partum glucose abnormalities (OR 2.62; CI 1.17-5.87), 
470 
while breast-feeding compared to bottle feeding had a protective effect (8.2% vs. 18.4%; P<0.001) (O 
471 
Reilly 2011). Women were again rescreened up to 5 years post the index pregnancy (mean 2.6 years) 
472 
and on-going glucose abnormalities were present in 26% of women with prior GDM compared to 4% 
473 
of women with NGT in the index pregnancy (Noctor 2016). Persistent glucose abnormalities 
474 
correlated with fasting blood glucose > 5.1 mmol/l on pregnancy OGTT (OR 2.9; CI 1.5 to 5.3). The 
475 
likelihood of persistent glucose abnormalities increased in OW and OB women with OR 2.5; CI 1.1 to 
476 
5.7 and OR 3.7; CI 1.6 to 8.5 respectively. Breast feeding was once again protective OR 0.5; CI 0.3 to 
477 
0.9 (Noctor 2012). As well as glucose related problems, women also have an increased risk of 
478 
metabolic syndrome (Noctor 2015). Internationally GDM mothers are seven times more likely to 
479 
develop type 2 diabetes (RR 7ꞏ43, 95% CI 4ꞏ79—11ꞏ51)(Bellamy 2009). As well as the perinatal 
480 
impacts of GDM, children of GDM mothers are at increased risk of glucose abnormalities in childhood 
481 
(Zhu 2016) metabolic syndrome (MetS) and obesity (Vaarasmaki 2009; Clausen 2009) in 
482 
adolescence and pre-diabetes and diabetes in early adult life (Launenborg 2011). In addition, there is 
483 
a growing body of evidence linking metabolic diseases in pregnancy to Autism Spectrum Disorders 
484 
(ASD) in offspring (Krakowiak 2012). 
485 
 
486 
6.1.5. 
Does Treating GDM Improve Clinical Outcomes?  
487 
 
488 
While active management of GDM is associated with significantly improved perinatal outcomes 
489 
(Crowther 2005; Landon 2009) there are limitations to our current approach. Once a mother is 
490 
diagnosed with GDM, the initial approach to management is medical nutritional therapy (MNT) and 
491 
exercise (30 minutes per day) for 2 weeks, which is successful in controlling glucose levels in 
492 
approximately 60% of women with GDM and in reducing perinatal morbidities and infant size to that of 
493 
women with NGT (Kgosidialwa 2015). When glucose targets are not met (approximately 35-40% of 
494 
GDM women), insulin therapy is ordinarily prescribed usually after 2-4 weeks, and considered usual 
495 
care in Ireland. Insulin therapy is also effective in normalising perinatal outcomes to that of women 
496 
with NGT (Bogdanet 2016) but is associated with increased rates of Caesarean delivery and need for 
497 
NNU care. In the USA glyburide is advocated as first line therapy by the American College of 
498 
Obstetrics and Gynaecology (ACOG) while the recently updated NICE guidelines advocate metformin 
499 
as first line therapy in the UK. A recent meta-analysis of treatments for GDM found metformin to be 
500 
slightly better than insulin with glyburide inferior to both treatments (Balsells 2015). In the USA 
501 
analysis of glyburide compared to insulin for treatment of GDM found glyburide to be associated with 
502 
an increase in adverse perinatal outcomes (Castillo 2015). 
503 
 
504 
6.1.6. 
Limitations of Insulin Therapy 
505 
 
506 
Insulin therapy administered by injection is associated with an increased risk of maternal 
507 
hypoglycaemia, excess maternal weight gain and increased risk of operative delivery (Egan 2013). In 
508 
addition, the excess weight gain, associated with insulin use, increases insulin requirements further. 
509 
Furthermore, 40% of women have an extended period (2-4 weeks) of possible hyperglycaemia 
510 
between initiation of MNT and exercise and introduction of insulin therapy. This may predispose to 
511 
sub optimal glycaemic control, which is associated with an increased risk of hypoglycaemia in the 
512 

 
 
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infant following delivery. Gestational weight gain (GWG) is defined by the American Institute of 
513 
Medicine (IOM) according to the woman’s booking BMI. Excessive GWG is gaining momentum as an 
514 
additional independent risk factor contributing to a higher odds ratio of development of macrosomia 
515 
and LGA. We recently carried out analysis of the Atlantic DIP dataset to determine how many women 
516 
exceeded the IOM guidelines for appropriate weight gain in pregnancy and whether excessive GWG 
517 
was associated with a further increase in adverse outcomes in pregnancies already at risk. We found 
518 
that excessive GWG occurred in > 60% of women with GDM. Excessive GWG defined by IOM 
519 
guidelines further increased the odds ratio of LGA (aOR 2.008; CI 1.241 to 3.248) and macrosomia 
520 
(aOR 2.166; CI 1.321 to 3.550) significantly on a multivariate analysis when all other contributing 
521 
variables were adjusted for (Egan 2013). Treatment with insulin further increased the adjusted odds 
522 
for LGA (aOR 2.802; CI 1.231 to 6.379). Excessive GWG in women with GDM also increased OR of 
523 
pregnancy induced hypertension (aOR 1.719; CI 1.037 to 2.852). This suggests that a focus on 
524 
minimising excessive GWG is important and opens the debate regarding the usefulness and 
525 
effectiveness of insulin as the preferred treatment modality in women where MNT fails. 
526 
 
527 
6.1.7. 
Metformin use for GDM 
528 
 
529 
In many European countries oral hypoglycaemic agents (e.g. metformin or glyburide) are used for 
530 
glucose control, when diet and exercise interventions have failed. National Irish guidelines do not 
531 
advocate the use of oral hypoglycaemic agents for glucose control in GDM. However, there is now a 
532 
good body of research that has evaluated the use of metformin in GDM. The most conclusive 
533 
evidence on the safety of metformin comes from the MiG study (Rowan 2008) in which 752 
534 
participants were randomly assigned to metformin or insulin. Metformin did not increase the risk of 
535 
perinatal morbidities, compared to insulin. However, in that trial, metformin was only used in obese 
536 
patients (BMI >30) who had failed lifestyle interventions. An open label prospective RCT (Ljas 2011) 
537 
reported less macrosomia especially in lean (BMI < 25) or moderately overweight (BMI > 25<30) 
538 
participants with metformin treatment. Studies on the long-term effects of metformin are also 
539 
encouraging. Glueck (2004) followed offspring whose mothers received metformin and found normal 
540 
weight, height, social and motor skills at 18 months with no differences when compared to unexposed 
541 
infants. Rowan (2011) showed reassuring results when 2 year olds were examined following the MiG 
542 
trial, and found no difference in total body fat in children of mothers treated with metformin compared 
543 
to those treated with insulin, but a suggestion of more favourable metabolic distribution of fat. Rowan 
544 
et al also reported metformin to be a more acceptable and satisfying treatment than insulin (Rowan 
545 
2008), more participants said they would choose metformin in a subsequent pregnancy (76.6%) 
546 
compared with 27.2% in the insulin group (p<0.001). In a cross-sectional study of 197 participants 
547 
with GDM, Latif (2013) found that participants treated with metformin alone were more satisfied with 
548 
treatment and had higher Quality of Life scores than participants treated with insulin. It seems likely 
549 
therefore that metformin may have an important role to play in patient reported outcomes affecting the 
550 
lives of women diagnosed with GDM. Finally a recent meta-analysis of treatments for GDM found 
551 
metformin to be slightly better than insulin with glyburide inferior to both treatments (Balsells 2015). 
552 
 
553 
While metformin crosses the placenta (Vanky 2005), there are a large number of studies reporting the 
554 
safety of metformin in pregnancy, for mother and child. Metformin has been used extensively in 
555 
women with Polycystic Ovarian Syndrome (PCOS) who have become pregnant (Tang 2010), and no 
556 
increase in adverse effects has been reported. Metformin has been used in South Africa since the 
557 
1970s and perinatal mortality is similar in women treated with metformin and insulin (Coetzee 1984). 
558 
Goh (2011) examined pregnancy outcomes for 1269 women, 465 of whom received metformin. Those 
559 
receiving metformin had fewer adverse outcomes compared to those treated with insulin. Three meta-
560 
analyses (Gutzin 2003; Gilbert 2006; Juan Gui 2013) including over 1500 participants reported no 
561 
increase in congenital abnormalities or neonatal deaths with metformin. Juan Gui (2013) concluded 
562 
that metformin was comparable with insulin for glycaemic control and neonatal outcomes, favouring 
563 
metformin in respect of GWG, size at delivery, incidence of pregnancy induced hypertension (PIH) 
564 

 
 
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and preeclampsia (PET) and that metformin might be especially suitable for mild GDM patients. A 
565 
recently published study looking at the benefits of metformin in obese pregnant participants without 
566 
GDM (EMPOWER) was not associated with adverse events related to metformin use (Chiswick 
567 
2015). Finally a large RCT is being conducted to examine the benefits of metformin in participants 
568 
with Type 2 diabetes in pregnancy (MiTy trial). 
569 
 
570 
The evidence to date on the safety of metformin in GDM is robust in selective and selectively 
571 
screened populations. However, the evidence of the benefits of metformin in a broader spectrum of 
572 
'all' GDM pregnancies in women of all Body Mass Index (BMI) categories and irrespective of the 
573 
success of lifestyle interventions for the treatment of GDM undergoing universal screening with 
574 
IADPSG criteria is absent. Additionally, interventions to improve glycaemia and at the same time 
575 
minimise excess gestational weight gain in GDM are also needed. 
576 
 
577 
Overall therefore we have found a rising prevalence of GDM and obesity in women in Ireland, both 
578 
associated with an increase in adverse outcomes for mother and infant in the index pregnancy and a 
579 
worrying prevalence of persistent glucose abnormalities over time. More recently the impact of 
580 
excessive GWG and insulin treatment on the already established increased adverse outcomes adds 
581 
further complexity to this condition and its management. We now wish to explore if the introduction of 
582 
metformin in addition to usual care at the time of initial GDM diagnosis (i.e. along with diet and 
583 
exercise interventions) in all women screened and diagnosed by IADPSG criteria, is effective in 
584 
reducing the incidence of hyperglycemia, measured by the need for insulin treatment during 
585 
pregnancy or reducing rate of fasting glucose ≥5.1 mmol/l at gestational week 32 or 38. We will also 
586 
determine its effect on excessive GWG, and translating these effects into better outcomes for mothers 
587 
and their babies. We also wish to establish if early intervention with metformin is more cost effective 
588 
and acceptable to, and increases satisfaction for women with GDM. Finally, this study will form the 
589 
basis of future applications to establish the benefits of metformin on prevalence of Type 2 diabetes 
590 
and obesity in the mother and offspring longitudinally. 
591 
 
592 
6.2. RATIONALE FOR THE STUDY 
593 
 
594 
GDM results from a combination of reduced insulin sensitivity and/or reduced insulin production. 
595 
Metformin increases insulin sensitivity and thus it has potential as a treatment option in GDM. 
596 
Metformin is weight neutral and not associated with hypoglycaemia, two factors that would increase 
597 
its acceptability for pregnancy, and represents an advantage over insulin. Metformin has been shown 
598 
to be safe in pregnancy (for mother and baby), when it is introduced after failure of diet and exercise. 
599 
However, in many countries (including Ireland), insulin therapy remains the standard of care for 
600 
treatment of GDM, in women who have failed to achieve normo-glycemia after diet and exercise. 
601 
Distinct from previous clinical trials, we plan to evaluate the use of metformin (compared to placebo) 
602 
at the time of initial GDM diagnosis (i.e. at the same time as diet and exercise interventions), and 
603 
evaluate its use in all women with GDM, not just those with elevated BMIs.   
604 
 
605 
The EMERGE trial will evaluate metformin introduced at the time of GDM diagnosis in participants of 
606 
all BMI categories, to determine whether treating all participants with GDM (rather than just those who 
607 
fail MNT/exercise) results in better outcomes for mothers and babies. The primary outcome is the 
608 
development of hyperglycemia, represented as the composite of initiation of insulin (as this reflects 
609 
clinically meaningful hyperglycemia) or a venous fasting glucose measurement ≥5.1mmol/l at weeks 
610 
32 or 38 of gestation. Secondary outcome measures include excessive GWG, neonatal and maternal 
611 
outcomes. Finally, we will conduct an extensive cost benefit and cost utility analysis of metformin use 
612 
in GDM pregnancy. Results of the EMERGE trial may have a considerable impact on clinical practice 
613 
by providing evidence to support early active management with metformin at the time of diagnosis in a 
614 
broader GDM population. 
615 

 
 
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Study Drug administration: Metformin and matched placebo are administered orally. Both will be 
616 
administered from the time of GDM diagnosis (up to 28 weeks + 6 days gestation) to delivery or 
617 
termination of the pregnancy. Metformin will be given in tablets of 500mg. The dose will be titrated 
618 
over a two-week period and will commence at 1 tablet per day (500mg) increasing to maximum of 5 
619 
tablets per day (2500mg). This dosing regimen will minimise any possible nausea associated with 
620 
metformin and is in line with the dosing schedule of metformin in a previous GDM trial (MiG), the 
621 
EMPOWER study of obese pregnant participants and an on-going trial in Type 2 diabetes in 
622 
pregnancy (MiTy). 
623 
 
624 
7. STUDY OBJECTIVES 
625 
 
626 
The overall objective of the EMERGE trial is to determine whether metformin + usual care, compared 
627 
to placebo + usual care (introduced at the time of initial diagnosis of GDM), reduces a) the need for 
628 
insulin use or hyperglycemia (primary outcome measure); b) excessive maternal weight gain; c) 
629 
maternal and neonatal morbidities and, d) cost of treatment for participants with Gestational Diabetes 
630 
Mellitus. 
631 
 
632 
7.1. Primary objective 
633 
 
634 
The primary objective is to determine if metformin reduces the requirement for insulin or reduces the 
635 
rate of fasting hyperglycaemia (≥ 5.1 mmol/l) at gestational weeks 32 or 38. 
636 
 
637 
7.2. Secondary objectives 
638 
 
639 
Additional secondary objectives of this study are: 
640 
1. To determine if metformin delays the initiation of insulin  
641 
2. To determine if metformin reduces the insulin dose required (and dose/kg/week of gestation)  
642 
3. To determine if metformin impacts on maternal body weight, BMI, waist circumference, blood 
643 
glucose status, insulin resistance status and metabolic syndrome postpartum  
644 
4. To determine if metformin reduces the proportion of infants with morbidities 
645 
5. To determine if metformin in addition to usual care reduces infant birth weight when compared to 
646 
usual care alone  
647 
6. To determine if metformin reduces the proportion of maternal morbidities when compared to usual 
648 
care alone  
649 
7. To determine if metformin in addition to usual care reduces excessive maternal gestational weight 
650 
gain (GWG)  
651 
8. To determine if participants consider metformin a more acceptable treatment than insulin  
652 
9. To determine the cost, cost effectiveness, and budget impact of metformin in addition to usual 
653 
care for GDM  
654 
 
