Study Title: Emergency Cerclage in Twin Pregnancies at Imminent Risk of Preterm Birth: an Open-Label Randomised Controlled Trial
Phase: NA
Conditions: Preterm Birth, Twin Pregnancy With Antenatal Problem, Twin to Twin Transfusion Syndrome
Sponsor: St George's, University of London

 
                      
 
 
 
 
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Study Protocol Template (non CTIMP Interventional)  
 
 
Study Title: Emergency Cerclage in Twin Pregnancies at 
Imminent Risk of Preterm Birth: an Open-Label Randomised 
Controlled Trial 
 
ENCIRCLE Trial (Emergency Cerclage in Twin Pregnancies at 
Imminent Risk of Preterm Birth: an Open-Label Randomised 
Controlled Trial) 
 
 
 
Sponsor’s Project Number: 17.004 
REC Reference Number: 17/EE/0040 
IRAS ID: 222216 
 
Version 1.7 15th May 2018 
 
CHIEF INVESTIGATOR (CI): 
 
Dr Asma Khalil 
Consultant in Obstetrics and Fetal Medicine 
Fetal Medicine Unit 
4th Floor Lanesborough Wing 
St George's University Hospitals NHS Foundation Trust 
Tooting 
London 
SW17 0QT 
 
Phone: 0208 725 0071/07917400164 
Email: akhalil@sgul.ac.uk 
Fax: +44 20 8725 0079 
 
SPONSOR: St George’s University Hospitals NHS Foundation Trust 
 

 
                      
 
 
 
 
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SPONSOR REPRESENTATIVE: 
 
Name        Nadia Azzouzi 
Address:  St George's Joint Research Enterprise Office 
     Hunter Wing, Ground Floor,   
     Cranmer Terrace, London SW17 ORE 
Phone:     02082666488 
Email:      nazzouzi@sgul.ac.uk 
Fax:         020 8725 0794 
 
 
Funding Source: The trial is partially funded by the Twins And Mutiple Births Association 
(TAMBA). 
 
 
 
Information in this protocol is confidential and should not be disclosed, other than to those 
directly involved in the execution or the ethical review of the study, without written 
authorisation from St George’s Joint Research & Enterprise Office (JREO) or its affiliates. 

 
                      
 
 
 
 
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UK Collaborators:  
 
Public and Patient Involvement Representative 
Mr Keith Reed  
Chief Executive  
Twins and Multiple Birth Association (TAMBA)  
Manor House  
Manor Park  
Church Hill  
Aldershot  
  
 
Prof. Baskaran Thilaganathan 
Fetal Medicine Unit  
St George’s NHS Foundation Trust  
Blackshaw Road  
Tooting  
LONDON  
SW17 0RE  
Email: basky@pobox.com 
 
Miss Rosemary Townsend 
Fetal Medicine Unit  
St George’s NHS Foundation Trust  
Blackshaw Road  
Tooting  
LONDON  
SW17 0RE 
Email: rosemary.townsend1@nhs.net  
 
Mr Amar Bhide  
Fetal Medicine Unit  
St George’s NHS Foundation Trust  
Blackshaw Road  
Tooting  
LONDON  
SW17 0RE  
abhide@sgul.ac.uk 
  
Mr Austin Ugwumadu  
Fetal Medicine Unit  
St George’s NHS Foundation Trust  
Blackshaw Road  
Tooting  
 

 
                      
 
 
 
 
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LONDON  
SW17 0RE  
Austin.Ugwumadu@stgeorges.nhs.uk 
 
Mr George Attilakos  
Fetal Medicine Unit 
University College Hospital  
235 Euston Road  
Bloomsbury  
LONDON 
NW1 2BU  
Email: George.Attilakos@uclh.nhs.uk 
 
Miss Melanie Griffin 
Senior Clinical fellow and Clinical Lecturer in Obstetrics and Gynaecology  
St Michael’s Hospital  
Southwell Street  
Bristol  
BS2 8EG 
Email: Melanie.Griffin@UHBristol.nhs.uk 
 
Prof. Alan Cameron  
Queen Elizabeth University Hospital  
1345 Govan Road  
Glasgow  
G51 4TF  
Email: Alan.cameron@clinmed.gla.ac.uk  
 
Ms Christina Yu  
Queen Charlotte’s Hospital 
Du Cane Road  
Shepherd’s Bush  
LONDON  
W12 0HS  
Email: Christina.Yu@imperial.nhs.uk 
 
Prof. Christoph Lees  
Queen Charlotte’s Hospital 
Du Cane Road  
Shepherd’s Bush  
LONDON  
W12 0HS  
Email: christoph.Lees@imperial.nhs.uk 

 
                      
 
 
 
 
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Mr Andrew Breeze 
Leeds Teaching Hospitals NHS Trust 
Great George Street  
Leeds  
LS1 3EX 
Email: andrewbreeze@nhs.net 
 
Ms Catriona Monaghan  
Regional Fetal Medicine Unit 
Royal Jubilee Maternity Hospital  
274 Grosvenor Road  
Belfast  
BT12 6BA  
Email: camonaghan@doctors.org.uk 
 
Ms Ferha Saeed  
Newham University Hospital  
Glen Road  
Plaistow 
LONDON 
E13 8SL   
Email: Ferha.Saeed@bartshealth.nhs.uk 
 
Ms Luxmi Velauthar 
Newham University Hospital  
Glen Road  
Plaistow 
LONDON 
E13 8SL   
Email: Luxmimalar.Velauthar@bartshealth.nhs.uk 
 
Professor Shakila Thangaratinam  
Women’s Health Research Unit  
Barts and the London School of Medicine and Dentistry  
Yvonne Carter Building  
58 Turner Street  
Whitechapel  
LONDON  
D1 2AB  
Email: s.thangaratinam@qmul.ac.uk 
  
Dr Andrew Sharp  
Liverpool Womens Hospital 
Crown Street  

 
                      
 
 
 
 
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Liverpool  
L8 7SS  
Email: a.sharp@liverpool.ac.uk 
  
Professor Zarko Alfirevic  
Liverpool Womens Hospital  
Crown Street  
Liverpool  
L8 7SS  
Email: zarko@liv.ac.uk 
  
Dr Simon Grant  
North Bristol NHS Trust  
Southmead Hospital  
Southmead Road  
Westbury-on-Trym  
Bristol  
BS10 5NB  
Email: simon.grant@nbt.nhs.uk 
  
Dr Amanda Bellis  
Royal Preston Hospital  
Sharoe Green Lane North  
Fulwood  
Preston  
PR2 9HT  
Email: Amanda.Bellis@lthtr.nhs.uk 
 
Dr Penelope McParland  
Leicester Royal Infirmary  
Infirmary Square  
Leicester  
LE1 5WW  
Email: Penelope.mcparland@uhl-tr.nhs.uk 
  
Dr Tommy Mousa  
Leicester Royal Infirmary  
Infirmary Square  
Leicester  
LE1 5WW  
Email: tommy.mousa@uhl-tr.nhs.uk 
 
Dr Latha Vinyakarao 
Poole Hospital NHS Trust  
Longfleet Road  
Poole 
BH15 2JB  

 
                      