655 
7.3. Primary and secondary outcome measures 
656 
 
657 
7.3.1. 
Primary Outcome Measure 
658 
 
659 
A composite primary outcome of insulin initiation or fasting venous glucose ≥ 5.1 mmol/l on study 
660 
specific fasting laboratory glucose at gestational weeks 32 or 38 will be used. This approach allows us 
661 
to measure ‘treatment failure’ in two discreet ways. Introduction of insulin reflects clinically meaningful 
662 
hyperglycaemia, and is measured at any time during the clinical trial. In addition, a standardised 
663 
fasting glucose will be completed at gestational weeks 32 or 38 to capture additional participants who 
664 
have fasting hyperglycaemia but have not had insulin introduced during the clinical trial.  
665 

 
 
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7.3.2. 
Secondary Outcome Measures 
666 
 
667 
1. Time to insulin initiation and insulin dose required 
668 
2. Maternal morbidity at delivery (hypertensive disorders, antepartum and postpartum haemorrhage) 
669 
3. Mode and time of delivery 
670 
4. Postpartum glucose status, insulin resistance, and metabolic syndrome 
671 
5. Postpartum BMI, gestational weight gain, and waist circumference 
672 
6. Infant birth weight 
673 
7. Neonatal height and head circumference at delivery 
674 
8. Neonatal morbidities (Need for neonatal care unit, respiratory distress, jaundice, congenital 
675 
anomalies, Apgar score) 
676 
9. Neonatal hypoglycaemia  (defined as plasma glucose <2.6mmol/L on one or more occasions 
677 
starting 30-60 minutes after birth) 
678 
10. Cost effectiveness and budget impact of metformin treatment in addition to usual care 
679 
11. Treatment acceptability (DTSQ and Rowan questionnaires) 
680 
12. Quality of Life determined by EQ5D-5L questionnaire 
681 
 
682 
8. TRIAL DESIGN 
683 
 
684 
8.1. Design Summary 
685 
 
686 
A phase III, parallel, randomised double-blind, placebo-controlled, trial of metformin (in addition to 
687 
usual care) versus usual care in 550 participants with Gestational Diabetes Mellitus (GDM) across 
688 
upto 3 sites in the Republic of Ireland, followed until 12 weeks post-partum (+/- 4 weeks). 
689 
 
690 
Eligible participants will be randomised to one of two groups; treatment group or placebo group. 
691 
 
692 
8.1.1. 
Treatment Group 
693 
 
694 
Participants randomised to the metformin group will receive metformin 500mg OD, with the dose 
695 
titrated upwards every 2 days over 10 days increasing to a maximum of 2500mg metformin daily (5 
696 
tablets) or maximum tolerated dose, in addition to usual care (exercise and MNT), and taken until 
697 
delivery. 
698 
 
699 
8.1.2. 
Placebo Group  
700 
 
701 
Participants randomised to the placebo group will receive 1 placebo tablet OD, with the dose titrated 
702 
upwards every 2 days over 10 days increasing to a maximum of five placebo tablets daily, in addition 
703 
to usual care (exercise and MNT), and taken until delivery. 
704 
 
705 
Participants will be followed up at 4 weeks (+/- 7days) and at 12 weeks (+/- 4 weeks) post-partum for 
706 
additional maternal and neonatal outcomes. 
707 
 
708 
8.1.3. 
Usual Care  
709 
 
710 
Both the treatment and metformin group will receive usual care which consists of medical nutritional 
711 
therapy (MNT) and information on exercise provided by the Diabetes team or trained delegate. The 
712 
Diabetes team or trained delegate will instruct participants on the use of a glucometer and the 
713 
participants will perform 7-point glucose testing before and 1 hour after meals and before bed. 
714 
Participants will be supported by telephone contact from the Diabetes team or trained delegate 
715 

 
 
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weekly throughout gestation and attend at 2-4 weekly intervals at an antenatal/diabetes clinic. Usual 
716 
care is outlined in more detail in section 9.1.1.  
717 
 
718 
Figure 1: Schematic Diagram of Trial Design 
719 
 
720 
721 
722 

 
 
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723 
8.2. Selection of Study Population 
724 
 
725 
8.2.1. 
Population 
726 
 
727 
The population for the trial is pregnant participants between the ages of 18-50 years, with a diagnosis 
728 
of GDM up to 28 weeks gestation (+ 6 days). 
729 
 
730 
Participants diagnosed using a 75g oral glucose tolerance test (OGTT) and International Association 
731 
of Diabetes in Pregnancy Study Groups (IADPSG) criteria for diagnosis will be eligible to be enrolled 
732 
in the study. Eligible participants must be resident and intending to deliver within the selected trial 
733 
sites. The geographical area and study population includes participants from urban and rural locations 
734 
and participants in both public and private health care. 
735 
 
736 
In order to be eligible for the trial participants must meet all of the inclusion criteria and none of the 
737 
exclusion criteria listed below. 
738 
 
739 
8.2.2. 
Inclusion Criteria 
740 
 
741 
a) Willing and able to provide written informed consent 
742 
b) Participants aged 18-50 years 
743 
c) Pregnancy gestation up to 28 weeks (+ 6 days) confirmed by positive pregnancy test 
744 
d) Singleton pregnancy as determined by scan 
745 
e) Positive diagnosis of Gestational Diabetes Mellitus on a OGTT according to IADPSG criteria if 
746 
any one of the following are achieved: 
747 
a. Fasting glucose >/= 5.1mmol/l and <7mmol/l, or 
748 
b. 1 hour post glucose load of >/=10mmol/l, or 
749 
c. 2 hour post glucose load of >/=8.5 mmol/l and <11.1mmol/l 
750 
f) 
Resident in the locality and intending to deliver within the trial site 
751 
 
752 
8.2.3. 
Exclusion Criteria 
753 
 
754 
Participants who meet any one or more of the following exclusion criteria will not be eligible to take 
755 
part in the trial: 
756 
 
757 
a) Participants who have an established diagnosis of diabetes (Type 1, Type 2, Monogenic or 
758 
secondary) 
759 
b) Participants with a fasting glucose ≥ 7mmol/l or a 2h value ≥ 11.1 mmol/l 
760 
c) Multiple pregnancies (twins, triplets etc.) as determined by scan 
761 
d) Known intolerance to metformin 
762 
e) Known contraindication to the use of metformin which include:  
763 
i. 
renal insufficiency (defined as serum creatinine of greater than 130 µmol/L or 
764 
creatinine clearance <60 ml/min) 
765 
ii. 
moderate to severe liver dysfunction (aspartate aminotransferase (AST)  or alanine 
766 
aminotransferase (ALT) greater than 3 times the upper limit of normal)  
767 
iii. 
shock or sepsis, and 
768 
iv. 
previous hypersensitivity to metformin 
769 
f) 
Major congenital malformations or an abnormality deemed unsuitable for metformin by the 
770 
site PI or attending consultant.  
771 
g) Known small for gestational age1  
772 
h) Known current gestational hypertension,  pre-eclampsia, or ruptured membranes  
773 

 
 
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Version 6.0, dated 02-May-2019          Confidential 
i) 
Participants who have a history of drug or alcohol use that, in the opinion of the investigator, 
774 
would interfere with adherence to study requirements 
775 
j) 
Participants with significant gastrointestinal problems such as severe vomiting, Crohn’s 
776 
disease or colitis which will inadvertently affect absorption of the study drug 
777 
k) Participants with congestive heart failure or history of congestive heart failure 
778 
l) 
Participants with serious mental illness which would affect adherence to study medication or 
779 
compliance with study protocol in the opinion of the investigator 
780 
m) Participants with rare hereditary problems of galactose intolerance,  Lapp lactase deficiency 
781 
or glucose-galactose malabsorption  
782 
 
783 
1Small for gestational age (SGA) refers to fetal growth less than the 10th percentile (RCOG, 2014), or 
784 
as determined by the treating obstetrician 
785 
 
786 
8.3. Study Visits and procedures 
787 
 
788 
8.3.1. 
Screening and Randomisation Visit and Procedures 
789 
 
790 
Screening for GDM will be conducted in the trial sites for all participants. Participants will receive a 
791 
75g OGTT scheduled as part of routine care which they can opt out of if they wish. GDM will be 
792 
diagnosed according to the IADPSG criteria if any one of the following are achieved; fasting glucose 
793 
>/= 5.1mmol/l and <7mmol/l, 1 hour post glucose load of >/= 10 mmol/l, and 2 hour post glucose load 
794 
of >/= 8.5 mmol/l and <11.1mmol/l. Those with a positive OGTT will receive usual care of MNT and 
795 
exercise advice from the Diabetes team or trained delegate, and will also be approached for consent 
796 
for screening into the trial. Consenting participants will then be screened for eligibility. 
797 
 
798 
Screening will consist of the following procedures: 
799 
1. Review of inclusion/exclusion criteria 
800 
2. Review of medical history including previous pregnancy history 
801 
3. Review of concomitant medications  
802 
4. Current pregnancy information including date of last menstrual period, estimated date of delivery, 
803 
gestational week, para and gravida. 
804 
 
805 
All screening procedures will be documented in the medical notes by the research nurse. 
806 
 
807 
The results of the screening visit will be reviewed and eligibility will be signed off by the investigator or 
808 
delegate. Once eligibility has been confirmed, participants will be randomised to a study arm and 
809 
assigned a Participant ID using the web based randomisation service. The timeline for randomisation 
810 
is up to 28 weeks (+6 days) gestation, which can occur on the same day as screening or up to 7 days 
811 
post-screening. 
812 
 
813 
Participants at all trial sites will also be invited to partake in a bio-banking sub-study which involves 
814 
obtaining maternal blood samples at randomisation and gestational age 38 weeks (+/- 1 week) and 
815 
also a cord blood sample at delivery. This is executed under a separate Ethics Committee approved 
816 
protocol and is executed as guided by local practice patterns and the availability of resources 
817 
(including staff). 
818 
 
819 
Once the participant has been randomised, additional data collected will include: 
820 
 
821 
1. Physical measurements and vital signs (heart rate, BP, height, weight) 
822 
2. Demographics (date of birth (DOB), race) 
823 

 
 
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3. Social history (smoking and alcohol) 
824 
4. Socioeconomic status 
825 
5. Baseline gastrointestinal symptoms 
826 
6. EQ5D-5L Questionnaire 
827 
7. Laboratory tests (see section 8.4.5)  
828 
8. Medical resources used since diagnosis of pregnancy 
829 
9. Usual care received 
830 
 
831 
The participant will then be dispensed study medication and administration instructions. The pack 
832 
numbers of dispensed medication will be documented on the dispensation log. 
833 
 
834 
8.3.2. 
Prenatal Visit and Procedures 
835 
 
836 
Prenatal visits will occur approximately every 2 weeks post randomisation in line with routine 
837 
antenatal clinic visits. Visits that do not require an in person physical measurement, laboratory 
838 
assessment or drug dispensation can be completed over the telephone. The following data will be 
839 
collected and procedures will be performed: 
840 
 
841 
1. Gestational age in weeks 
842 
2. Review of concomitant medications  
843 
3. Review of insulin requirements 
844 
4. Review of adverse events 
845 
5. Gastrointestinal symptom review 
846 
6. Review of hypoglycaemic events 
847 
7. Review of medical resources used 
848 
8. Glucometer data download (at in person visits only, see section 8.4.7.) 
849 
 
850 
The following data will be collected in addition to the above: 
851 
 
852 
1. Study drug dispensing (every 4 weeks) 
853 
2. Physical measurements and vital signs (heart rate, BP and weight to be taken at gestational 
854 
weeks 32 (+/- 1 week) and 38 (+/- 1 week)) 
855 
3. Usual care received (week 4) 
856 
4. Laboratory tests (at gestational week 32 (+/- 1 week) AND at gestational week 38 (+/- 1 
857 
week), see section 8.4.5.) 
858 
5. DTSQ (gestational week 38 (+/- 1 week) or as soon as possible thereafter) 
859 
6. Study Drug Accountability (every 4 weeks) 
860 
 
861 
8.3.3. 
Delivery Visit 
862 
 
863 
The delivery visit will occur up to 72 hours post-delivery, while the participant is in the post natal ward.  
864 
Should the participant be discharged early, or it is not possible to see the participant within the visit 
865 
window (e.g. delivery occurs out of hours), every effort will be made to gather the information from the 
866 
medical notes or through telephone contact. The following data will be collected and procedures will 
867 
be performed: 
868 
 
869 
1) Vital signs (heart rate, BP) 
870 
2) Review of concomitant medications 
871 
3) Review of adverse events (mother and baby) 
872 
4) Last routine HbA1c recorded 
873 
5) Delivery information (time, date and mode of delivery, and complications) 
874 

 
 
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6) Feeding method initiated 
875 
7) Neonatal procedures (status of baby, sex, neonatal measurments, Apgar score, 
876 
hypoglycaemia, respiratory distress, jaundice and congenital anomalies) 
877 
8) Neonatal care unit data 
878 
9) Neonatal medical resources 
879 
 
880 
8.3.4. 
Phone Visit (Visit 1 Post-Partum) 
881 
 
882 
A phone visit will take place 4 weeks (+/- 7 days) post-partum. The following data will be collected: 
883 
 
884 
1) Status of the baby 
885 
2) Current Feeding method 
886 
3) Neonatal complications 
887 
4) Discharge date 
888 
5) Questionnaires (EQ5D-5L, Rowan Questionnaire) 
889 
6) Adverse Events (mother and baby) 
890 
 
891 
An appointment will be scheduled for the 12 week post-partum visit by the research nurse. 
892 
 
893 
8.3.5. 
12 Week Post-Partum Visit (Visit 2 Post-Partum) 
894 
 
895 
The post-partum visit will take place 12 weeks post-partum (+/- 4 weeks) and will be conducted in 
896 
person. The following data will be collected and procedures will be performed: 
897 
 
898 
1) Physical measurements (heart rate, BP, height, weight and waist circumference) 
899 
2) 75g OGTT 
900 
3) Laboratory tests (see section 8.4.5)  
901 
4) Questionnaires (EQ5D-5L) 
902 
5) Study medication returns 
903 
6) Status of baby 
904 
7) Neonatal complications 
905 
8) Current feeding method 
906 
9) Return Glucometer and data download 
907 
10) Medical care received since delivery 
908 
11) Adverse Events (mother and baby) 
909 
 
910 
An outline of scheduled study assessments and procedures are outlined below in figure 2. 
911 
 
912 
 
913 
 
914 
 
915 
 
916 
 
917 
 
918 
 
919 

 
 
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Version 6.0, dated 02-May-2019          Confidential 
 
 
Schedule of Visits 
 
Visit1 
Visit2 
Visit3
Visit4
Visit5
Visit6
Visit7
Additional 
Visit (s) 
Delivery 
Visit 
Visit1 
pp  
Visit2 
pp 
 
Weeks Post-
Randomisation 
 
 
 
 
 
 
 
 
 
 
 
Maternal Procedures 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Demographics/social 
history 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Current Pregnancy 
X 
 
 
 
 
 
 
 
 
 
 
Randomisation 
X 
 
 
 
 
 
 
 
 
 
 
Socioeconomic status 
X 
 
 
 
 
 
 
 
 
 