 
 
 
 
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Email: Latha.Vinayakarao@poole.nhs.uk 
 
Dr Sharmila Sivarajan  
Surrey and Sussex NHS Trust 
East Surrey Hospital 
Canada Avenue  
Redhill 
RH1 5RH 
Email: sharmila.sivarajan@sash.nhs.uk 
 
Miss Renata Hutt 
Royal Surrey County Hospital  
Egerton Road  
Guildford  
GU2 7XX 
Email: renata.hutt@gmail.com 
 
Miss Kasia Gajewska-Knapik 
Cambridge University Hospitals 
The Rosie Hospital  
Robinson Way 
Cambridge 
CB2 0SW 
Email: kgajewska@doctors.org.uk 
 
Mr Hiran Samarage 
Northwick Park  
Watford Road 
Harrow 
Middlesex 
HA1 3UJ 
Email: hiran.samarage@nhs.net  
 
Miss Surabhi Nanda  
St Thomases Hospital  
Westminster Bridge Road 
Lambeth 
LONDON 
SE1 7EH  
 
TBC  
Lewisham Hospital  
Lewisham High Street 

 
                      
 
 
 
 
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LONDON  
SE13 6LH 
 
Non-UK Collaborators:  
 
 
Prof. Dr. Liesbeth Lewi 
University Hospitals Leuven 
Fetal Medicine Unit 
Herestraat  49 
3000 Leuven, Belgium 
Tel: +32 16 34 28 62 
Email: liesbeth.lewi@uzleuven.be 
 
Prof. Dr. Yves Ville 
University Clinic Necker-Enfants Malades 
Department of Gynaecology and Obstetric 
149 Rue de Sevres, 75015 Paris, France 
E-mail: ville.yves@gmail.com 
Phone: +33 144381710 
 
Prof. Dr. Eduardo Gratacos 
Hospital Clínic Sede Maternitat  
Fetal Medicine Center 
C/ Sabino de Arana, 1, 08028  
Barcelona, Spain 
E-mail: Gratacos@clinic.ub.es 
Phone:  +34 932279931 
 
Dr. Greg Ryan 
Mount Sinai Hospital  
Joseph and Wolf Lebovic Health Complex 1001-522  
University Avenue Toronto, Ontario, Canada 
E-mail: gryan@mtsinai.on.ca 
Phone:  +1 4165868403 
 
Prof. Dr. Jon Hyett 
RPA Women and Babies, Royal Prince Alfred Hospital 
Missenden Road 
Camperdown NSW 2050, Australia 
E-mail: jon.hyett@sswahs.nsw.gov.au 
Phone:  +61 295158887 
 
Prof. Dr. Christoph Berg 

 
                      
 
 
 
 
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Universitätsklinikum Bonn  
Sigmund-Freud Strasse 25 
53105 Bonn, Germany 
E-mail: christoph.berg@ukb.uni-bonn.de 
Phone:  +49 228-28714728 
 
Dr. Romain Favre 
CMCO-SIHCUS 
Schiltigheim/Strasbourg, France  
E-mail: romain.favre3@orange.fr 
Phone:  +33 388628329 – 0621720553 
 
Dr. Peter Lindgren 
Karolinska University Hospital 
S 141 86 Stockholm, Sweden 
E-mail: peter.lindgren@karolinska.se 
Phone:  +46 706092923 
 
Dr. Francisca Molina 
San Cecilio University Hospital  
C/ Dr Oloriz, 16.18012 Granada, Spain 
E-mail: fsoniamolina@gmail.com 
 
 
Dr. Roland Zimmerman 
University Hospital Zurich 
Frauenklinikstrasse 10, Zürich, Switzerland 
E-mail: roland.zimmermann@usz.ch 
Phone: +41 442555101 
 
Dr. Nicola Persico 
Ospedale Maggiore Policlinico 
Via della Commenda 12 
20122 Milan, Italy  
E-mail: Nicola.persico@gmail.com 
 
Prof. Dr. Dick Oepkes  
Leiden University Medical Center 
Department of Obstetrics, K-06-35 
P.O. Box 9600, 2300RC Leiden, The Netherlands 
Tel: +31 715 26 28 96 
Email: d.oepkes@lumc.at 
 
Dr. Enrico Lopiore 

 
                      
 
 
 
 
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Leiden University Medical Center 
Department of Pediatrics, Division of Neonatology 
P.O Box 9600, 2300 RC Leiden The Netherlands 
Email: e.lopriore@lumc.nl 
 
Prof. Tiran Dias 
Faculty of Medicine 
University of Kelaniya 
Colombo North Teaching Hospital  
Ragama, Colombo  
Email: thiran_dias@yahoo.com 
 
Prof. Rogelio Cruz Martinez  
Unit for Investigation of Fetal Medicine and Surgery  
Hospital de Especialidades del Nino y la Mujer de Queretaro  
Universidad Nacional Autónoma de México (UNAM)  
Querétaro, México 
Email: rcruz@medicinafetalmexico.com 
   
Dr  Minu Nath 
Senior Biomedical Statistician  
Department of Cardiovascular Sciences  
University of Leicester 
British Heart Foundation Cardiovascular Research Centre 
Glenfield General Hospital , Groby Road, 
Leicester, LE3 9QP, UK 
E-mail:  mn193@leicester.ac.uk 
 

 
 
 
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Statement 
The Chief Investigator (CI) and the Sponsor representative have discussed this protocol 
version. The investigators agree to perform the investigations and to abide by this protocol 
except where departures from it are mutually agreed in writing. 
 
The Investigator agrees to conduct the trial in compliance with the protocol, GCP, the Data 
Protection Act (1998), the Trust Information Governance Policy (or other local equivalent), 
the Research Governance Framework (2005 2nd Edition), the Sponsor’s SOPs, and other 
regulatory requirements as appropriate. 
 
This protocol has been written in accordance to the Sponsor’s procedure identified as: 
JREOSOP0039 "Protocol Design” and is intended for use at UK sites only 
 
Chief Investigator 
Asma Khalil 
Consultant in Obstetrics and Fetal 
Medicine  
St George’s University Hospitals NHS 
Foundation Trust  
Signature 
 
Date 
 
20.11.2016 
 
Acknowledgements and Protocol contributories 
 
 
 
 
 
 
 

 
 
 
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Contents  
1 
List of abbreviations ................................................................................................. 14 
2 
Roles and Responsibilities ...................................................................................... 15 
3 
Study synopsis ....................................................................................................... 16 
4 
Background ............................................................................................................ 11 
5 
Study objectives ..................................................................................................... 13 
5.1 
Primary objective ............................................................................................. 13 
5.2 
Secondary objectives ....................................................................................... 13 
6 
Trial design ............................................................................................................. 13 
7 
Participation selection criteria ................................................................................. 13 
7.1 
Inclusion criteria ............................................................................................... 22 
7.2 
Exclusion criteria .............................................................................................. 22 
8 
Participant Recruitment process ............................................................................. 22 
9 
Study procedures ................................................................................................... 23 
9.1 
Informed consent ............................................................................................. 23 
9.2 
Randomisation procedure ................................................................................ 24 
9.3 
Discontinuation/withdrawal of participants and stopping rules .......................... 24 
9.5     Participant transfers ......................................................................................... 25 
9.4     Lost to Follow up .............................................................................................. 25 
9.5     Definition of the End of Trial ............................................................................. 25 
10 Study Procedures ................................................................................................... 25 
10.1 
Measurement of cervical length  ................................................................... 23 
10.2 
Screening for infections ................................................................................ 25 
10.3 
Baseline assessment .................................................................................... 26 
10.4 
Intervention ................................................................................................... 24 
10.5 
Follow-up visits ............................................................................................. 26 
10.6 
Data collection ............................................................................................... 26 
10.7 
Summary flow chart of study assessments ................................................... 26 
11 Study Timeline ........................................................................................................ 27 
12 Safety Events ......................................................................................................... 27 
12.1 
Definitions ..................................................................................................... 27 
12.2 
Recording Adverse Events (AEs) ................................................................. 27 
12.3 
Investigator Responsibilities relating to Safety Reporting ............................. 20 
12.4 
Notification of deaths .................................................................................... 20 
13 Data management and quality assurance .............................................................. 20 
13.1 
Confidentiality ............................................................................................... 20 
13.2 
Data collection tool ....................................................................................... 20 
13.3 
Incidental Findings ........................................................................................ 21 
13.4 
Data handling and analysis ........................................................................... 21 
14 Archiving arrangements .......................................................................................... 21 
15 Statistical design ..................................................................................................... 21 
15.1 
Endpoints ...................................................................................................... 21 
15.1.1 
Primary endpoints .................................................................................. 21 
15.1.2 
Secondary endpoints ............................................................................. 21 

 
 
 
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15.2 
Sample size calculation ................................................................................ 22 
15.3 
Statistical analysis plan ................................................................................. 22 
16 Ethics and Research Governance requirements .................................................... 31 
16.1       Annual Progress Reports (APRs) ................................................................. 32 
16.2       Notification of Serious Breaches of GCP and/or the protocol ....................... 32 
16.3 
Direct access to source data......................................................................... 32 
17 Finance ................................................................................................................... 32 
18 Insurance and indemnity......................................................................................... 33 
19 IP and development policy ...................................................................................... 33 
22 Publication policy .................................................................................................... 33 
20.1 
Before the official completion of the Trial ...................................................... 33 
20.2 
Up to 180 days after the official completion of the Trial ................................ 34 
20.3 
Beyond 180 days after the official completion of the Trial ............................. 34 
21 Statement of Compliance ....................................................................................... 34 
22    List of Protocol appendices .................................................................................... 35 
23    References ............................................................................................................ 35 
 

 
 
 
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1 
List of abbreviations  
CI 
Chief Investigator 
CRF 
Case Report Form 
GCP 
Good Clinical Practice 
ICF 
Informed Consent Form 
ISF 
Investigator Site File 
NHS R&D 
National Health Service Research & Development   
PI 
Principal Investigator 
PIS 
Participant Information Sheet 
RCT 
Randomised Controlled Trial 
REC 
Research Ethics Committee 
SDV 
Source Document Verification 
SOP 
Standard Operating Procedure  
SSA 
Site Specific Assessment 
TMG 
Trial Management Group 
TSC 
Trial Steering Committee 
 
 
 
 
 
 
 

 
 
 
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2 
Roles and Responsibilities  
CHIEF INVESTIGATOR (CI): 
 
Dr Asma Khalil 
Consultant in Obstetrics and Fetal Medicine 
Fetal Medicine Unit 
4th Floor Lanesborough Wing 
St George's University Hospitals NHS Foundation Trust 
Tooting 
London 
SW17 0QT 
 
Phone: 07917400164/0208 725 0071 
Email: akhalil@sgul.ac.uk 
Fax: +44 20 8725 0079 
 
SPONSOR: St George’s University Hospitals NHS Foundation Trust 
 
SPONSOR REPRESENTATIVE: 
 
Name        Nadia Azzouzi 
Address:  St George's Joint Research Enterprise Office 
     Hunter Wing, Ground Floor,   
     Cranmer Terrace, London SW17 ORE 
Phone:     02082666488 
Email:      nazzouzi@sgul.ac.uk 
Fax:         020 8725 0794 
 
 
 

 
 
 
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3 
Study synopsis   
Brief title: 
ENCIRCLE trial 
Official title:  
Emergency Cerclage in Twin Pregnancies at Imminent Risk of 
Preterm Birth: an Open-Label Randomised Controlled Trial 
 
Sponsor reference  
number: 
17.0004 
Public database 
identifier  
TBC 
Study design 
Pilot randomised controlled trial 
Study 
Population/disease 
condition 
2 groups 
 
 
Twin pregnancies between 14 – 26 weeks’ gestation presenting 
with an open cervix 
 
 
Monochorionic twin pregnancies complicated by twin-to-twin 
transfusion syndrome (TTTS) treated by Laser surgery between 
16+0 and 26+0 weeks’ gestation in whom a short cervix 
(<15mm) is identified 
Eligibility criteria: 
Inclusion criteria: 
 
Twin pregnancies presenting with an open cervix between 14 
and 26 weeks of gestation, OR 
 
Twin pregnancies complicated by TTTS treated by Laser 
surgery between 16+0 and 26+0 weeks’ gestation in whom a 
short cervix (<15mm) is identified. 
 
 
Age >18 years 
 
Informed consent 
Exclusion criteria: 
 
Cervical dilatation ≥5cm 
 
Amniotic membranes prolapsed beyond external os into the 
vagina, unable to visualise cervical tissue 
 
Preterm premature rupture of the membranes (PPROM) at 
the time of diagnosis of dilated cervix 
 
Major fetal malformations unrelated to TTTS 
 
Intrauterine death of one or both fetuses 
 
Symptoms or signs of threatened imminent delivery, e.g. 
painful regular uterine contractions, active vaginal 
bleeding, history of ruptured membranes 
 
Suspected chorioamnionitis [based on maternal uterine 
tenderness, a temperature of 38°C or greater, significant 
leucocytosis (>15,000 x 106/L) or elevated C-reactive 
protein (>15 mg/L), or maternal tachycardia]. 

 
 
 
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 
Placenta praevia 
 
Monochorionic monoamniotic twin pregnancies 
 
Prophylactic cervical cerclage  
 
Women who are not able to give valid consent, e.g. 
unconscious or severely ill 
 
Mental health disorder which impairs the ability to give 
fully informed consent 
 
Women under the age of 18 years 
 
Higher order multiple pregnancies  
 
Target number of 
participants 
We have more than 8 UK centres willing to participate in the 
study. One concern is that recruitment to this study might be 
difficult, as women might not agree to be randomised to no 
intervention. As this a pilot study, we plan to recruit 20 women in 
the first group (13 women in the cerclage group and 7 women in 
the control group) and 11 women in the second group (7 women 
in the cerclage group and 4 women in the control group), so 31 
participants in total. The rational for choosing randomisation of 
2:1 (cerclage:expectant management) is that women often 
request the cerclage as a treatment in view of the favourable 
published observational data and the extremely poor outcome in 
the pregnancies which are expectantly managed. Therefore, 
participating in the trial has 2 out of 3 chance of receiving the 
cerclage and 1 out of 3 of being randomised to the expectant 
management. This pilot trial will provide the data required for a 
full funding application to the NIHR RFPB programme. 
 