 
Gastrointestinal 
symptoms 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Medical resources 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Vital signs 
X 
 
Xi
Xi 
Xi
Xi
Xi
Xi
X 
 
X 
Height and Weight 
X 
 
Xi 
Xi
Xi
Xi
Xi
Xi
 
 
X 
Waist Circumference 
 
 
 
 
 
 
 
 
 
 
X 
OGTT 
X 
 
 
 
 
 
X 
Laboratory tests 
X 
 
Xg 
Xg 
Xg 
Xg 
Xg 
Xg
 
 
X 
Usual Care 
X 
 
X 
 
 
 
 
 
 
 
 
Study Drug Dispensing 
X 
 
X 
 
X 
 
X 
Xj
 
 
 
Glucometer Data 
 
Xk 
Xk
Xk
Xk
Xk
Xk
Xk
 
 
X 
Hypoglycaemic events 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Insulin Initiation data 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Study Drug Accountability 
 
 
X 
 
X 
 
X 
Xl
 
 
X 
Return Study Drug 
 
 
X 
 
X 
 
X 
Xl
 
 
X 
Delivery information 
 
 
 
 
 
 
 
 
X 
 
 
Mode of Delivery 
 
 
 
 
 
 
 
 
X 
 
 
Time of Delivery 
 
 
 
 
 
 
 
 
X 
 
 
Delivery complications  
 
 
 
 
 
 
 
 
X 
 
 
DTSQ 
 
 
 
 
 
 
Xh
 
 
 
 
EQ5D-5L 
X 
 
 
 
 
 
 
 
 
X 
X 
Rowan Questionnaire 
 
 
 
 
 
 
 
 
 
X 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Neonatal Procedures 
 
 
 
 
 
 
 
 
 
 
 
Status of Baby 
 
 
 
 
 
 
 
 
X 
 
X 
Sex 
 
 
 
 
 
 
 
 
X 
 
 
Feeding Method 
 
 
 
 
 
 
 
 
X 
X 
X 
Neonatal measurements 
 
 
 
 
 
 
 
 
X 
 
 
Apgar Score 
 
 
 
 
 
 
 
 
X 
 
 
Hypoglycaemia 
(<2.6mmol/l) 
 
 
 
 
 
 
 
 
X 
 
X 
NNU care 
 
 
 
 
 
 
 
 
X 
X 
X 
Jaundice 
 
 
 
 
 
 
 
 
X 
 
X 
Week 0a 
Week 2c 
Week 4c 
Week 6c  
Week 8c 
Week 10c  
Deliveryd 
4 weeks 
Post-partume  
12 weeks 
Post-partumf  
Week 12c  
Additional 
Visit (s)bc 

 
 
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Version 6.0, dated 02-May-2019          Confidential 
 
Figure 2: Schedule of Visits and Procedures for the EMERGE Trial 
 
 
 
a Participants may be randomised up to 28 weeks gestation (+6 days) 
b Additional 2 weekly visits may occur before delivery 
cVisits that do not require an in person physical measurement, laboratory assessment or drug dispensation can be completed 
over the telephone 
dThe delivery visit should take place within 72 hours of birth 
e The 4 week post-partum visit window is +/- 7days 
f The 12 week post-partum visit window is +/- 4 weeks 
g Lab tests should be completed at 32 gestational weeks (+/- 1 week) AND at 38 gestational weeks (+/- 1 week) 
hThe DTSQ will be administered at the 12 week visit, or as soon as possible thereafter 
i Vital signs and height and weight measurements should be completed at 32 gestational weeks (+/- 1 week) AND at 38 
gestational weeks (+/- 1 week), in line with routine antenatal clinic visits. 
jStudy drug dispensing should be completed every 4 weeks 
kIn cases where study visits are completed over the telephone, glucometer data should be downloaded at a subsequent in-person 
study visit 
lStudy Drug Return and Accountability should be completed every 4 weeks during the pre-natal study period
Neonatal medical 
resources 
 
 
 
 
 
 
 
 
X 
X 
X 
Neonatal morbidities 
 
 
 
 
 
 
 
 
X 
 
X 
Discharge date 
 
 
 
 
 
 
 
 
 
X 
 
Adverse Events 
 
 
 
 
 
 
 
 
X 
X 
X 

 
 
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941 
8.4.  Description of Study Procedures 
942 
 
943 
8.4.1. 
Informed Consent  
944 
 
945 
The study will be conducted in accordance with the ethical principles that have their origin in the 
946 
Declaration of Helsinki and in accordance with ICH-GCP. Eligible participants may only be included in 
947 
the trial after providing written informed consent. Informed consent must be obtained prior to 
948 
conducting any trial specific procedures and the process for obtaining informed consent must be 
949 
documented in the patient’s medical records (source documents which will be reviewed at the time of 
950 
on-site monitoring visits).  
951 
 
952 
The central ethics committee (EC) approved Patient Information Leaflet and Informed Consent Form 
953 
(PIL and ICF) will be provided to potential participants, which the Principal Investigator and/or 
954 
delegate will explain and discuss the nature of the study. Participants will have ample time to ask and 
955 
have answered any questions by the investigator prior to making a decision regarding participation.  
956 
 
957 
Upon providing consent, the ICF will be signed and dated by the participant, and the investigator who 
958 
administered the ICF. The complete original ICF will be filed by the site in the site file, a copy of the 
959 
ICF will be given to the participant and a copy will be filed in the participant’s notes.  
960 
 
961 
8.4.2. 
Medical History 
962 
 
963 
A review of each participants medical history will be completed at the screening visit to document the 
964 
following relevant medical conditions:  
965 
 
966 
 
Psychiatric disorders 
967 
 
Asthma 
968 
 
Gastrooesophageal reflux disease 
969 
 
Cardiovascular disease 
970 
 
Irritable bowel syndrome 
971 
 
Inflammatory bowel disease 
972 
 
Coeliac disease 
973 
 
Polycystic ovary syndrome 
974 
 
Hypercholesterolemia 
975 
 
Epilepsy 
976 
 
Cancer 
977 
 
Thyroid disorder 
978 
 
Essential Hypertension 
979 
 
Any longstanding medical condition for which the participant is currently taking treatment  
980 
 
981 
A review of all concomitant medications will be documented by interview or review of medical records 
982 
at the screening visit. Changes in medical history and concomitant medications will be reviewed at 
983 
each subsequent visit. 
984 
 
985 
 
986 
 
987 
 
988 

 
 
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8.4.3. 
Physical Assessments 
989 
 
990 
Standardised measurement of BP will be used. Weight will be measured in kg, height in meters and 
991 
body mass index (BMI) as kg/m2. BMI will be calculated categorised according to World Health 
992 
Organization (WHO) standards: underweight, <18.5 kg/m 2; normal, 18.5–24.5 kg/m2; overweight 
993 
(OW), 25–29.9 kg/m2; obese (OB), >30 kg/m2. Waist circumference will be taken using a tape 
994 
measure half way between the hip bone and the lowest rib, about 5 cm (2 in) above the belly button. 
995 
 
996 
8.4.4. 
OGTT  
997 
 
998 
A 75g OGTT will be carried out at screening and 12 weeks (+/- 4 weeks) post-partum. 
999 
The OGTT at screening will determine the presence of GDM according to IADPSG/WHO 2013 criteria 
1000 
based on any one of the following values: Fasting >/= 5.1 and <7, 1 h >/=10, and 2h >/= 8.5 and 
1001 
<11.1 mmol/l. Results of the post -partum OGTT will categorize participants as one of the following: 1) 
1002 
Negative: fasting blood glucose (FBG) < 5.6 mmol/l, 2h blood glucose <7.8 mmol/l; 2) Impaired fasting 
1003 
glucose (IFG) FBG >5.6 <7mmol/l; 2h blood glucose <7.8mmol/l. 3) Impaired glucose tolerance FBG 
1004 
5.6-7mmol/l; 2h blood glucose 7.8-11.1mmol/. 4) Diabetic FBG >7mmol/l or 2h blood glucose 
1005 
>11.1mmol/l. We will use a fasting venous sample as venous glucose is more accurate than capillary 
1006 
measurements.  
1007 
 
1008 
8.4.5. 
Laboratory Tests 
1009 
 
1010 
Lab tests should be completed at the randomisation visit, 32 gestational weeks (+/- 1 week) AND at 
1011 
38 gestational weeks (+/- 1 week), and 12 weeks post-partum (+/- 4 weeks). If the participant is 
1012 
administered steroids at 32 weeks gestation or 38 weeks gestation, defer lab tests for 48 hours. 
1013 
 
1014 
The following laboratory assessments will be analysed locally:  
1015 
 
1016 
Randomisation: HbA1c, fasting glucose, Insulin, c-peptide, total cholesterol, high density lipoprotein 
1017 
(HDL) cholesterol, low density lipoprotein (LDL) cholesterol, triglycerides (Tg), urea, creatinine, 
1018 
alanine aminotransferase (ALT), and aspartate transaminase (AST). 
1019 
 
1020 
32 weeks gestation: HbA1c, fasting glucose, total cholesterol, high density lipoprotein (HDL) 
1021 
cholesterol, low density lipoprotein (LDL) cholesterol, triglycerides (Tg), urea, creatinine, alanine 
1022 
aminotransferase (ALT), and aspartate transaminase (AST). 
1023 
 
1024 
38 weeks gestation: HbA1c, fasting glucose, total cholesterol, high density lipoprotein (HDL) 
1025 
cholesterol, low density lipoprotein (LDL) cholesterol, triglycerides (Tg), urea, creatinine, alanine 
1026 
aminotransferase (ALT), and aspartate transaminase (AST). 
1027 
 
1028 
12 weeks post-partum: fasting glucose, 2h glucose, fasting insulin, fasting c-peptide, HbA1c, total 
1029 
cholesterol, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, 
1030 
triglycerides (Tg). 
1031 
 
1032 
 
1033 
8.4.6. 
Bio-banking 
1034 
 
1035 
Participants at all trial sites will also be invited to partake in a GDM bio-banking sub-study which 
1036 
involves obtaining maternal blood samples at randomisation and gestational age 38 weeks (+/- 1 
1037 

 
 
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week) and also a cord blood sample at delivery. This is executed under a separate Ethics Committee 
1038 
approved protocol and is executed as guided by local practice patterns and the availability of 
1039 
resources (including staff). 
1040 
 
1041 
8.4.7 Glucometer data 
1042 
 
1043 
Home capillary blood glucose measurements will occur as per routine practice in both groups using a 
1044 
Contour Next One Glucometer (Ascensia). Capillary glucose values will be downloaded from the 
1045 
glucometer at a subsequent in person study visit. The downloaded glucometer data will be stored and 
1046 
analysed as part of a future observational study, and will not be monitored as part of trial care. All 
1047 
clinically relevant glucometer readings will be reviewed at each on-site visit, as per usual care.   
1048 
 
1049 
8.4.8. 
Study Drug Accountability 
1050 
 
1051 
A pill count will be performed by the study nurse/site staff at prenatal visits every 4 weeks and at the 
1052 
12 week post-partum visit to facilitate study medication accountability and check compliance.  
1053 
Non-compliance is defined as less than 80% drug adherence of the participants maximum tolerated 
1054 
dose. 
1055 
8.4.9. 
Neonatal Measurements 
1056 
 
1057 
The neonatal anthropometric measurements will be taken within 72 hours of delivery by trained 
1058 
personnel and will include: 
1059 
 
Crown-heel length 
1060 
 
Head circumference 
1061 
 
Weight 
1062 
 
1063 
Where feasible, abdominal circumference and mid-upper arm circumference measurements will also 
1064 
be taken. 
1065 
 
 
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1067 
8.5. Randomisation 
1068 
 
1069 
Participants will be randomly assigned to receive either metformin or placebo in a 1:1 ratio. Random 
1070 
permuted blocks will be used to ensure similar numbers of participants in each intervention arm 
1071 
throughout the trial and equal numbers in each arm by the end of the study. A minimisation strategy 
1072 
will be used; this will allow equal numbers of participants with a BMI ≤/>30 and with a past history of 
1073 
GDM to be distributed between groups. 
1074 
 
1075 
A web-based randomisation system will be used to allow participating sites to login and obtain 
1076 
allocated treatment numbers and participant IDs after confirming eligibility through inclusion and 
1077 
exclusion criteria. The treatment number will correspond to a treatment kit at the site. This centralised 
1078 
system will ensure allocation concealment; preventing trial staff from knowing which treatment group 
1079 
will be allocated. Blocks of varying length will also be used to reduce the predictability of the allocation 
1080 
sequence. 
1081 
 
1082 
8.6. Blinding 
1083 
 
1084 
This trial will be conducted in a double-blind fashion with placebo control identical to metformin tablets 
1085 
to avoid bias in the assessment of outcomes. Site Investigators, site personnel, participants, and 
1086 
outcome assessors will be blinded to treatment allocation. 
1087 
 
1088 
In the case of an emergency, when knowledge of the participants’s study treatment assignment is 
1089 
essential for the clinical management of the participant, an investigator may un-blind a participant. 
1090 
Any intentional or unintentional breaking of the blind will be recorded and reported to the sponsor as 
1091 
soon as possible.  
1092 
 
1093 
8.6.1. 
Emergency Unblinding 
1094 
 
1095 
Emergency unblinding should only be undertaken when it is essential for the participants safety and 
1096 
will only be provided for the treatment that requires unblinding. Most often, study drug interruption and 
1097 
knowledge of the possible treatment assignments are sufficient to treat a study participant who 
1098 
presents with an emergency condition. In case of unblinding, only those individuals who are 
1099 
required to know treatment allocation may be given this information. Should the treating clinician 
1100 
consider it necessary to un-blind for clinical care of the participant, the treating clinician will be un-
1101 
blinded. All other staff must remain blinded to treatment, including the participant. All participants 
1102 
should resume study treatments after recovery if it is medically appropriate to do so and should be 
1103 
followed until the end of the study. 
1104 
 
1105 
Emergency unblinding will be available on the web-based randomisation service. 
1106 
 
1107 
8.7. Definition of end-of-trial 
1108 
 
1109 
The end of trial will be the date of the last visit of the last participant post-partum. The Sponsors 
1110 
and/or Data safety and monitoring board/trial steering committee have the right at any time to 
1111 
terminate the study for clinical or administrative reasons. 
1112 
 
1113 
The end of the study will be reported to the approving EC and HPRA within 90 days of the end of the 
1114 
clinical trial, or within 15 days if the study is terminated prematurely by the Sponsor or the Sponsors 
1115 

 
 
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Representative. The EU Declaration of the End of Trial form must be used for this. The investigators 
1116 
will inform participants and ensure that the appropriate follow-up is arranged for all involved. 
1117 
 
1118 
8.7.1. 
Premature termination of the study 
1119 
 
1120 
The trial may be terminated prematurely if: 
1121 
 
1122 
 
new information about safety or efficacy appears 
1123 
 
there is unsatisfactory progress of the study 
1124 
 
if deemed necessary by the DSMB 
1125 
 
1126 
If the trial ends prematurely then the HPRA and the approving EC will need to be informed as 
1127 
required. 
1128 
 