Criteria for 
evaluation 
 
Primary outcome measure(s) 
Time to delivery (from randomisation to birth). 
Secondary outcome measure(s) 
1. Gestation at delivery 
2. Preterm birth before 28, 32 and 34 weeks’ gestation 
3. Birthweight 
4. Stillbirth 
5. Neonatal death 
6. Survival to discharge 
7. Days of admission to the neonatal intensive care unit  
8. Composite outcome of stillbirth, neonatal death, 
intraventricular haemorrhage, periventricular leukomalacia, 
respiratory distress syndrome, bronchopulmonary dysplasia, 
retinopathy of prematurity, necrotising entercolitis, proven 
neonatal sepsis, or the need for ventilation 
9. Days of maternal admission for preterm labour 

 
 
 
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10. Maternal morbidity (deﬁned as thromboembolic  complications, 
chorioamnionitis, urinary  tract  infection  treated  with  
antibiotics,  pneumonia,  endometritis,  eclampsia,  HELLP  
syndrome, death, or any other significant morbidity) 
 
 
Sources of funding 
This study is planned to take place in a number of centres in the 
UK. The trial is partially funded by the Twins And Mutiple Births 
Association (TAMBA). 
Anticipated start 
date: 
March 1st, 2017 
Anticipated primary 
completion date: 
December 31st, 2018 
Sponsor/Co-Sponsor 
Nadia Azzouzi  
Tel: 02082666488 
Fax: 020 8725 0794 
Email:nazzouzi@sgul.ac.uk 
Key Contact names 
Sponsor representative: Nadia Azzouzi  
Tel: 02082666488 
Fax: 020 8725 0794 
Email:nazzouzi@sgul.ac.uk 
 
Chief Investigator: Dr Asma Khalil 
Email: akhalil@sgul.ac.uk 
Tel: 0208 725 0071 
Fax: +44 20 8725 0079 

 
 
 
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4 
Background 
 
Preterm birth remains the leading cause of perinatal mortality and morbidity.1 It is also 
associated with societal and economic burden, with a substantial risk of long-term mental 
and physical disability.1 Twin pregnancies are at increased risk of perinatal mortality and 
morbidity largely due to preterm birth and complications related to monochorionicity such as 
twin to twin transfusion syndrome (TTTS).2-5 Up to 2-3% of births in the UK are from multiple 
pregnancies and the incidence continues to rise, mainly due to increasing maternal age and 
the widespread use of assisted reproductive technologies.2 More than half of twin 
pregnancies deliver before 37 weeks and approximately 15% have preterm birth prior to 34 
weeks’ gestation.2,6 Adverse neonatal outcomes include neonatal death, respiratory and 
neurological complications, the likelihood of which are related to the gestational age at 
delivery, ranging from 77% in those born before 28 weeks to less than 2% at term.7 
Cervical insufficiency, defined as painless second-trimester cervical dilatation, is a well-
recognised aetiology of preterm birth. In twin pregnancies measurement of cervical length 
can be used to predict those at increased risk of spontaneous early preterm delivery.2,8-10 
However, an effective prevention strategy for preterm delivery has yet to be discovered. In 
singleton pregnancies, progesterone treatment in women identified as being at increased 
risk of preterm birth was associated with an almost 50% reduction in the incidence of 
preterm birth before 34 weeks.11-13 Furthermore, in women at increased risk of (singleton) 
preterm labour, placement of cervical cerclage when cervical shortening was detected has 
been associated with a reduction in the risk of preterm birth.14,15 Unfortunately, however, 
preventive measures such as bed rest, progesterone therapy and cervical cerclage, have 
had disappointing results in twin pregnancies.11,16-19 In fact, bed rest was associated with a 
significant increase in the rate of early preterm delivery. Progesterone therapy and elective 
cervical cerclage did not reduce the risk significantly.11,17-20 
In women presenting with an already dilated cervix and/or bulging membranes in the 
second trimester, the rate of preterm birth has been reported to be as high as 90%, leading 
to miscarriage, neonatal death or extreme prematurity, and often associated with 
chorioamnionitis.21-25 According to the published observational and limited randomised 
controlled trials, placement of an emergency cerclage was associated with a longer mean 
cerclage-to-delivery interval, and lower rates of preterm delivery before 34 weeks and of 
neonatal morbidity.21-26 Therefore, emergency cerclage is likely to be associated with 
improved perinatal outcome in a cohort of pregnancies with a painless dilated cervix putting 
them at very high risk of extremely preterm birth. 21-26 However, most of these studies 
included singleton pregnancies. In their trial including 11 twin pregnancies, Gupta et al 
reported that emergency cerclage was associated with a “good outcome”, where the 
pregnancy reached 32 weeks, with a healthy neonate in 36.4% of twin pregnancies.27 In 
these studies, predictors of poor outcome included prolapsed membranes, evidence of 
intra-amniotic or systemic infection, symptomatic presentation, cervical dilatation greater 
than 3 cm, or gestational age beyond 22 weeks at placement of the cerclage.27,28  
There are no randomised clinical trials investigating the role of emergency cerclage 
solely in multiple pregnancies. Only one randomised study included a very small number 
of twin pregnancies, along with several singleton pregnancies.21 This compared a group 
of 13 women (10 singleton and 3 twin pregnancies) allocated to emergency cerclage 
with a second group of 10 women (6 singleton and 4 twin pregnancies) who had bed 

 
 
 
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rest only. This study demonstrated that the cerclage group did signiﬁcantly better 
compared with the bed-rest group in mean randomisation-to-delivery interval (54 vs 20 
days, P=0.046), preterm delivery before 34 weeks (54% vs 100%, P=0.02), and 
compound neonatal morbidity, deﬁned as admission to the neonatal intensive care unit 
and/or neonatal death (62.5% vs 100%; P=0.02; relative risk, 1.6; 95% conﬁdence 
interval, 1.1-2.3). The main criticism of this study was its very small size. Observational 
studies in twin pregnancies have reported promising results.29,30 Levin et al reported the 
pregnancy outcome in 14 women with twin gestations complicated by cervical 
shortening/effacement only or bulging membranes through the external os, who 
underwent emergency cerclage. The average time interval between cerclage placement 
and delivery was 80.2 days in the group with cervical shortening/effacement, and 48.5 
days in the group with bulging membranes.29 More recently, Aguilera et al reported 
mean pregnancy prolongation of 60.25 days with 76.9% neonatal survival in a case 
series of 12 multiple pregnancies with painless cervical dilation and exposed fetal 
membranes that underwent emergency cerclage. A recent retrospective cohort study 
has demonstrated that the combination of cerclage, indomethacin, and antibiotics in twin 
pregnancies with cervix dilated ≥1 cm before 24 weeks was associated with signiﬁcantly 
longer latency period from diagnosis to delivery (6.7 weeks; 10.5 vs 3.7 weeks), 
decreased incidence of spontaneous preterm birth at any given gestational age (52.6% 
vs 94.7%, 44.7% vs 89.4%, 31.6% vs 89.4% for preterm birth <34 weeks, <32 weeks 
and <28 weeks’ gestation, respectively), and improved perinatal outcome (reduced 
perinatal mortality 27.6% vs 59.2%, neonatal intensive care unit admission 75.9% vs 
97.6%, and composite adverse neonatal outcome 33.9% vs 90.5%) when compared 
with expectant management.31 A summary of the studies of cerclage in twin pregnancies 
with dilated cervix is shown in Table 1. 
 
These results are promising, but these studies are retrospective, include small numbers 
of pregnancies and are likely to be biased in view of their observational nature and the 
possibility of selecting less favourable cases for intervention versus conservative 
management. Moreover, there are risks associated with insertion of an emergency 
cerclage, such as rupture of the membranes during the procedure, which inevitably is 
followed by delivery. 
 
Severe TTTS, which affects 10-15% of monochorionic twin pregnancies, is associated 
with an over 50% risk of delivering before 34 weeks.32,33 Studies have demonstrated 
that, in addition to factors predicting fetal survival, such as fetal Doppler or Quintero 
staging, cervical length is a strong predictor of preterm delivery in pregnancies 
complicated by TTTS.33,34 Cervical shortening in TTTS is likely to be mainly because of 
increased pressure in the amniotic cavity secondary to the severe polyhydramnios.35,36 
Therefore, it could be argued that in this subgroup of twin pregnancies, emergency 
cerclage following laser therapy might be an effective intervention in those pregnancies 
with a short cervix. In fact, an observational study has reported that placement of an 
emergency cerclage in these pregnancies was associated with prolongation of the 
pregnancy.34 In this small study which included 5 pregnancies with a short cervix 
(<15mm; less than the 5th centile) which were managed expectantly and 9 pregnancies 
with a short cervix which had emergency cerclage inserted following the Laser surgery, 
the gestational age at delivery was 23.1 weeks and 30.5 weeks, respectively 
(p=0.004).34  Furthermore, there were 16 (89%) and 4 (40%) surviving twins in cases 

 
 
 
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with and without cerclage, respectively (p=0.01).34 Despite these promising results, a 
multicentere, retrospective cohort study including 163 patients with a short cervix 
(defined as ≤25mm) at the time of the Laser surgery for TTTS, reported no difference in 
the gestational age at delivery (28.8 ± 5.4 vs 29.1 ± 5.6 weeks with and without cerclage, 
respectively) or perinatal mortality between the group which had cerclage (n=79) and the 
group which did not (n=84).37 However, the cerclage was performed more frequently for 
a cervical length of ≤ 15 mm, so this group was at a higher risk of preterm birth and 
adverse outcome. To date there are no randomised trials investigating the role of 
emergency cerclage in these high-risk pregnancies. 
 
The study hypothesis is that the placement of an emergency cervical cerclage prolongs 
the pregnancy in (1) twin pregnancies with a dilated internal cervical os between 14+0 
and 26+0 weeks, and (2) in monochorionic twin pregnancies complicated by TTTS 
treated by Laser surgery between 16+0 and 26+0 weeks’ gestation in whom a short 
cervix (<15mm) is identified. 
 
5 
Study objectives 
5.1 Primary objective 
The main objective of the study is to investigate whether the insertion of an emergency 
cerclage will prolong the pregnancy in twin pregnancies in each of the two study groups. 
 
5.2 Secondary objectives 
Other study objectives include determining the effect of the emergency cerclage on adverse 
perinatal outcome, defined as preterm birth less than 32 weeks’ gestation, a composite 
outcome of stillbirth, neonatal death, intraventricular haemorrhage, periventricular 
leukomalacia, respiratory distress syndrome, bronchopulmonary dysplasia, retinopathy of 
prematurity, necrotising entercolitis, proven neonatal sepsis, or the need for ventilation. We 
also plan to investigate the length of admission to the neonatal unit and maternal morbidity. 
 
6 
Trial design 
Open-label multi-centre randomised controlled trial. 
 
7 
Participation selection criteria 
There will be no exceptions (waivers) to eligibility criteria prior to participant inclusion into the 
study. Any questions raised about eligibility should be addressed prior to entering the 
participant. 
The eligibility criteria have been carefully considered and are standards used to ensure the 
trial results can be appropriately used to make future treatment decisions for other people 

 
 
 
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with similar disease or medical condition. It is therefore vital that exceptions are not made to 
the following detailed selection criteria.  
All participants that are screened for inclusion into the study must be entered onto the 
Sponsor screening log JREOLOG0001 and will be assigned a sequential number. 
Participants will be considered eligible for enrolment into this trial if they fulfil all of the 
inclusion criteria and none of the exclusion criteria as defined below.  
Eligible participants will be entered onto the Sponsors Subject ID log JREOLOG0002 and 
assigned a Trial specific Identification number in a pre-agreed format in accordance with Site 
Identifier and next sequential numerical value, e.g. SG001. 
 
7.1 Inclusion criteria 
 
Twin pregnancies presenting with an open cervix between 14 and 26 weeks, OR 
 
Monochorionic twin pregnancies complicated by TTTS treated by Laser surgery 
between 16+0 and 26+0 weeks’ gestation in whom a short cervix (<15mm) is 
identified. 
 
 
Age >18 years 
 
Informed consent 
 
7.2 Exclusion criteria 
 
Cervical dilatation ≥5cm 
 
Amniotic membranes prolapsed beyond external os into the vagina, unable to 
visualise cervical tissue 
 
Preterm premature rupture of the membranes (PPROM) at the time of diagnosis of 
dilated cervix 
 
Major fetal malformations unrelated to TTTS 
 
Intrauterine death of one or both fetuses 
 
Symptoms or signs of threatened imminent delivery, e.g. painful regular uterine 
contractions, active vaginal bleeding, history of ruptured membranes, or suspected 
chorioamnionitis [based on maternal uterine tenderness, a temperature of 38°C or 
greater, significant leucocytosis (>15,000 x 106/L) or elevated C-reactive protein 
(>15 mg/L), or maternal tachycardia].38 
 
Placenta praevia 
 
Monochorionic monoamniotic twin pregnancies 
 
Prophylactic cervical cerclage  
 
Women who are not able to give valid consent, e.g. unconscious or severely ill 
 
Mental health disorder which impairs the ability to give fully informed consent 
 
Women under the age of 18 years 
 
Higher order multiple pregnancies  

 
 