1129 
8.8. Discontinuation/withdrawal of participants from study treatment 
1130 
 
1131 
Participants have the right to voluntarily discontinue study treatment or withdraw from the study at any 
1132 
time for any reason without any consequences. The investigator has the right to discontinue a 
1133 
participant from study treatment or withdraw a participant from the study at any time if it is in the best 
1134 
interest of the participant, in circumstances such as: 
1135 
 
1136 
1. any medical condition that the investigator or sponsor determines may jeopardise the 
1137 
participant’s safety if she continues receiving the study treatment 
1138 
2. ineligibility (either arising during the study or retrospectively having been overlooked at 
1139 
screening) 
1140 
3. an adverse event which requires discontinuation of the study medication 
1141 
4. renal or hepatic concerns, shock or sepsis 
1142 
5. lack of compliance with the study and/or study procedures (e.g., dosing instructions, study 
1143 
visits). 
1144 
 
1145 
All participants who discontinue study medication will be invited to continue with protocol specified 
1146 
follow-up procedures. The only exception to this requirement is when a participant withdraws consent 
1147 
for all study procedures and contact.  
1148 
 
1149 
If a participant discontinues study medication, or withdraws full study consent before completing the 
1150 
study, the reason for this must be entered on the appropriate case report form (CRF) page. 
1151 
 
1152 
If a participant is withdrawn due to an adverse event, the investigator will arrange for follow-up visits 
1153 
until the adverse event has resolved or stabilised. 
1154 
 
 
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1156 
9. 
TREATMENT OF TRIAL PARTICIPANTS 
1157 
 
1158 
9.1. Description of study treatments 
1159 
 
1160 
Once a diagnosis of GDM is made, participants will be randomised to either the placebo or metformin 
1161 
arm and medication will commence and continue in addition to usual care.  
1162 
 
1163 
9.1.1. 
Usual Care 
1164 
 
1165 
All participants participating in the Emerge trial will receive usual care as follows: Following a 
1166 
diagnosis of GDM participants will be seen by the diabetes team or trained delegated personnel within 
1167 
1 week of diagnosis who will explain the diagnosis of GDM and its implications for her and her infant. 
1168 
The DNS or trained delegated personnel will instruct participants on the use of a glucometer and the 
1169 
participants will perform 7-point glucose testing before and 1 hour after meals and before bed. 
1170 
Glucose targets of </=5 mmol/l fasting and before meals and </= 7mmol/l 1 hour after meals will be 
1171 
given. Literature will be given and a contact name and telephone number given for any queries or 
1172 
urgent matters. Participants will be seen either by the diabetes physician/DNS/or trained delegate to 
1173 
impart dietary advice (medical nutritional therapy (MNT)) and information on exercise. Participants will 
1174 
be supported by telephone contact from the DNS or trained delegate weekly throughout gestation and 
1175 
attend at 2-4 weekly intervals at an antenatal/diabetes clinic.  
1176 
 
1177 
Two weeks following the commencement of MNT and exercise, each participant is reviewed at the 
1178 
diabetes/antenatal clinic to review blood sugars and decide on the need for insulin intervention. At this 
1179 
time, an ultrasound scan to assess fetal growth is available, which contributes to the decision making 
1180 
progress. If/when insulin is required; the participant is seen by the Investigator, DNS, or trained 
1181 
delegate for instruction on insulin type and frequency, dealing with low and high glucose and use of a 
1182 
glucagon pen, and sick day rules. Diet, exercise, and principles of monitoring are re-enforced at each 
1183 
visit and participants are encouraged to phone the service as necessary.  
1184 
 
1185 
At each subsequent clinic visit, the following measurements are taken; weight, blood pressure, 
1186 
urinalysis, and glycated haemoglobin (HbA1C). Ultrasound scanning occurs every 4 weeks for fetal 
1187 
growth. Mode of delivery is individualised according to mother and fetal health, fetal growth and 
1188 
previous delivery type. A detailed plan is written in the case notes and protocols are available for 
1189 
management of delivery of women with GDM; both treated with MNT only or requiring insulin. 
1190 
Following delivery, all insulin is discontinued and participants resume usual diet and lifestyle. 
1191 
Breastfeeding is encouraged and infant glucose is tested by heel prick within the first 4 hours and as 
1192 
required thereafter. Prior to discharge participants are scheduled for a repeat 75g oral glucose 
1193 
tolerance test (OGTT) at 12 weeks post-partum through the diabetes service. 
1194 
 
1195 
9.1.2. 
Treatment Group 
1196 
 
1197 
Participants randomised to the treatment arm will receive active metformin in addition to usual care. 
1198 
Metformin tablets will be titrated according to a dosing schedule to achieve the pre-specified glucose 
1199 
targets (fasting ≤ 5mmol/l, 1hour post prandial ≤ 7mmol/l). Tablets will be in 500mg doses and will 
1200 
commence at 1 tablet per day (500mg) increasing to a maximum of 5 tablets per day (2500mg) as 
1201 
follows: 
1202 
 
Stage 1) Day 1, 2: 1 tablet with breakfast each day 
1203 
 
Stage 2) Day 3, 4: 1 tablet with breakfast and 1 tablet with dinner each day 
1204 
 
Stage 3) Day 5, 6: 2 tablets with breakfast and 1 tablet with dinner each day 
1205 

 
 
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 
Stage 4) Day 7, 8: 2 tablets with breakfast and 2 tablets with dinner each day 
1206 
 
Stage 5) Day 9, 10: 3 tablets with breakfast and 2 tablets with dinner each day 
1207 
 
1208 
If a participant experiences uncomfortable side effects (e.g. diarrhoea or nausea) at any stage, the 
1209 
site will instruct the participant to go back to the previous dose and then try again to increase the dose 
1210 
after 4-7 days. If the participant cannot tolerate the study medication at the higher dose, but can 
1211 
tolerate the study medication at a lower dose, the participant may continue at that lower dose for the 
1212 
treatment period. 
1213 
 
1214 
9.1.3. 
 Placebo Group 
1215 
 
1216 
Participants randomised to the placebo arm will receive placebo in addition to usual care. Placebo will 
1217 
be titrated according to the dosing schedule to achieve the pre-specified glucose targets (fasting 
1218 
≤5mmol/l, 1hour post prandial ≤ 7mmol/l). Placebo tablets will commence at 1 tablet per day and will 
1219 
be increased to a maximum of 5 tablets per day over 10 days as with the treatment group.  
1220 
 
1221 
9.1.4. 
Requirement for Insulin  
1222 
 
1223 
Insulin will be commenced in each group as per normal practice if 2 or more home glucose readings 
1224 
are outside the pre-specified glucose targets (fasting ≤ 5mmol/l, 1hour post prandial ≤ 7mmol/l) 
1225 
(without reason) despite maximum oral therapy and MNT at any clinic visit. For this reason, insulin is 
1226 
considered a non-IMP in this trial (see safety reporting for NIMP section 10.3.3.). If insulin is initiated, 
1227 
tablets will also be continued at the maximum tolerated dose. Off study metformin is unlikely to be 
1228 
used as this is not routine clinical practice currently. The intervention will continue up to birth of the 
1229 
infant or end of pregnancy due to pregnancy loss.  
1230 
 
1231 
 
1232 
9.2. Formulation, packaging, and handling 
1233 
 
1234 
The IMPs are Glucophage (Metformin) 500mg film-coated tablets and placebo to match tablets 
1235 
supplied to the trial by the marketing authorisation holder Merck Santé (France).  
1236 
 
1237 
The tablets will be repacked for the trial into bottles containing 170 active or placebo tablets and each 
1238 
bottle will be labelled according to Annex 13 requirements. 
1239 
The Sponsor has contracted MODEPHARMA for arranging the clinical trials packaging, labelling, QP 
1240 
release and distribution of trial IMPs in compliance with Good Manufacturing Practice (GMP) and 
1241 
Good Distribution Practice (GDP).  Please refer to the Summary of product Characteristics and 
1242 
Investigational Medicinal Product Dossier (IMPD) for further details about the IMP manufacture and 
1243 
labelling. 
1244 
 
1245 
9.3. Storage of study treatments(s) 
1246 
 
1247 
Metformin and placebo tablets are packaged in high density polyethylene (HDPE) bottles with a 
1248 
desiccant cartridge inside. They must be stored at room temperature (below 30°C) in a secure 
1249 
location with restricted access. A temperature log recording storage temperature should be 
1250 
maintained. Any deviations from the normal range should be reported to the sponsor. 
1251 
 
1252 
9.4. Accountability of the study treatment(s) 
1253 
 
1254 

 
 
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The study medication will be supplied to site as per the sponsor supply process. Shipment records 
1255 
must be maintained by the investigator at the site. The investigator will use a standard prescription 
1256 
form and the investigator/research delegate will collect the medication from its designated storage 
1257 
space.  
1258 
Metformin and matching placebo will be dispensed by authorised personnel according to local 
1259 
regulations. A dispensing log will be kept for each participant to document all pack numbers 
1260 
dispensed to the participant.  
1261 
 
1262 
9.5. Assessment of compliance 
1263 
 
1264 
The investigator should promote compliance by counselling the participant to take the study drug as 
1265 
prescribed. Participants will be provided with a medication instruction sheet to aid with the titration 
1266 
phase of the study. The participant should be instructed to contact the investigator if unable for any 
1267 
reason to take the study drug as prescribed.  Treatment compliance will be assessed by confirmatory 
1268 
tablet counts to be conducted  at each study dispensing visit every 4 weeks post randomisation.   
1269 
 
1270 
Participants will be asked to return all unused study drug and packaging at study dispensing visits, the 
1271 
end of the study or at the time of study drug discontinuation. The Research Nurse or delegate will 
1272 
perform a pill count and calculate adherence. Drug accountability will also be noted by the clinical 
1273 
monitor during site visits and at the completion of the trial. Compliance of the participant with study 
1274 
treatments will be assessed by maintaining return records. Non-compliance is defined as less than 
1275 
80% drug adherence of the participants maximum tolerated dose. In the event of non-compliance, 
1276 
women will be re-counselled about drug adherence. 
1277 
 
1278 
 
1279 
9.5.1. 
Missed Dose 
1280 
 
1281 
If the participant forgets to take a dose of Metformin / placebo she should wait for the next dose at the 
1282 
usual time. She should not double the dose to make up the forgotten dose. 
1283 
 
1284 
9.6. Overdose of study treatment 
1285 
 
1286 
Overdose of metformin hydrochloride has occurred if the ingestion amount is greater than 50 grams 
1287 
(100 x 500mg tablets). Hypoglycaemia has been reported in approximately 10% of cases, but no 
1288 
causal association with metformin hydrochloride has been established. Lactic acidosis has been 
1289 
reported in approximately 32% of metformin overdose cases.  Metformin is dialyzable with a 
1290 
clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, haemodialysis may 
1291 
be useful for removal of accumulated drug from participants in whom metformin over dosage is 
1292 
suspected.  
1293 
 
1294 
Available information concerning treatment of a massive over dosage of metformin is very limited. It 
1295 
would be expected that adverse reactions of a more intense character including epigastric discomfort, 
1296 
nausea and vomiting followed by diarrhoea, drowsiness, weakness, dizziness, malaise and headache 
1297 
might be seen. Should those symptoms persist, lactic acidosis should be excluded. The drug should 
1298 
be discontinued and proper supportive therapy instituted. 
1299 
 
1300 
9.7. Prior and concomitant therapy 
1301 
 
1302 

 
 
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Throughout the study, investigators may prescribe any concomitant medications or treatments 
1303 
deemed necessary to provide adequate supportive care except for those listed in Section 9.7.2.  
1304 
Participants will be instructed to inform the investigator prior to starting any new medications. Any 
1305 
medication, including non-prescription medication(s) and herbal product(s), other than the study 
1306 
medication taken during the study will be recorded in the CRF from the date the participant signs 
1307 
informed consent to the last visit, except those listed below which are expected pregnancy related 
1308 
concomitant medications; 
1309 
 
1310 
a) Pain relief [entonox, pethidine, fentanyl (for epidural), bupivicaine (for epidural)] 
1311 
b) Local Anesthesia for perineal repair 
1312 
c) Prophylactic uterotonic administration or drugs for active management of the third stage of 
1313 
labour i.e., oxytocin (syntocinon) 10 units IM or ergometrine maleate/oxytocin (Syntometrine) 
1314 
500mcg/5 units IM 
1315 
d) Ranitidine 
1316 
e) Sodium Citrate 
1317 
f) 
Routine vaccines in the baby (BCG/TB, Diphtheria, Tetanus, Pertussis, Haemophilus 
1318 
Influenza B (Hib), Polio, Hep B, Pneumococcal (PCV), Meningococcal (Men B) 
1319 
g) Maternal vaccinations 
1320 
h) Vitamin K administration (baby only)  
1321 
i) 
Anti D for mother 
1322 
j) 
Over-the-counter antenatal multivitamins 
1323 
 
1324 
 
1325 
9.7.1. 
Permitted Medications/Non-Investigational Medicinal Products 
1326 
 
1327 
The following medications are permitted for routine use throughout the duration of the trial: 
1328 
1. Paracetamol 
1329 
2. Aspirin 
1330 
3. Low molecular weight heparin 
1331 
4. Antihypertensives 
1332 
5. Routine pregnancy supplements 
1333 
6. Folic Acid 
1334 
7. Vitamin D 
1335 
8. Antacids 
1336 
9. Prescribed medications for established chronic diseases 
1337 
10. Insulin 
1338 
 
1339 
Insulin taken for less than 72 hours will be recorded but will not be considered a primary outcome 
1340 
measure. 
1341 
 
1342 
9.7.2. 
Prohibited Medications 
1343 
 
1344 
The following medications are not permitted for routine use throughout the duration of the trial: 
1345 
 
1346 
 
Non-study oral hypoglycaemic medications 
1347 
 
Intravascular contrast studies with iodinated materials  
1348 
 
1349 
Intravascular contrast studies with iodinated materials can lead to acute alteration of renal function 
1350 
and have been associated with lactic acidosis in patients receiving metformin. Metformin/placebo 
1351 
must be discontinued prior to or at the time of the imaging procedure and not restarted until at least 
1352 
48 hours after, provided that renal function has been re-evaluated and found to be stable. 
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1354 
If for any clinical reason the patient requires treatment with any of the above, the patient must 
1355 
discontinue study treatment either temporarily or permanently and this must be documented in the 
1356 
CRF. 
1357 
 
1358 
9.7.3. 
Cautionary Medications 
1359 
 
1360 
Some medicinal products, such as NSAIDs (including selective cyclo-oxygenase (COX) II inhibitors), 
1361 
ACE inhibitors, angiotensin II receptor antagonists and diuretics (particularly) loop diuretics) may 
1362 
adversely affect renal function and may increase the risk of lactic acidosis. When starting or using 
1363 
such products in combination with metformin/placebo, monitoring of renal function may be required. 
1364 
 
1365 
Medicinal products with intrinsic hyperglycaemic activity (e.g. systemic or local glucocorticoids and 
1366 
sympathomimetics) may require more frequent blood glucose monitoring. 
1367 
 