 
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8 
Participant Recruitment process 
Patient recruitment at a site will commence only once there is evidence that the following 
approval/essential documents are in place:  
1. REC approval  
2. Final sponsorship and host site permissions 
All subjects who wish to enter the study will be fully screened and consented by the Chief 
Investigator or an appropriate delegate.  
Patients will be invited to participate in the trial if they have (1) a twin pregnancy and 
present with an open cervix or (2) a monochorionic twin pregnancy complicated by TTTS 
treated by Laser surgery, and have a short cervix. These women usually present with an 
incidental finding of a shortened dilated cervix on cervical length surveillance, or they 
present with subjective complaints of increased pelvic pressure or vaginal discharge and 
then undergo cervical length assessment (either ultrasound or speculum examination, or 
both). Eligible women will be identified by staff in the antenatal clinic, delivery suite, 
ultrasound department, fetal medicine unit and day assessment unit.  All eligible women will 
be given verbal and written information about the trial and be invited to take part. 
The trial will be conducted by the sponsor, participating sites and all investigators in 
accordance with the protocol, the Declaration of Helsinki, the guidelines on Good Clinical 
Practice (GCP) and all legal requirements, including applicable national legislation, for the 
conduct of this trial. 
9 
Study procedures  
9.1 Informed consent 
It is essential that all trial teams undertaking the informed consent process have signed the 
Sponsor’s Delegation of Responsibilities Log JREOLOG0004 to ensure that the person has 
been delegated the responsibility by the study CI/PI. All personnel taking informed consent 
must be GCP trained. Refer to Sponsor SOP JREOSOP0027. 
Informed consent will be obtained from eligible women by a member of the research 
team after confirming the eligibility, inclusion and exclusion criteria. 
The Principal Investigator or designee will explain to the patient that she is under no 
obligation to enter the trial and can withdraw at any time during the trial, without having to 
give a reason. Those who agree to take part will be asked to sign a Consent Form prior to 
any study investigation or treatment. The participants’ general practitioners will be informed 
in writing about the trial, and the hospital notes of those receiving an emergency cerclage 
will be marked with a sticker labelled ‘emergency cerclage’. Those who decline to 
participate in the randomised trial will be asked if they consent to the research team 
following up their pregnancy outcomes and recording anonymised pregnancy and 
neonatal outcome data in the study registry. The consent form will allow women to 

 
 
 
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specify that they are willing for their data to be collected but prefer not to participate 
in the randomised controlled study.   
A copy of the signed Informed Consent Form (ICF) along with a copy of the most recent 
approved Patient Information Sheet (PIS) will be given to the study participant.  An original 
signed & dated ICF will be retained in the medical notes and a copy will be placed in the 
Investigator Site File (ISF). A copy of the signed ICF will also be given to the participant. 
If new information results in significant changes to the risk-benefit assessment, the ICF will 
be reviewed and updated as necessary. All participants, including those already being 
treated, will be informed of the new information, given a copy of the revised ICF and asked 
to re-consent if they choose to continue in the study. 
9.2 Randomisation procedure 
Within each of the two study groups, participants will be randomly assigned (2:1) to the 
‘emergency cerclage’ or ‘control/expectant management’ groups,  using  a  web-based  
application. Participants and investigators will be aware of the allocation, as masking will be 
impossible because of the nature of the intervention. At the time of randomisation, the 
patients will be informed of the possible side-effects of emergency cerclage, such as risk of 
rupture of the membranes during the procedure. 
 
 
9.3 Discontinuation/withdrawal of participants and stopping rules 
In consenting to the trial, participants are consenting to trial treatments, trial follow-up and 
data collection. However, an individual participant may stop treatment early or be stopped 
early for any one of the following reasons: 
Intercurrent illness that prevents further protocol treatment 
Any change in participant’s condition that in the investigator’s opinion justifies the 
discontinuation of treatment. 
Withdrawal of consent by the participant 
As participation in the trial is entirely voluntary, the participant may choose to discontinue 
participation at any time without penalty or loss of benefits to which she may be entitled. 
Although not obliged to give a reason for discontinuing her participation, a reasonable effort 
should be made to establish this reason, whilst remaining fully respectful of the participant’s 
rights.  Participants who discontinue study participation for any of the above reasons should 
remain in the study for the purpose of follow-up and data analysis. 
If a participant chooses to discontinue they should be continued to be followed up as closely 
as possible to the follow-up schedule defined in the protocol, providing they are willing. 
However, if the participant confirms they do not wish to participate in the scheduled follow-up 
data collection visits, then data that have already been collected should be kept and 
analysed according to the ITT principle for all participants who stop follow-up early. 
Participants who stop the trial follow-up early will not be replaced. 

 
 
 
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9.4 Participant transfers 
If a participant moves from the area making, continued follow-up at their consenting centre 
inappropriate, every effort should be made for them to be followed up at another sponsor 
approved trial centre. Written consent should be taken at the new centre and then a copy of 
the participant’s CRF should be provided to the new centre. Responsibility for the participant 
remains with the original consenting centre until the new consent process is complete. 
9.5 Lost to Follow-up 
For studies conducted in the UK, the NHS number may be used to trace participants who 
may have changed their GP; specific consent may be required to utilise this. 
 9.6 Definition of the End of Trial 
The trial will be completed as soon as 10 patients are included in each of the 4 arms. The 
End of the Trial is defined as the Last Patient Last Visit (LPLV) or the last data entry point. 
The REC and the Sponsor will be notified of the end of trial within 90 days of its planned 
completion or within 15 days if the study is terminated early.  
10 Study Procedures 
10.1 Measurement of cervical length 
Cervical length will be measured in the usual way (part of the routine care; not considered 
as a specific study investigation). The woman will be asked to empty her bladder, placed in 
the lithotomy position, and the transvaginal probe will be placed in the anterior fornix of the 
vagina. A sagittal view of the cervix will be obtained and the calipers used to measure the 
distance between the triangular area of echodensity at the external os and the V-shaped 
notch at the internal os. Each examination will be performed over a period of around three 
minutes. In around 1% of cases, dynamic cervical changes, due to uterine contractions, are 
observed. In such cases the shortest measurement will be recorded. Presence or absence 
of funnelling/cervical dilatation at the internal os will be documented. The researchers will 
receive appropriate training on measurement of cervical length.  
10.2 Screening for infections 
Women will routinely (not considered as a specific study investigation) have bacteriological 
investigation. Treatment using the appropriate antibiotic will be given if there is an infection. 
If they are allocated to the cerclage group, the cerclage will be inserted after completion of 
the treatment.   
An amniocentesis of the presenting twin might be performed, according to local protocols, 
to quantify amniotic glucose, leucocytes, IL-6 and leucocyte esterase levels and for 
microbiological film. If the initial assessment (within 24 hours) suggests the presence of 
infection [positive gram stain/amniotic fluid leucocyte count (≥6 leucocytes per high-power 
field or >30 cells/mm3) and/or amniotic fluid glucose concentration of ≤15 mg/dL]39, women 
will not be randomised. 
 

 
 
 
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10.3  Baseline assessments 
The planned baseline assessments include assessment for the inclusion and exclusion 
criteria and data collection. 
10.4  Interventions (Insertion of Cerclage) 
A McDonald or Shirodkar-type rescue cerclage will be placed. The choice of surgical 
approach will be at the discretion of the operating clinician and in line with local common 
practice. The local practice will be clarified during the initial site capacity and capability 
assessments. The cerclage will be inserted by a competent obstetrician that has performed 
more than 15 cerclage procedures (including both elective and emergency). Distension of 
the urinary bladder and/or a Foley balloon will be used when necessary to replace the fetal 
membranes into the uterine cavity. Participants will be admitted pre-operatively and re-
evaluated for the previously described exclusion criteria. They will receive peri-operative 
indomethacin for a period of between 6 and 24 hours. Post-operatively, women can be 
discharged if there is no uterine activity, rupture of the membranes, symptoms or signs of 
infection after 24 to 48 hours.  
In women aiming for a vaginal birth, the cervical suture will be removed by a simple 
speculum examination at 35-36 weeks’ gestation. If the woman is planning Caesarean 
section, the suture will be removed at the time of the Caesarean, at the end of the 
procedure.  
However, if at any time rupture of the membranes occurs, or the mother develops 
symptoms or signs of uterine infection (chorioamnionitis), significant vaginal bleeding or 
regular painful uterine contractions, the cervical suture should be removed without delay.  
If the pregnancy continues without complications, delivery will be planned in line with NICE 
guidelines (dichorionic twin pregnancy at 37 weeks’ gestation and monochorionic twin 
pregnancy at 36 weeks’ gestation).2 Monochorionic twin pregnancy complicated by TTTS 
treated by Laser will have planned delivery at 34-36 weeks according to local protocols. 
 
10.5 Follow-up visits 
Follow-up visits for ultrasound assessment of fetal growth and cervical length will be carried 
out as per the local protocol (approximately every four weeks in dichorionic diamniotic twin 
pregnancies and every 2-3 weeks in monochorionic diamniotic twin pregnancies). A course 
of steroids (two intramuscular injections of betametasone/dexametasone 12 mg, 24 hours 
apart) will be administered in the week before any planned birth after 23 weeks’ gestation.  
 
 
10.6 Data collection 
Information on the baseline characteristics of the patients, including demographic data, 
measurements for calculation of body mass index, and obstetrical and medical histories, will 
be collected at recruitment and recorded in a computer database. Data on pregnancy 
outcomes will be obtained from the hospital maternity and neonatal records or the patients' 
general medical practitioners. The obstetric records of all women who experience preterm 
birth will be examined to determine whether the delivery was medically indicated or 

 
 
 
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spontaneous. Spontaneous deliveries will include those with spontaneous onset of labour 
and those with rupture of membranes before labour. Quality control of the collected data 
and verification of adherence to protocols at the different centres will be performed on a 
regular basis by the trial coordinator.  
 
10.7 Study flow chart and summary table of study assessments 
Please refer to Appendix 1 and Appendix 2. 
11 Study Timeline 
Please refer to Appendix 3. 
12 Safety Events 
12.1 Definitions 
Adverse Event (AE)—any untoward medical occurrence in a participant whether it is 
considered to be related to the intervention or not, that includes a clinical sign, symptom, or 
condition and/or an observation of a near incident. This does not include pre-existing 
conditions recorded as such at baseline; continuous persistent disease or a symptom 
present at baseline that worsens following administration of trial intervention. 
Serious Adverse Event (SAE) - any Adverse Event or untoward medical occurrence in a 
trial participant that can be wholly or partly due to the intervention which resulted in any of 
the following: 
 
Death 
 
Is life-threatening (places the participant, in the view of the Investigator, at immediate risk 
of death) 
 
Requires hospitalisation or prolongation of existing hospitalisation (hospitalisation is 
defined as an inpatient admission, regardless of length of stay, even if it is a 
precautionary measure for observation, including hospitalisation for an elective 
procedure for a pre-existing condition) 
 
Results in persistent or significant disability or incapacity (substantial disruption of one’s 
ability to conduct normal life functions) 
 
Consists of a congenital anomaly or birth defect (in offspring of participants regardless of 
time of diagnosis) 
 
Is another important medical condition 
Important medical events that may not be immediately life-threatening or result in death or 
hospitalisation but may jeopardise the participant or require intervention to prevent one of 
the outcomes listed in the definition of serious AE will also be considered serious. 
12.2 Recording Adverse Events (AEs) 
All Adverse Events will be recorded in the hospital notes in the first instance.   

 
 
 
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A record of all AEs, whether related or unrelated to the treatment, will also be kept in the 
CRF and the Sponsor’s AE Log JREOLOG0007.   
If the Investigator suspects that the disease or condition has progressed faster due to the 
intervention, then she will report this as an unexpected adverse event to the sponsor.  
12.3 Investigator Responsibilities relating to Safety Reporting  
Collection, recording and reporting of AEs (including serious and non-serious events and 
reactions) to the Sponsor will be done according to the Sponsor’s Safety reporting for non-
CTIMP studies SOP JREOSOP0033. 
All SAEs will be recorded in the hospital notes and the CRF, and the Sponsor’s AE 
Recording Log JREOLOG0007. The AE Log will be sent to the Sponsor on request and 
every 2 months.  
All SAEs will be reported both to the Sponsor via the JREO & REC using the SAE report 
form for research other than CTIMPs (non-CTIMPs) published on the HRA website. 
The Chief or Principal Investigator, or a member of the research team, at any participating 
site will complete the SAE form which will be faxed both to the JREO on 020 8725 0794 or 
E-mailed to adverseevents@sgul.ac.uk, within 48hrs of the Investigator becoming aware of 
the event, and via email to the relevant REC. 
The Chief or Principal Investigator will respond to any SAE queries raised by the Sponsor as 
soon as possible. Follow-up reports must continually be completed within an acceptable 
time-frame and sent as detailed above until the reportable event is considered resolved. 
Events will be followed up until resolution; any appropriate follow-up information will be 
clearly marked as such and reported to the sponsor via the JREO as above in a timely 
manner. 
Full reports should be completed and submitted to REC within 15 days of the event. 
12.4 Notification of deaths 
Only deaths that are assessed to be caused by the trial intervention will be reported to the 
Sponsor.  This report will be immediate. 
13 Data management and quality assurance 
13.1 Confidentiality 
All data will be handled in accordance with the Data Protection Act 1998. 
The Case Report Forms (CRFs) will not bear the participant’s name or other directly 
identifiable data. The participant’s trial Identification Number (ID) only will be used for 
identification. The sponsor Subject ID log JREOLOG0002 can be used to cross reference 
participants’ identifiable information. 