1368 
As metformin is a substrate of the OCT1 and OCT2 organic cation transporters, co-administration with 
1369 
agents that are metabolised via these transporters may modify the efficacy of metformin. 
1370 
Coadministration of metformin/placebo with inhibitors of OCT1 (such as verapamil) may reduce the 
1371 
efficacy of metformin, and coadministration with inducers of OCT1 (such as rifampicin) may increase 
1372 
the gastrointestinal absorption and efficacy of metformin. Coadministration of metformin/placebo with 
1373 
inhibitors of OCT2 (such as cimetidine, dolutegravic, ranolazine, trimethoprim, vandentanib and 
1374 
isavuconazole) may decrease the renal eliminiation of metformin thereby leading to an increase in the 
1375 
plasma concentration of metformin. Coadministration if metformin/placebo with inhibitors of both 
1376 
OCT1 and OCT2 (such as crizotinib and olaparib) may alter the efficacy and renal elimination of 
1377 
metformin. 
1378 
 
1379 
Caution is therefore advised, when these drugs are co-administered with metformin/placebo, as 
1380 
metformin plasma concentration may increase. Investigators should review if dose adjustment of 
1381 
metformin/placebo is required. 
1382 
 
1383 
10. SAFETY REPORTING 
1384 
 
1385 
10.1. 
Definitions 
1386 
 
1387 
10.1.1. Adverse event (AE) 
1388 
 
1389 
Any untoward medical occurrence in a patient or clinical trial participant administered a medicinal 
1390 
product and which does not necessarily have a causal relationship with this treatment.  
1391 
 
1392 
An adverse event can therefore be any unfavourable and unintended sign (including an abnormal 
1393 
laboratory finding, for example), symptom or disease temporally associated with the use of a 
1394 
medicinal product, whether or not considered related to the medicinal product. 
1395 
Each individual unintended sign, symptom or disease is considered a separate adverse event unless 
1396 
an overarching diagnosis can be made for a collection of signs or symptoms that are clinically linked 
1397 
and temporally related. The overarching diagnosis should be as specific as possible, using all 
1398 
available clinical data. 
1399 
 
1400 
All events in the mother and baby must undergo an assessment to determine if any of the 
1401 
seriousness criteria (section 10.1.3) are met and each event must be reported to the Sponsor. 
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1403 
10.1.2. Adverse reaction (AR) 
1404 
 
1405 
All untoward and unintended responses to a medicinal product related to any dose. 
1406 
The phrase ‘responses to a medicinal product’ means that a causal relationship between a study 
1407 
medication and an AE is at least a reasonable possibility, i.e., the relationship cannot be ruled out. 
1408 
All cases judged by either the reporting medically qualified professional or the sponsor as having a 
1409 
reasonable suspected causal relationship to the study medication qualify as adverse reactions.   
1410 
 
1411 
10.1.3. Serious adverse event (SAE) 
1412 
 
1413 
Any untoward medical occurrence or affect that at any dose meets one or more of the following 
1414 
criteria:  
1415 
 
results in death,  
1416 
 
is life-threatening*,  
1417 
 
requires hospitalisation (defined as >24 hour hospital stay, or formal admission to an 
1418 
inpatient hospital area) or prolongation of existing hospitalisation,  
1419 
 
results in persistent or significant disability or incapacity,  
1420 
 
is a congenital anomaly or birth defect 
1421 
 
is medically important** 
1422 
 
1423 
* this refers to an event in which the participant was at risk of death at the time of the event; it does 
1424 
not refer to an event which hypothetically might have caused death if it were more severe.  
1425 
 
1426 
**Some medical events may jeopardise the participant or may require an intervention to prevent one 
1427 
of the above characteristics/consequences. Such events (hereinafter referred to as ‘medically 
1428 
important’) should also be considered as ‘serious’ in accordance with the definition. 
1429 
 
1430 
10.1.4. Severe adverse events 
1431 
 
1432 
The term ‘severity’ is used here to describe the intensity of a specific event. This has to be 
1433 
distinguished from the term ‘serious’.  
1434 
 
1435 
10.1.5. Suspected unexpected serious adverse reactions 
1436 
 
1437 
An adverse reaction, the nature or severity of which is not consistent with the applicable product 
1438 
information (e.g. investigator’s brochure for an unauthorised investigational medicinal product or 
1439 
summary of product characteristics for an authorised medicinal product). 
1440 
 
1441 
10.2. 
Evaluations of AEs and SAEs 
1442 
 
1443 
The investigator or delegate will report all AEs and SAEs to the sponsor as outlined in section 10.3, 
1444 
except for those identified as outcomes identified below. Figure 3 outlines the cases whereby safety 
1445 
exemptions may require AE/SAE reporting.  
1446 
 
1447 
The following maternal events related to prenatal period, labour, delivery and the postnatal period are 
1448 
commonly experienced and are therefore exempt from safety reporting unless fatal, life threatening, 
1449 
medically important or results in persistent disability or incapacity: 
1450 
 
1451 
i. 
Peripheral Oedema  
1452 

 
 
NUIG-2016-01 
 
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Version 6.0, dated 02-May-2019          Confidential 
ii. 
Leg cramping 
1453 
iii. 
Back, hip or pelvic pain/discomfort or symphysis pubis dysfunction 
1454 
iv. 
Ketonuria, proteinuria, haematuria, glycosuria or leucocytes in the urine that do not 
1455 
require intervention 
1456 
v. 
Vaginal discharge, unless requiring treatment 
1457 
vi. 
Haemorrhoids or pregnancy related rectal bleeding 
1458 
vii. 
Varicose veins 
1459 
viii. 
Palpitations 
1460 
ix. 
Carpal tunnel syndrome 
1461 
x. 
Maternal tachycardia, transient hypotension, epidural related hypotension, nausea or 
1462 
vomiting occurring during the time of hospitalisation for labour or delivery 
1463 
xi. 
Group B Strep colonisation 
1464 
xii. 
Non-medically significant events associated with breast feeding 
1465 
 
1466 
The following maternal events are considered study outcomes and collected on case report forms, 
1467 
and are therefore exempt from safety reporting unless fatal, life threatening, medically important or 
1468 
results in persistent disability or incapacity: 
1469 
 
1470 
i. 
Symptoms common and expected during pregnancy, unless requiring hospitalisation: 
1471 
a. Nausea 
1472 
b. Heartburn 
1473 
c. Vomiting 
1474 
d. Flatulence 
1475 
e. Constipation 
1476 
 
1477 
ii. 
Gastro-intestinal side effects from metformin therapy, unless requiring hospitalisation or 
1478 
cessation of study drug: 
1479 
a. Nausea 
1480 
b. Vomiting 
1481 
c. Diarrhoea 
1482 
d. Flatulence 
1483 
 
1484 
iii. 
Anaemia, unless requiring hospitalisation (anaemia in pregnancy is defined as first trimester 
1485 
haemoglobin (Hb) less than 11.0 g/dl, second/third trimester Hb less than 10.5 g/dl, and 
1486 
postpartum Hb less than 10.0 g/dl, in line with British Committee for Standards in 
1487 
Haematology (BCSH) guidance) 
1488 
iv. 
Hypoglycaemia, unless requiring hospitalisation 
1489 
v. 
Polyhydramnios, unless requiring hospitalisation 
1490 
vi. 
Abnormal OGTT at the 12 week post partum follow up visit (+/- 4 weeks) 
1491 
vii. 
Hypertensive disorder of pregnancy (including elevated blood pressure, pregnancy induced 
1492 
hypertension (PIH) or Preeclampsia (PET)) not requiring hospitalisation, throughout the study 
1493 
period 
1494 
viii. 
Admission to hospital for pre-natal or post-natal care, including: 
1495 
a. Cardiotocograph monitoring (day case) 
1496 
b. BP monitoring 
1497 
c. Monitoring or management of elevated blood pressure, pregnancy induced 
1498 
hypertension or preeclampsia 
1499 
d. Bed rest  
1500 
e. External cephalic version 
1501 
f. 
Observation of placenta praevia or other placental location abnormality 
1502 
g. Unstable fetal lie in utero 
1503 

 
 
NUIG-2016-01 
 
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Version 6.0, dated 02-May-2019          Confidential 
h. Antepartum Haemorrhage 
1504 
i. 
Postpartum haemorrhage 
1505 
j. 
Cholestasis 
1506 
k. Unexplained vaginal bleeding 
1507 
l. 
Iron infusion 
1508 
m. Betamethasone administration 
1509 
n. Premature rupture of membranes 
1510 
o. Anti-D administration 
1511 
ix. 
Wound infection (obstetric origin) 
1512 
x. 
Mastitits 
1513 
xi. 
Admission to hospital for delivery 
1514 
a. Early stages of labour 
1515 
b. Elective or emergency caesarean section (ELCS) 
1516 
c. Induction of labour 
1517 
d. Spontaneous labour 
1518 
 
1519 
If a baby is admitted to the Neonatal Intensive Care Unit (NICU) for monitoring or care-giving 
1520 
purposes only, with monitoring all within normal parameters, without evidence of any abnormality, 
1521 
sign, diagnosis or therapeutic intervention, this is not considered an adverse event. All other 
1522 
admissions to the NICU are considered medically important; the primary reason for NICU admission 
1523 
should be reported as serious adverse events. 
1524 
 
1525 
 
1526 
The following neonatal events are exempt from safety reporting unless fatal, life threatening, 
1527 
medically important or results in persistent disability or incapacity: 
1528 
 
1529 
i. 
Non-medically significant events related to delivery 
1530 
ii. 
Non-medically significant events occurring during the postpartum study follow-up 
1531 
phase 
1532 
 
1533 
 
1534 
The following neonatal events are considered study outcomes and collected on case report forms, 
1535 
and are therefore exempt from safety reporting unless fatal, life threatening, medically important or 
1536 
results in persistent disability or incapacity: 
1537 
 
1538 
 
1539 
iii. 
Neonatal jaundice (with or without phototherapy) 
1540 
iv. 
Neonatal hypoglycaemia  (defined as plasma glucose <2.6mmol/L on one or more 
1541 
occasions starting 30-60 minutes after birth) 
1542 
 
1543 
 
1544 
 
1545 
 
1546 
 
1547 
 
1548 
 
1549 
 
1550 

 
 
NUIG-2016-01 
 
Page 48 of 64 
 
Version 6.0, dated 02-May-2019          Confidential 
 
Non-
Serious 
Event 
Seriousness Criteria^ 
New 
Hospitalisation 
Prolongation of 
Hospitalisation 
Medically 
important 
Life-
threatening Fatal 
Results in persistent or 
significant disability or 
incapacity 
Congenital 
anomaly or 
birth defect 
Symptoms common or expected during 
pregnancy: nausea, heartburn, vomiting, 
flatulence or constipation 
No 
Yes 
Yes 
Yes 
Yes 
Yes 
 
Yes 
 
Yes 
Gastro-intestinal side effects from 
metformin therapy*, nausea, vomiting, 
diarrhoea and flatulence 
No 
Yes 
Yes 
Yes 
Yes 
Yes 
Yes 
Yes 
Anaemia 
No 
Yes 
Yes 
Yes 
Yes 
Yes 
Yes 
Yes 
Cardiotocograph monitoring (day case) 
No 
No 
No 
Yes 
Yes 
Yes 
Yes 
Yes 
BP monitoring 
No 
No 
No 
Yes 
Yes 
Yes 
Yes 
Yes 
Monitoring or management of elevated 
blood pressure, pregnancy induced 
hypertension or preeclampsia 
No 
No 
No 
Yes 
Yes 
Yes 
Yes 
Yes 
Bed rest 
No 
No 
No 
Yes 
Yes 
Yes 
Yes 
Yes 
External cephalic version 
No 
No 
No 
Yes 
Yes 
Yes 
Yes 
Yes 
Betamethasone administration 
No 
No 
No 
Yes 
Yes 
Yes 
Yes 
Yes 
Anti-D administration 
No 
No 
No 
Yes 
Yes 
Yes 
Yes 
Yes 
Iron Infusion 
No 
No 
No 
Yes 
Yes 
Yes 
Yes 
Yes 
Hypoglycaemia 
No 
Yes 
Yes 
Yes 
Yes 
Yes 
Yes 
Yes 
Polyhydramnios 
No 
Yes 
Yes 
Yes 
Yes 
Yes 
Yes 
Yes 
Abnormal OGTT at the 12 week post 
partum follow up visit (+/- 4 weeks) 
No 
No 
No 
Yes 
Yes 
Yes 
Yes 
Yes 
Observation of placenta praevia or other 
placental location abnormality 
No 
No 
No 
Yes 
Yes 
Yes 
Yes 
Yes 
 
Non-
Seriousness Criteria^

 
 
NUIG-2016-01 
 
Page 49 of 64 
 
Version 6.0, dated 02-May-2019          Confidential 
Figure 3: Instances requiring reporting for AE and SAE safety exemptions  
1551 
 
1552 
Yes = Event is reportable as an adverse event; No = Event is not reportable as an adverse event 
1553 
^Where ‘Yes’ is indicated, the event must be reported to the Sponsor in an expedited manner 
1554 
*If study drug is stopped, the event is reportable as an adverse event 
1555 
 
1556 
Admission to hospital for symptoms suggestive of the early stages of labour, or admission to hospital for spontaneous labour, induction of labour or elective 
1557 
or emergency caesarean section are expected outcomes of pregnancy and are not reportable as safety events. All of these hospitalisations must be 
1558 
reviewed for other events that could be reportable adverse events. 
1559 
Serious 
Event 
New 
Hospitalisation 
Prolongation of 
Hospitalisation 
Medically 
important 
Life-
threatening Fatal 
Results in persistent or 
significant disability or 
incapacity 
Congenital 
anomaly or 
birth defect 
Hypertensive disorder of pregnancy 
(including elevated blood pressure, 
pregnancy induced hypertension (PIH) or 
preeclampsia (PET)) not requiring 
hospitalisation, throughout the study 
period 
No 
Yes 
Yes 
Yes 
Yes 
Yes 
Yes 
Yes 
Unstable fetal lie in utero 
No 
No 
No 
Yes 
Yes 
Yes 
Yes 
Yes 
Antepartum haemorrhage 
No 
No 
No 
Yes 
Yes 
Yes 
Yes 
Yes 
Postpartum haemorrhage 
No 
No 
No 
Yes 
Yes 
Yes 
Yes 
Yes 
Unexplained vaginal bleeding 
No 
No 
No 
Yes 
Yes 
Yes 
Yes 
Yes 
Premature rupture of membranes 
No 
No 
No 
Yes 
Yes 
Yes 
Yes 
Yes 
Cholestasis 
No 
No 
No 
Yes 
Yes 
Yes 
Yes 
Yes 
Wound Infection (Obstetric Origin) 
No 
No 
No 
Yes 
Yes 
Yes 
Yes 
Yes 
Mastitis 
No 
No 
No 
Yes 
Yes 
Yes 
Yes 
Yes 
Neonatal jaundice (with or without 
phototherapy) 
No 
No 
No 
Yes 
Yes 
Yes 
Yes 
Yes 
Neonatal hypoglycaemia 
No 
No 
No 
Yes 
Yes 
Yes 
Yes 
Yes 

 
 
NUIG-2016-01 
 
Page 50 of 64 
 
Version 6.0, dated 02-May-2019          Confidential 
 
1560 
10.2.1. Assessment of seriousness 
1561 
 
1562 
The investigator should make an assessment of seriousness as defined in section 10.1.3. 
1563 
 
1564 
10.2.2. Assessment of casuality 
1565 
 
1566 
All adverse events judged by either the investigator or the sponsor as having a reasonable suspected 
1567 
causal relationship to an investigational medicinal product or with the non-investigational medicinal 
1568 
product qualify as adverse reactions. 
1569 
 
1570 
The investigator must make an assessment of whether the AE/SAE is likely to be related to treatment 
1571 
according to the following definitions: 
1572 
 
1573 
 
Unrelated: Where an event is not considered to be related to the study medication. 
1574 
 
Unlikely: where a temporal relationship to the study medication makes a relationship 
1575 
improbable (but not impossible) and disease or other drugs provide plausible explanations. 
1576 
 
Possible: Although a relationship to the study medication cannot be completely ruled out, the 
1577 
nature of the event, the underlying disease, concomitant medication or temporal relationship 
1578 
make other explanations possible. 
1579 
 
Probable: The temporal relationship and absence of a more likely explanation suggest the 
1580 
event could be related to the study medication. 
1581 
 
Definite: Plausible temporal relationship and cannot be explained by disease or other drugs. 
1582 
 
1583 
The causality assessment given by the investigator should not be downgraded by the sponsor. All 
1584 
AEs/SAEs judged as having a reasonable suspected causal relationship (e.g. definite, possible, 
1585 
probable) to the study medication will be considered as ARs/SARs. All AEs/SAEs judged as being 
1586 
related (e.g. definite, possible, probable) to the non-IMP will also be considered to be ARs/SAR. All 
1587 
AEs/SAEs judged as being related (e.g. definite, possible, probable) to an interaction between the 
1588 
IMP and non-IMP will also be considered to be ARs/SAR. 
1589 
 
1590 
Alternative causes such as natural history of the underlying disease, concomitant therapy, other risk 
1591 
factors and the temporal relationship of the event to the treatment should be considered. 
1592 
The causality assessment will also be reviewed by the sponsor.  
1593 
 
1594 
10.2.3. Assessment of severity 
1595 
 
1596 
The investigator will make an assessment of severity for each AE/SAE and record this on the CRF 
1597 
according to one of the following categories: 
1598 
 
1599 
 
Mild: An event that is easily tolerated by the participant, causing minimal discomfort and not 
1600 
interfering with every day activities. 
1601 
 
Moderate: An event that is sufficiently discomforting to interfere with normal everyday 
1602 
activities. 
1603 
 
Severe or medically significant: An event that prevents normal everyday activities. 
1604 
 
Life threatening: An event that has life-threatening consequences 
1605 
 
1606 
Note: the term ‘severe’, should not be confused with ‘serious’ which is a regulatory definition based on 
1607 
participant/event outcome or action criteria 
1608 

 
 
NUIG-2016-01 
 
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Version 6.0, dated 02-May-2019          Confidential 
10.2.4. Assessment of expectedness 
1609 
 
1610 
An expectedness assessment will be carried out by the sponsor for each serious adverse reaction to 
1611 
the IMP or an interaction between the IMP and non-IMP. The expectedness of a serious adverse 
1612 
reaction will be determined by the sponsor according to the reference safety information as contained 
1613 
in section 4.8. of the SmPC for Metformin. 
1614 
 
1615 
10.3. 
Reporting Responsibilities of the investigator 
1616 
 
1617 
10.3.1. Adverse Events/Serious Adverse Events 
1618 
 
1619 
Any AE whose onset occurred after the time of informed consent and the last completed visit, 
1620 
observed by the investigator or reported by the participant, whether or not attributed to the study 
1621 
medication, will be recorded on the AE form in the CRF. The Site Investigator or delegate will follow 
1622 
AE’s and SAE’s reported during the treatment period until resolved, considered stable, or completion 
1623 
of participant participation in the EMERGE trial (i.e. 12 week Postpartum Visit). Follow up information 
1624 
will be sought and submitted as it becomes available. All SAEs will be followed up until resolution or 
1625 
they are clearly determined to be due to a participant’s stable or chronic condition or intercurrent 
1626 
illness(es). 
1627 
 
1628 
The following information will be recorded in the adverse event form: Adverse event term, description, 
1629 
date of onset, outcome, date of resolution, seriousness, severity, assessment of relatedness to the 
1630 
study medication, assessment of relatedness to non-IMP, and assessment of relatedness to 
1631 
interaction between IMP and non-IMP, and action taken with study drug. The Site Investigator is 
1632 
responsible for the assessment of severity (intensity), causality/relatedness to IMP, non-IMP or an 
1633 
interaction between IMP and non-IMP, for all AEs and SAEs. An SAE should also be substantiated by 
1634 
a source document(s). Follow-up information should be provided as necessary. 
1635 
 
1636 
It will be left to the investigator’s clinical judgment whether or not an AE is of sufficient severity to 
1637 
require the participant’s removal from medication. A participant may also voluntarily withdraw from 
1638 
medication due to what he or she perceives as an intolerable AE. If either of these occurs, the 
1639 
participant must undergo an end-of-study assessment and be given appropriate care under medical 
1640 
supervision until symptoms cease or the condition becomes stable. 
1641 
 
1642 
10.3.2. Timelines for reporting 
1643 
 
1644 
Adverse event information will be reported by site personnel in a timely fashion from the time the site 
1645 
becomes aware of the event. 
1646 
 
1647 
Serious adverse event information will be reported by site personnel within 24 hours to the sponsor 
1648 
from the time the site becomes aware of the event, except for those that the protocol identifies as not 
1649 
requiring immediate reporting. The site team are considered aware of an adverse event from the time 
1650 
of first notification of the first member of the EMERGE site team, as per the Site Delegation Log. All 
1651 
SAE’s will be submitted by the site by completing the required fields on the AE CRF within 24 hours of 
1652 
site awareness of the event. A valid SAE report must include all of the following: 
1653 
 
1654 
 
Adverse event term (based on what is known at the time of reporting) 
1655 
 
Seriousness criteria 
1656 
 
Severity 
1657 

 
 
NUIG-2016-01 
 
Page 52 of 64 
 
Version 6.0, dated 02-May-2019          Confidential 
 
Causality assessments (for metformin/placebo, insulin [if applicable] and the potential 
1658 
interaction betweem metformin/placebo and insulin [if applicable]) 
1659 
 
Investigator sign-off 
1660 
 
1661 
The immediate report will be followed by detailed, written reports. The immediate and follow-up 
1662 
reports will identify participants by unique code numbers. 
1663 
 
1664 
10.3.3. Safety Reporting for Non-IMP  
1665 
 
1666 
Insulin is considered a non-IMP and therefore must follow safety reporting guidelines for non-IMP. 
1667 
All AEs and SAEs considered by the investigator to be related to the non-IMP will be reported to the 
1668 
sponsor within the required timeframes (section 10.3.2). 
1669 
All AEs and SAEs which are considered by the investigator to be related to an interaction between 
1670 
IMP and non-IMP will be reported to the sponsor within the required timeframes (section 10.3.2). 
1671 
 
1672 
10.4. 
Reporting responsibilities of the sponsor 
1673 
 
1674 
10.4.1. Regulatory Authorities 
1675 
 
1676 
The sponsor will keep detailed records of all adverse events which are reported to him by the 
1677 
investigator or investigators. The sponsor will report all SUSARs to the competent authority (HPRA) or 
1678 
EudraVigilance (as required) and the approving ethics committees concerned, and all principal 
1679 
investigators. Fatal or life-threatening SUSARs must be reported within 7 days. 
1680 
 
1681 
If the initial report is incomplete, e.g. all the information/assessment has not been provided, the 
1682 
sponsor will submit a completed follow up report within an additional eight days. 
1683 
 
1684 
SUSARs which are not fatal and not life-threatening are to be reported within 15 days to the sponsor. 
1685 
If significant new information on an already reported case is received by the sponsor, the clock starts 
1686 
again at day zero, i.e. the date of receipt of new information. This information will be reported as a 
1687 
follow-up report within 15 days. 
1688 
 
1689 
10.4.2. Safety Reports 
1690 
 
1691 
The sponsor will distribute masked expedited SUSAR reports, to each participating Site Investigator, 
1692 
as appropriate. 
1693 
SUSARs of which the treatment allocation of the participant is un-blinded should be reported by the 
1694 
sponsor to the national competent authority as well as the Ethics Committee. 
1695 
 
1696 
10.4.3. Annual Reports 
1697 
 
1698 
In addition to the expedited reporting above, the sponsor shall submit once a year throughout the 
1699 
clinical trial or on request, a safety report to the competent authority (HPRA) and ethics committees. 
1700 
The annual safety report will be presented in the development safety update reports (DSUR) format 
1701 
as per ICH guideline E2F - Note for guidance on DSUR.  
1702 

 
 
NUIG-2016-01 
 
Page 53 of 64 
 
Version 6.0, dated 02-May-2019          Confidential 
 
1703 
10.4.4. Safety reports for non-IMP 
1704 
The sponsor will report SARs for non-IMP to the Regulatory Authorities or the marketing authorisation 
1705 
holder. The sponsor will report SUSARs for interactions between the IMP and non-IMP to the 
1706 
competent authority (HPRA) or EudraVigilance (as required) and Ethics Committee. 
1707 
 
1708 
The sponsor will distribute masked expedited SUSAR reports for interactions between IMP and non-
1709 
IMP to each participating Site Investigator, as appropriate. 
1710 
 
1711 
10.5. 
Data safety monitoring board (DSMB) 
1712 
 
1713 
A DSMB is established and members will serve in an individual capacity and provide their expertise 
1714 
and recommendations. The primary responsibilities of the DSMB will be to: 
1715 
 
1716 
1. Become familiar with the research protocol and the procedures for data safety/monitoring. 
1717 
2. Review interim analyses of outcome data/adverse event reports. 
1718 
3. Make written recommendations to the TSC concerning the continuation, modification, or 
1719 
termination of the trial. 
1720 
4. Consider any requests for release of interim trial data and make recommendations to the TSC 
1721 
on the advisability of this. 
1722 
5. Review major proposed modifications to the study prior to their implementation (e.g., 
1723 
termination, increasing target sample size). 
1724 
6. Maintain confidentiality during all phases of DSMB review and deliberations. 
1725 
7. Review SAEs and SUSARs as appropriate 
1726 
 
1727 
The responsibilities of the DSMB are outlined further in the DSMB charter. The membership of the 
1728 
DSMB reflects the professions necessary to interpret the data and results from the study and to 
1729 
evaluate participant safety fully.  
1730 
 
1731 
10.6. 
Trial Steering and Advisory Group 
1732 
 
1733 
The purpose of the TSAG is to provide strategic oversight for the overall direction and strategy for a 
1734 
clinical trial. The primary responsibilities of the TSAG are: 
1735 
1. To contribute to the design of the study 
1736 
2. Increase information exchange at an early stage of trial development 
1737 
3. Increase the efficiency of clinical trial collaboration 
1738 
4. To monitor and review a) Recruitment progress, b) Quality control, c) Ethical amendments, d) 
1739 
Financial aspects, and e) Publications 
1740 
5. To determine action points to facilitate the satisfactory progress of the EMERGE study. 
1741 
 
1742 
This committee includes investigators, other experts not otherwise involved in the trial, and 
1743 
representative of the sponsor. The responsibilities of the TSAG are outlined further in the TSAG 
1744 
charter. 
1745 
 
1746 
11. STATISTICS 
1747 
 
1748 
11.1. 
General Considerations 
1749 
General description of the statistical methods is outlined below. A more detailed statistical analysis 
1750 
plan (SAP) will be provided in a separate document. The SAP document will provide a more technical 
1751 

 
 
NUIG-2016-01 
 
Page 54 of 64 
 
Version 6.0, dated 02-May-2019          Confidential 
and detailed elaboration of the principal features of the planned analyses. The SAP will be finalised 
1752 
prior to study enrolment, at the latest before any substantial information in the trial has accumulated. 
1753 
 
1754 
Analyses will be performed using R software. 
1755 
 
1756 
11.2. 
Determination of sample size  
1757 
 
1758 
Our sample size is based on the following; a) 35% of participants will require insulin in the control 
1759 
arm, based on information from the MiG trial and data from University Hospital Galway and University 
1760 
Hospital Cork; b) ability to detect a minimum of 33% relative risk reduction in proportion of participants 
1761 
requiring insulin in the experimental (metformin) group (40% to 28% absolute reduction; in the MiG 
1762 
trial only 40% of participants on metformin required insulin); c) significance level of 0.05 and 80% 
1763 
power; d) drop-out rate of 5% or less; and e) non-adherence rate of 8% in metformin group. Based on 
1764 
these assumptions, we require a total of 550 participants. This sample size will also have 80% power 
1765 
to demonstrate a difference between the proportions of 12% or more (i.e. a reduction from 60-48%) in 
1766 
the secondary outcome of excessive GWG.  
1767 
 
1768 
There are 7,000 deliveries annually in participating sites. From ATLANTIC DIP 1 we have identified a 
1769 
prevalence of 12.4% for GDM using IADPSG criteria. In our previous universal screening project, we 
1770 
had a consent rate of 75% but a testing rate of circa 50%. On a second study examining uptake rates 
1771 
in primary v secondary care, the screening uptake rate was 88% for screening in secondary care. 
1772 
With prevalence of 12% we would expect to diagnose upto 840 pregnancies with GDM annually. For 
1773 
the secondary outcome of baseline to post-partum weight change, there is a greater concern with loss 
1774 
to follow-up, as post-pregnancy follow-up rates have been reported in some studies to be less than 
1775 
70%. For this outcome, even with a loss-to follow- up of 50% the resulting 138 per arm will have 80% 
1776 
power, at the 0.05 significance level, to detect a minimum difference in mean weight change of 
1777 
1.36kgs (assuming a standard deviation of the change in weight of 4kgs). However, every effort will 
1778 
be made to achieve follow-up rates of >95% for post-partum follow-up, and we will implement a 
1779 
number of strategies to enhance follow-up for this outcome (e.g. home monitoring of weight).  
1780 
 
1781 
11.3. 
Analysis Sets 
1782 
 
1783 
11.3.1. Intention-to-Treat Analysis Set 
1784 
 
1785 
The intention-to-treat analysis set, also termed full analysis set in the International Conference on 
1786 
Harmonization (ICH) E9 guideline, will include all randomized participants. 
1787 
 
1788 
11.3.2. Safety Analysis Set  
1789 
 
1790 
The safety analysis set will include all randomized participants who received at least one dose of 
1791 
study medication. 
1792 
 
1793 
11.4. 
Demographic and baseline disease characteristics 
1794 
 
1795 
Demographic and baseline characteristics of the study population will be summarized using graphical 
1796 
displays and descriptive statistics for each treatment group. 
1797 
 
1798 
 
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11.5. 
Effectiveness Analysis 
1800 
 
1801 
Suitable numerical and graphical techniques will be used to compare the primary and secondary 
1802 
responses and the balance in explanatory variables at baseline. The primary analysis will be a two-
1803 
sample comparison of reduction in the proportion of participants needing insulin between treatment 
1804 
and control arms using an exact test for a binomial response.  
1805 
 
1806 
We will also conduct a logistic regression analysis, to adjust for differences of baseline co-variates 
1807 
between treatment groups. Several strategies for including explanatory variables will be employed 
1808 
where penalisation for multicollinearity will be achieved using ridge penalties. Following this the most 
1809 
parsimonious subset of predictor variables will be identified using computationally intensive data 
1810 
driven techniques such as the classification trees and the Lasso penalty.  
1811 
 
1812 
A secondary exploratory analysis will involve a comparison of the time to insulin initiation between the 
1813 
treatment groups, initially using the log-rank test and then the proportional hazards model in order to 
1814 
adjust for patient characteristics as appropriate. Repeated measures ANOVA will be used to evaluate 
1815 
the effect of intervention on secondary outcome of mean change in weight (from baseline to post-
1816 
partum follow-up). 
1817 
 
1818 
11.5.1. Primary Effectivness Outcomes 
1819 
 
1820 
The primary efficacy outcome is a composite of: 
1821 
 
Insulin initiation (Yes/No) 
1822 
 
Fasting glucose value <5.1 mmol/l and ≥5.1 mmol/l 
1823 
 
1824 
11.5.2. Secondary Effectiveness Outcomes 
1825 
 
1826 
Secondary efficacy outcomes include: 
1827 
 
Maternal BMI, waist circumference, maternal gestational weight gain (GWG) blood glucose 
1828 
status, insulin resistance status and metabolic syndrome postpartum  
1829 
 
Proportion of infants with morbidities; 
1830 
 
Infant birth weight  
1831 
 
Proportion of maternal morbidities  
1832 
 
1833 
11.5.3. Health Economic Outcomes 
1834 
 
1835 
Health economic outcomes include: 
1836 
 
EQ5D-5L 
1837 
 
Quality Adjusted Life Years (QALYs) 
1838 
 
Costs of healthcare associated with the intervention and control arms 
1839 
 
1840 
11.6. 
The level of statistical significance 
1841 
 
1842 
The level of statistical significance will be set at =0.05 for all analyses i.e. a p-value <0.05 with 95% 
1843 
CI’s not containing zero will be considered statistically significant. 
1844 
 
1845 
11.7. 
Procedure for accounting for missing, unused and spurious data 
1846 
An analysis of all missing data will be carried out to identify the likely missing data mechanism (e.g. 
1847 
missing completely at random, missing at random, and missing not at random). A suitable multiple 
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imputation strategy will then be employed to determine the sensitivity of missing data on the inference 
1849 
gleaned from the final model. 
1850 
 
1851 
11.8. 
Health economic analysis 
1852 
The Health Economic and Policy Analysis (HEPA) research team at NUI Galway have previous 
1853 
experience, within an Irish healthcare context, in the design and conduct of economic evaluation 
1854 
alongside randomised controlled trials. The health economic analysis will consist of trial-based 
1855 
economic evaluation and will incorporate both cost effectiveness analysis and cost utility analysis to 
1856 
compare the alternative treatment strategies: (1) metformin in addition to usual care for GDM (that is, 
1857 
MNT and/or insulin); and (2) usual care for GDM. The economic evaluation will be undertaken in a 
1858 
manner consistent with the guidelines issued by Health Information and Quality Authority (HIQA) 
1859 
(2014) for the evaluation of technologies in Ireland. The basic tasks of the evaluation are to identify, 
1860 
measure, value and compare the costs and outcomes of the alternatives being considered. Evidence 
1861 
collected on resource use and clinical outcome measures alongside the trial will provide the basis for 
1862 
the analysis over the trial follow up period. A healthcare provider perspective will be adopted with 
1863 
respect to costing. This will reflect the healthcare resources consumed in operating both treatment 
1864 
strategies including those relating to health professional time input, diagnostic testing, dietary, 
1865 
exercise and prescription medication interventions (metformin and insulin), consumables and 
1866 
materials, equipment and overheads. Healthcare resource use for both treatment arms will be 
1867 
recorded alongside the trial. Unit costs will be applied to value resource use data and calculate the 
1868 
various costs of care. 
1869 
 
1870 
As detailed above, significant attention will also be paid to collecting relevant data on health outcomes 
1871 
alongside the trial. For the cost effectiveness analysis, the treatment strategies will be compared on 
1872 
the basis of the effectiveness data for the primary clinical outcome. For the cost utility analysis, 
1873 
effectiveness will be evaluated on the basis of Quality Adjusted Life-Years (QALYs), which is the 
1874 
preferred outcome measure for economic evaluation as it allows for comparison of relative cost 
1875 
effectiveness both within and beyond the clinical area of interest (Drummond et al, 2015). In this case, 
1876 
patient responses to the EQ5D 5L questionnaire (Euroqol Group, 1990) at baseline and follow up will 
1877 
be used to compute QALYs for the two treatment arms. The health economic analysis will employ the 
1878 
standard approach for the comparison of alternative treatment strategies in terms of costs and health 
1879 
outcomes. An incremental analysis will be undertaken to provide information on the marginal costs 
1880 
and effects of the metformin plus standard GDM care intervention relative to the standard GDM care 
1881 
alternative through the calculation of incremental cost effectiveness ratios. The analysis will report the 
1882 
incremental cost effectiveness from a publicly funded health system perspective in line with HIQA 
1883 
guidance (HIQA, 2014). Univariate, multivariate and probabilistic sensitivity analyses will be employed 
1884 
to address uncertainty in the study. Budget impact analysis will be undertaken for metformin in 
1885 
addition to usual care for GDM strategy. 
1886 
 
1887 
12. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
1888 
 
1889 
The agreement with the investigator will include permission for trial related monitoring, audits, ethics 
1890 
committee review and regulatory inspections, by providing direct access to source data and trial 
1891 
related documentation. Consent from patients/legal representatives for direct access to data will also 
1892 
be obtained. The patients’ confidentiality will be maintained and will not be made publicly available to 
1893 
the extent permitted by the applicable laws and regulations. 
1894 
 
1895 
 
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1897 
13. DATA HANDLING AND RECORD KEEPING 
1898 
 
1899 
13.1. 
Data collection, source documents and case report forms (CRF):  
1900 
 
1901 
Source documents for this study will include hospital records and procedure reports and data 
1902 
collection forms. These documents will be used to enter data on the CRFs. All data entered on CRFs 
1903 
must be entered legibly. If an error is made, the error will be crossed through with a single line in such 
1904 
a way that the original entry can still be read. The correct entry will then be clearly inserted, and the 
1905 
alterations will be initialled and dated. 
1906 
 
1907 
Data reported on the CRF that are derived from source documents must be consistent with the source 
1908 
documents or the discrepancies must be explained. All documents will be stored safely in confidential 
1909 
conditions. On all study-specific documents other than the signed consent, the participant will be 
1910 
referred to by the study participant identification number/code.  
1911 
 
1912 
Patient identification on the CRF and questionnaires will be through participant initials and their 
1913 
unique trial identifier allocated at the time of enrolment. No names or other identifying details will be 
1914 
recorded on the CRF or in any other format. 
1915 
 
1916 
13.2. 
Data reporting  
1917 
 
1918 
The Data Manager will develop a Data Management Plan (DMP) which will detail all activities relating 
1919 
to the management of the clinical data. All project specific data management documentation will be 
1920 
filed in a Data Management File (DMF). The Data management team will also develop a Clinical Data 
1921 
Management System (CDMS) to store the clinical data. This will be developed following the relevant 
1922 
Data Management SOPs and adhering to ISO guidelines. 
1923 
 
1924 
Once registered to a trial the patient will be provided with a unique, study-specific participant identifier 
1925 
and this and their initials will be the only way the patient will be identified in the database. Data 
1926 
collected on CRFs will be entered directly from the CRF onto the Clinical Data Management System 
1927 
by data processers at the CRFG. Data entry is by single data entry. A 100% manual verification of all 
1928 
data entered on the database will be performed prior to interim analysis to ensure consistency 
1929 
between the original CRF and the database. 
1930 
 
1931 
Data queries will be generated for the investigational site as required to clarify data discrepancies or 
1932 
request missing information. The designated site staff will be required to respond to these queries and 
1933 
send them back to the Data Management Team after they have been reviewed and signed by the 
1934 
Principal Investigator/delegated staff member. Any amended information will then be entered in the 
1935 
database. A copy of the signed query form should be retained with the CRF at the investigator site. 
1936 
 
1937 
14. RETENTION OF ESSENTIAL DOCUMENTS 
1938 
 
1939 
The investigator will maintain all trial records according to GCP and the applicable regulatory 
1940 
requirements. The trial master file (TMF) will be established at the beginning of the trial by the 
1941 
sponsor. The investigator site files will be maintained at the investigators site. These will contain the 
1942 
essential documents in line with ICH-GCP. On completion of the trial the essential documents will be 
1943 
maintained by the investigator for a period of at least 15 years or as otherwise specified in the 
1944 
regulations. 
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1946 
Following confirmation, the sponsor will notify the investigator when they are no longer required to 
1947 
maintain the files. If the investigator withdraws from the responsibility of keeping the trial records, 
1948 
custody must be transferred to a person willing to accept responsibility and this must be documented 
1949 
in writing to the sponsor. 
1950 
 
1951 
15. REGULATIONS, ETHICS, COMPLIANCE AND GOVERNANCE 
1952 
 
1953 
This clinical study was designed and shall be implemented and reported in accordance with the 
1954 
principles of ICH GCP, the requirements and standards set out by the EU Directives 2001/20/EC and 
1955 
2005/28/EC, the applicable regulatory requirements and their updates in Ireland and with the ethical 
1956 
principles laid down in the Declaration of Helsinki. 
1957 
 
1958 
15.1. 
Sponsorship 
1959 
 
1960 
National University of Ireland, Galway (NUIG) is the Sponsor for the trial. The Chief Investigator will 
1961 
take overall responsibility for the conduct of the trial. 
1962 
 
1963 
15.2. 
 Indemnity 
1964 
 
1965 
The sponsor maintains clinical trial insurance coverage for this study in accordance with Irish laws 
1966 
and regulations. The State Claims Agency, Clinical Indemnity Scheme, will provide clinical indemnity 
1967 
for any harm caused to patients by the design of the research protocol.  Additionally, indemnity to 
1968 
allow for no-fault compensation will be provided for by NUI Galway for Irish sites. The Agreements put 
1969 
in place between the Sponsors and individual participating sites will cover the indemnity provision for 
1970 
negligent harm. 
1971 
 
1972 
15.3. 
Finance 
1973 
 
1974 
The study is funded by the Health Research Board.  There is no industry funding provided for this 
1975 
study.  
1976 
 
1977 
15.4. 
Regulatory and Ethical Approvals 
1978 
 
1979 
The trial will be conducted in accordance with the ethical principles that have their origin in the 
1980 
Declaration of Helsinki. The protocol will be approved by a recognised Research Ethic Committees 
1981 
(REC) for all participating sites before start of the study. 
1982 
The trial will be conducted in accordance with the EU Directive 2001/20/EC and 2005/28/EC and will 
1983 
adhere to all regulatory requirements or updates as required.  A CTA will be obtained from the HPRA 
1984 
before the start of the trial. 
1985 
 
1986 
15.5. 
Audits and Inspections 
1987 
 
1988 
This trial may be subject to external auditing or inspections to ensure adherence to GCP. Access to 
1989 
all trial-related documents will be given at that time. 
1990 
 
1991 
15.6. 
Ethical Considerations 
1992 
 
1993 

 
 
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The vulnerability of this study group is fully appreciated and every effort will be undertaken to protect 
1994 
their safety and well-being. In line with the applicable regulatory requirements consenting processes 
1995 
will be standardised and a robust SOP for consenting participants will be adhered to. 
1996 
 
1997 
15.7. 
Protocol Compliance 
1998 
 
1999 
The investigators will conduct the study in compliance with the protocol given approval/favourable 
2000 
opinion by the Ethics Committee and the appropriate regulatory authority and as per investigator 
2001 
responsibilities outlined in ICH-GCP E6 R2. Changes to the protocol will require competent 
2002 
authority/ethics committee approval/favourable opinion prior to implementation, except when 
2003 
modification is needed to eliminate an immediate hazard(s) to patients. The TSC in collaboration with 
2004 
the Sponsor will submit all protocol modifications to the competent authority/research ethics 
2005 
committees for review in accordance with the governing regulations.   
2006 
 
2007 
Protocol compliance will be monitored by a monitor who will undertake site visits to ensure that the 
2008 
trial protocol is adhered to and that necessary paperwork (CRF’s, patient consent) are being 
2009 
completed appropriately. Any deviations from the protocol will be reported to a sponsor representative 
2010 
as per the process and timelines communicated. 
2011 
 
2012 
15.8. 
Patient Confidentiality 
2013 
 
2014 
In order to maintain confidentiality, all CRFs, questionnaires, study reports and communication 
2015 
regarding the study will identify the patients by the assigned unique trial identifier and initials only.  
2016 
Patient confidentiality will be maintained at every stage and will not be made publicly available to the 
2017 
extent permitted by the applicable laws and regulations.  
2018 
 
2019 
15.9. 
Good Clinical Practice 
2020 
 
2021 
The trial will be carried out in accordance with the principles of the International Conference on 
2022 
Harmonisation Good Clinical Practice (ICH-GCP) guidelines (www.ich.org).   
2023 
 
2024 
16. AUDITS AND INSPECTIONS 
2025 
 
2026 
This trial may be subject to internal or external auditing or inspections procedure to ensure adherence 
2027 
to GCP. Access to all trial-related documents will be given at that time. 
2028 
 
2029 
17. ETHICS 
2030 
 
2031 
17.1. 
Approvals 
2032 
 
2033 
Required documents including the protocol, ICF, participant information leaflet, investigational 
2034 
medicinal product dossier, investigators brochure and any other required documents will be submitted 
2035 
to a recognised research ethics committee and the competent authority for written approval.  
2036 
 
2037 
The sponsor will submit and obtain approval from the above parties for substantial amendments to the 
2038 
original approved documents. 
2039 

 
 
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2040 
17.2. 
Benefits and risks assessment  
2041 
 
2042 
Participants with a contraindication to the use of metformin will be excluded from the trial (see section 
2043 
8.2.3.) If such maternal contraindications develop, the study medication will be discontinued. Reduced 
2044 
vitamin B12 levels due to metformin use are not expected in this trial as this has been documented 
2045 
only in patients with long-term metformin use (4-6 years) (Tomkin et al. 1971). In order to reduce the 
2046 
known gastrointestinal side effects of metformin use, the dose will be titrated slowly upwards in 
2047 
500mg increments up to 2500mg over 10 days. 
2048 
 
2049 
Potential benefits for trial participants include delayed insulin initiation, reduced dose of insulin 
2050 
required, or insulin not required, hence minimising the risks associated with insulin use on maternal 
2051 
and neonatal outcomes. 
2052 
 
2053 
17.3. 
Participant confidentiality 
2054 
 
2055 
The trial staff will ensure that the participants’ anonymity is maintained. The participants will be 
2056 
identified only by initials and a participant’s identification number on the CRF and any database. All 
2057 
documents will be stored securely. The study will comply with the General Data Protection Regulation 
2058 
(GDPR) and any applicable data protection updates. Information on GDPR and rights of the 
2059 
participant will be provided to the participant on the ICF.  
2060 
 
2061 
18. CLINICAL STUDY REPORT AND PUBLICATION POLICY 
2062 
 
2063 
The results of this study will be disseminated to a wide audience locally nationally and internationally. 
2064 
Initially the results will be shared with the key stakeholders in the Disciplines of Medicine, Obstetrics, 
2065 
and economics and with a wider diabetes audience locally through the recently established Galway 
2066 
Diabetes Research Centre (GDRC). Results will be presented to the regional Diabetes Services 
2067 
Implementation group (DSiG). Nationally outcomes will be discussed with key workers and decision 
2068 
makers in the Health Services Executive (HSE) especially the lead for Quality and Improvement, 
2069 
the lead for Diabetes and the lead for obstetrics. We will communicate outcomes with the national 
2070 
professional body in diabetes, the diabetes subsection of the Irish Endocrine Society, the Institute of 
2071 
Obstetrics and Gynaecology, and the Faculty of Paediatrics.  
2072 
 
2073 
The results will be presented at national Diabetes, Obstetric, and Health Economics meetings. There 
2074 
will be dissemination in peer reviewed journals in Diabetes Obstetrics and Health Economics. We will 
2075 
aim for journals of high impact factor e.g. Lancet, NEJM, Diabetes Care, Diabetologia and JCEM. 
2076 
Internationally the results will be shared at the American, British and European meetings in Diabetes 
2077 
Obstetrics and Health Economics in particular the ADA EASD and DPSG through poster and podium 
2078 
presentations. We will also work with the Diabetes Federation of Ireland for dissemination using the 
2079 
media of radio television and print to reach participants with prior and current GDM. Dissemination in 
2080 
the Irish Times Medical Supplement will be important to reach a wide audience including patient’s 
2081 
professionals and policy makers.  
2082 
 
2083 
 
2084 
 
2085 
 
2086 
 
2087 
 
2088 

 
 
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19. REFERENCES 
2089 
ADA. American Diabetes Association Position statement: Gestational Diabetes Mellitus. Diabetes 
2090 
Care. 2004;27(Suppl 1):S88-S90. 
2091 
Bellamy L, Casas J-P, Hingorani AD, Williams D. Type 2 diabetes mellitus after gestational diabetes: 
2092 
a systematic review and meta-analysis. Lancet. 2009: 373(9677):1773 - 9. 
2093 
Bradley C(1994). The Diabetes Treatment satisfaction Questionnaire: DTSQ. In Bradley C (Ed) 
2094 
(1994). Handbook of Psychology and Diabetes: a guide to psychological measurement in diabetes 
2095 
research and practice. Chur. Switzerland: Harwood Academic Publishers. 
2096 
Camelo Castillo W, Boggess K, Stürmer T, Brookhart MA, Benjamin DK Jr, Jonsson Funk M. 
2097 
Association of Adverse Pregnancy Outcomes With Glyburide vs. Insulin in Women With Gestational 
2098 
Diabetes. JAMA Pediatr. 2015 May;169(5):452-8.  
2099 
Carmody L, Egan AM, Kirwan B, Dunne F. Atlantic Dip: Postpartum Screening in Women with 
2100 
Gestational Diabetes: Who Attends and Why? [abstract]. Diabetes. 2014; 63 (Suppl 1): A342 
2101 
Chiswick C, Reynolds RM, Denison F, Drake AJ, Forbes S, Newby DE, Walker BR, Quenby S, Wray 
2102 
S, Weeks A, Lashen H, Rodriguez A, Murray G, Whyte S, Norman JE. Effect of metformin on 
2103 
maternal and fetal outcomes in obese pregnant women (EMPOWaR): a randomised, double-blind, 
2104 
placebo-controlled trial. Lancet Diabetes Endocrinol. 2015 Oct;3(10):778-86 
2105 
Clausen TD, Mortensen EL, Schmidt L, Mathiesen ER, Hansen T, Jensen DM, Damm P. Cognitive 
2106 
function in adult offspring of women with gestational diabetes--the role of glucose and other factors. 
2107 
PLoS One. 2013 Jun 28;8(6):e67107.  
2108 
Clausen TD, Mathiesen ER, Hansen T, Pedersen O, Jensen DM, Lauenborg J, Schmidt L, Damm 
2109 
P.Overweight and the metabolic syndrome in adult offspring of women with diet-treated gestational 
2110 
diabetes mellitus or type 1 diabetes. J Clin Endocrinol Metab. 2009 Jul;94(7):2464-70 
2111 
Coetzee EJ, Jackson WPU. Oral hypoglycaemics in the first trimester and fetal outcome. S Afr Med J 
2112 
1984; 65:635-637. 
2113 
Crowther CA, Hiller JE, Moss JR, McPhee AJ, Jeffries WS, Robinson JS. Australian Carbohydrate 
2114 
Intolerance Study in Pregnant Women (ACHOIS) Trial Group. Effect of treatment of gestational 
2115 
diabetes mellitus on pregnancy outcomes. N Engl J Med 2005;352:2477-2486. 
2116 
Dennedy C Dunne F. ATLANTIC DIP: Raised Body mass index (BMI) is associated with adverse 
2117 
maternal and  infant outcomes in glucose tolerant women applying HAPO criteria. JCEM 2012; 
2118 
97(4):E608-612. 
2119 
Drummond, M.F., Sculpher, M.J., Torrance, G.W., O'Brien, J., Stoddart, G.L.: Methods for the 
2120 
Economic Evaluation of Health Care Programmes. Oxford University Press. (2005). 
2121 
Egan AM, Dennedy MC, Al-Ramli W, Heerey A, Dunne F. Atlantic DIP: gestational weight gain and 
2122 
pregnancy outcomes in women with pregestational and gestational diabetes mellitus. JCEM 2013 (in 
2123 
press). 
2124 
EuroQol Group. EuroQol-a new facility for the measurement of health-related quality of life. Health 
2125 
Policy 1990;16:199-208) 
2126 

 
 
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Page 62 of 64 
 
Version 6.0, dated 02-May-2019          Confidential 
Gilbert C, Valois M, Koren G. Pregnancy outcome after first-trimester exposure to metformin: a 
2127 
metaanalysis. Fertil Steril 2006; 86: 658-663 
2128 
Gillespie P, Cullinan J, Avalos G, Dunne F. The effect of Gestational Diabetes on Maternity Care 
2129 
Costs. Diabetes Care 2013. 
2130 
Glibenclamide, metformin, and insulin for the treatment of gestational diabetes: a systematic review 
2131 
and meta-analysis. Balsells M, García-Patterson A, Solà I, Roqué M, Gich I, Corcoy R. BMJ. 2015 
2132 
Jan 21;350:h102. 
2133 
Glueck CJ, Goldenberg N, Pranikoff J, Loftspring M, Sieve L, Wang P. Height weight and motor-social 
2134 
development during the first 18 months of life in 126 infants born to 109 mothers with polycystic ovary 
2135 
syndrome who conceived on and continued metformin through pregnancy. Hum Reprod 2004; 19: 
2136 
1323- 1330. 
2137 
Goh L E J, Sadler L, Rowan J. Metformin for gestational diabetes in routine clinical practice. Diabetic 
2138 
Medicine 2011; 1082-1087. 
2139 
Gutzin SJ, Kozer E, Magee LA, Feig DS, Koren G. The safety or oral hypoglycaemic agents in the 
2140 
first trimester of pregnancy: a meta-analysis. Can J Clin Pharmacol 2003; 10: 179-183 
2141 
Health Information Quality Assessment (HIQA): Guidelines for the Economic Evaluation of Health 
2142 
Technologies in Ireland. 2010. Available online: http://www.hiqa.ie/publication/guidelines-
2143 
economicevaluation- healthtechnologies- Ireland. 
2144 
International association of diabetes and pregnancy study groups recommendations on the diagnosis 
2145 
and classification of hyperglycemia in pregnancy. Diabetes Care. 2010: 33: 676-682 
2146 
Juan G, Qing L, Ling F. Metformin vs Insulin in the management of gestational diabetes: A meta-
2147 
analysis. PLOS one 2013: 8(5); e64585. 
2148 
Kgosidialwa O, Egan AM, Carmody L, Kirwan B, Gunning P, Dunne FP.Treatment With Diet and 
2149 
Exercise for Women With Gestational Diabetes Mellitus Diagnosed Using IADPSG Criteria. J Clin 
2150 
Endocrinol Metab. 2015 Dec; 100(12):4629-36 
2151 
Krakowiak P, Walker CK, Bremer AA, Baker AS, Ozonoff S, Hansen RL, Hertz-Picciotto I. Maternal 
2152 
metabolic conditions and risk for autism and other neurodevelopmental disorders. Pediatrics. 2012 
2153 
May;129(5):e1121-8. 
2154 
Lauenborg J, Jørgensen MK, Damm P, Major-Pedersen A, Eiberg H, Urhammer S, Pedersen O, 
2155 
Hansen T. The influence of parental history of diabetes and offspring birth weight on offspring glucose 
2156 
metabolism in adulthood. Acta Obstet Gynecol Scand. 2011 Dec;90(12):1357-63. 
2157 
Landon MB, Spong CY, Thom E et al. A multicentre randomized trial of treatment for mild gestational 
2158 
diabetes. N Engl J Med 2009; 361:1339-1348. 
2159 
Latif L, Hyer S, Shehata H. Metformin effects on treatment satisfaction and quality of life in gestational 
2160 
diabetes. The British Journal of Diabetes & Vascular Disease. Published online before print. Available 
2161 
fromhttp://intldvd. 
2162 
Metzger BE, Lowe LP, Dyer AR. Hyperglycemia and adverse pregnancy outcomes. N Engl J 
2163 
Med.2008: 358: 1991-2002 
2164 

 
 
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Noctor E, Crowe C, Carmody L, Wickham B, Avalos G, Gaffney G, O Shea P, Dunne F. ATLANTIC 
2165 
DIP: the prevalence of pre-diabetes/diabetes up to 5 years post-partum in women with previous 
2166 
gestational diabetes along the Atlantic coast. Diabetologia 2012; 55(1); S442 1077. 
2167 
Noctor E, Crowe C, Carmody LA, Kirwan B, O'Dea A, Glynn LG, McGuire BE, O'Shea PM, Dunne FP. 
2168 
ATLANTIC-DIP: prevalence of metabolic syndrome and insulin resistance in women with previous 
2169 
gestational diabetes mellitus by International Association of Diabetes in Pregnancy Study Groups 
2170 
criteria. Acta Diabetol. 2015 Feb;52(1):153-60 
2171 
O Reilly M, Avalos G, O Sullivan EP, Gaffney G Dennedy MC, Dunne F. High prevalence of abnormal 
2172 
glucose intolerance postpartum is reduced by breast feeding in women with prior GDM. European J of 
2173 
Endocrinology 2011; 165:953-959. 
2174 
O Sullivan EP, Avalos G, O Reilly M, Dennedy C, Dunne F. ATLANTIC DIP: The prevalence and 
2175 
outcomes of gestational diabetes mellitus using new diagnostic criteria. Diabetologia 2011; 
2176 
54(7):1670- 1675. 
2177 
O'Dea A, Tierney M, McGuire B, Newell JN, Glynn L, Gibson I, Dunne F. An evaluation of Croi 
2178 
MyAction community lifestyle modification programme compared to standard care to reduce 
2179 
progression to diabetes/pre-diabetes in women with prior gestational diabetes mellitus (GDM). Irish 
2180 
Journal of Medical Science. 2014; 183 (Suppl 9): S461 
2181 
Pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and 
2182 
subfertility. Cochrane Database Syst Rev 2010; CD003053. 
2183 
Rowan J, Rush E, Obolonkin V, Battin M, Wouldes T, Hague W. Metformin in Gestational Diabetes: 
2184 
The offspring follow-up (MiG TOFU). Diabetes Care 2011;34: 2279-2284. 
2185 
Rowan J, Rush E, Obolonkin V, Battin M, Wouldes T, Hague W. Metformin in Gestational Diabetes: 
2186 
The offspring follow-up (MiG TOFU). Diabetes Care 2011;34: 2279-2284. 
2187 
Royal College of Obstetricians and Gynaecologists (2014). The Investigation and Management of the 
2188 
Small–for–Gestational–Age Fetus, Greentop Guideline No. 31. 2ND edn. Royal College of 
2189 
Obstetricians and Gynaecologists, London. 
2190 
Sacks DA, Hadden DR, Maresh M, Deerochanawong C, Dyer AR, Metzger BE, Lowe LP, Coustan 
2191 
DR, Hod M, Oats JJ, Persson B, Trimble ER; HAPO Study Cooperative Research Group Frequency 
2192 
of gestational diabetes mellitus at collaborating centres based on IADPSG consensus panel-
2193 
recommended criteria: the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. Diabetes 
2194 
Care. 2012 Mar;35(3):526-8. doi: 10.2337/dc11-1641. 
2195 
Tang T, Lord JM, Normal RJ, Yasmin E, Balen AH. Insulin-sensitizing drugs (metformin, rosiglitazone, 
2196 
Tierney M, O'Dea A, Glynn L, Carmody L, McGuire B, Dunne F. The prevalence rate and uptake of 
2197 
screening for gestational diabetes mellitus (GDM) in primary versus secondary care. Irish Journal of 
2198 
Medical Science. 2014; 183 (Suppl 9): S447 
2199 
Tomkin GH. Et al. Vitamin-B12 status of patients on long-term metformin therapy. BMJ 1971;2685-
2200 
687) 
2201 

 
 
NUIG-2016-01 
 
Page 64 of 64 
 
Version 6.0, dated 02-May-2019          Confidential 
Vaarasmaki M, Pouta A, Elliot P. Adolescent manifestations of the metabolic syndrome among 
2202 
children born to women with gestational diabetes in a general-population birth cohort. Am J Epidemiol 
2203 
2009: 169:1209-15. 
2204 
Vanky E, Zahlsen K, Spigset O, Carlsen SM. Placental passage of metformin in women with 
2205 
polycystic ovary syndrome. Fertil Steril 2005; 83: 1575-1578. 
2206 
Zhu Y, Olsen SF, Mendola P, Yeung EH, Vaag A, Bowers K, Liu A, Bao W, Li S, Madsen C, Grunnet 
2207 
LG, Granström C, Hansen S, Martin K, Chavarro JE, Hu FB, Langhoff-Roos J, Damm P, Zhang C. 
2208 
Growth and obesity through the first 7 y of life in association with levels of maternal glycemia during 
2209 
pregnancy: a prospective cohort study. Am J Clin Nutr. 2016 Mar;103(3):794-800. 
2210 
 
2211 
 
2212 
 
2213 
 
2214 
 
2215 
 
2216