 
 
 
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13.2  Data collection tool  
Case Report Forms will be designed by the CI. All data will be entered legibly in black ink 
with a ball-point pen.  If the Investigator makes an error, it will be crossed through with a 
single line in such a way as to ensure that the original entry can still be read. The correct 
entry will then be clearly inserted. The amendment will be initialled and dated immediately by 
the person making the correction. Overwriting or use of correction fluid will not be permitted. 
It is the Investigator’s responsibility to ensure the accuracy of all data entered and recorded 
in the CRFs. The Staff Delegation of Responsibilities Log JREOLOG0004 will identify all trial 
personnel responsible for data collection, entry, handling and managing the database. 
13.3 Incidental Findings 
All subjects will be informed in a timely manner, both verbally and in writing, of any new 
information, findings or changes to the way the research will be conducted that are of 
potential relevance for participants or their families and might influence their willingness 
to continue in this study. 
13.4 Data handling and analysis 
The trial will use an online secure database. Quality Control will be applied at each stage of 
data handling to ensure that all data are reliable and have been processed correctly.  
14 Archiving arrangements 
The trial essential documents along with the trial database will be archived in accordance 
with the sponsor SOP JREOSOP0016. The agreed archiving period for this trial will be 10 
years.  
15 Statistical design 
15.1 Endpoints 
15.1.1   
Primary endpoints 
Time to delivery (from randomisation to birth). 
15.1.2  
Secondary endpoints 
 
Gestation at delivery 
 
Preterm birth before 28, 32 and 34 weeks’ gestation 
 
Birthweight 
 
Stillbirth 
 
Neonatal death 
 
Survival to discharge 

 
 
 
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 
Days of admission to the neonatal intensive care unit  
 
Composite outcome of stillbirth, neonatal death, intraventricular haemorrhage40, 
periventricular leukomalacia, respiratory distress syndrome, bronchopulmonary 
dysplasia, retinopathy of prematurity41, necrotising entercolitis42, proven neonatal 
sepsis, or the need for ventilation 
 
Days of maternal admission for preterm labour 
 
Maternal morbidity (deﬁned as thromboembolic complications, chorioamnionitis, 
urinary tract  infection  treated  with  antibiotics,  pneumonia,  endometritis,  
eclampsia,  HELLP  syndrome, death, or any other significant morbidity) 
 
15.2 Sample size calculation 
Study 1: Twin pregnancies presenting with an open cervix Group 
We performed a sample size calculation based on the GA and preterm birth percentage (45% and 
99% for with and without cerclage). Also included the outputs based on the preterm birth percentage 
of 45% and 95% for with and without cerclage. 
An experiment with 6 women in the cerclage group and 3 women in the control group will have 80% 
power to detect the gestational age (at delivery) difference of 6 weeks or greater between cerclage 
and control groups at a significance level of 5%. Assuming the percentage of preterm birth at less 
than 32 weeks for the cerclage and control groups as 45% and 99%, respectively, an experiment 
with 15 women in the cerclage group and 8 women in the control group will achieve 80% power with 
the statistical significance of 5%. With the assumption that approximately 14 births occurring among 
these women in less than 32 weeks, an experiment with 20 women will also detect a hazard ratio of 
0.34 or less in favour of the cerclage group - the cerclage group will be 66% less likely to give a birth 
at any time point before 32 weeks compared with the control group - with at least 80% power. These 
calculations do not include the loss to follow-up which should be considered by including one 
additional subject in each group. 
Preterm birth percentage: 
Cerclage group = 45% 
Control group = 95% 
Sample size: 
Cerclage group = 19 
Control group = 10 
HR = 0.39 
 
Study 2: Monochorionic Twin pregnancies complicated by TTTS treated by Laser 
surgery with short cervix (<15mm) Group 
 
We have more than 8 UK centres willing to participate in the study. One concern is that 
recruitment to this study might be difficult, as women might not agree to be randomised 

 
 
 
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to no intervention. As this a pilot study, we plan to recruit 20 women in the Study 1 (13 
women in the cerclage group and 7 women in the control group) and 11 women in the 
second Study 2 (7 women in the cerclage group and 4 women in the control group), so 31 
participants in total. The rational for choosing randomisation of 2:1 (cerclage:expectant 
management) is that women often request the cerclage as a treatment in view of the 
favourable published observational data and the extremely poor outcome in the 
pregnancies which are expectantly managed. Therefore, participating in the trial has 2 
out of 3 chance of receiving the cerclage and 1 out of 3 of being randomised to the 
expectant management.  
 
An experiment with 13 women in the cerclage group and 7 women in the control group in the 
Study 1 will have 80% power to detect the gestational age (at delivery) difference of 6 weeks 
or greater between cerclage and control groups at a significance level of 5%. Similarly, an 
experiment with 7 women in the cerclage group and 4 women in the control group in the 
Study 2 will have 80% power to detect the gestational age (at delivery) difference of 6 weeks 
or greater between cerclage and control groups at a significance level of 5%. These 
calculations include the 5% loss to follow-up by including one additional subject in each 
group. The above calculations also assume that the between centre variability is negligible 
for the outcome of interest. This pilot trial will provide the data required for a full funding 
application to the NIHR RFPB programme.  
 
 
15.3 Statistical analysis plan 
Statistical analyses will be performed according to intention to treat. The primary 
analysis will compare the time to delivery (from randomisation to birth) in weeks. Other 
outcomes, such as gestational age at delivery, preterm birth before 28, 32 and 34 
weeks’ gestation, median birthweight, stillbirth, neonatal death and survival to discharge 
will be compared between the 2 arms of each study group as secondary outcomes. A 
number of statistical tests, including Pearson’s chi-squared test [RR, (95%CIs)], Log-
rank test [HR, (95%CIs)] and 2-sample student’s t-test [mean ± SD], will be used to 
analyse the various outcomes.  
 
 
16 Ethics and Research Governance requirements 
Before any site can enrol patients into the trial, the Principal Investigator must ensure that 
written permission to proceed has been granted by that Trust Research & Development 
(R&D). The site must conduct the trial in compliance with the protocol as agreed by the 
Sponsor and which was accepted by the Research Ethics Committee (REC).  
The Chief Investigator will be provided (via the Sponsor) with file indices, e.g. 
JREODOC0003 TMF index and JREODOC0004 ISF index, for use with SOP 
JREOSOP0019 ‘Preparation and Maintenance of the TMF’. The CI will be responsible for 
the maintenance of the TMF and may delegate the responsibility of ISF file maintenance to 
the PI at each participating site. 

 
 
 
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It is the responsibility of the PI at each site to ensure that all subsequent amendments gain 
the necessary approval. Refer to JREOSOP0011 ‘Management of Amendments’. 
Within 90 days after the end of the trial, the CI and Sponsor will ensure that the REC is 
notified that the trial has finished.  If the trial is terminated prematurely, those reports will be 
made within 15 days after the end of the trial. Refer to JREOSOP0015 ‘End of study 
declaration’. 
The CI will supply an End of Study report of the clinical trial to the REC within one year after 
the end of the trial. The sponsor can provide JREODOC0059 End of study Report template. 
16.1  Annual Progress Reports (APRs) 
The Chief Investigator will prepare the APR in accordance with JREOSOP0043. Following 
review by the sponsor the report will be sent to the REC. The APR is due for submission 
annually within 30 days of the anniversary date on which the favourable opinion was given 
by the Ethics committee, until the trial is declared ended. 
16.2 Notification of Serious Breaches of GCP and/or the protocol 
Any Protocol Deviations or Violations will be documented using JREODOC0061, and 
entered onto the Sponsor’s log JREOLOG0005. Potential Serious Breaches and Urgent 
Safety Measures will be recorded both on the Sponsor’s Log JREOLOG0005 and processed 
according to JREOSOP0012 and where necessary JREOSOP0032. 
A “serious breach” is a breach which is likely to affect to a significant degree: 
(a) The safety or physical or mental integrity of the participants of the trial; or 
(b) The scientific value of the trial. 
The CI will notify the Sponsor immediately of any case where there is a possible serious 
breach. 
16.3 Direct access to source data 
The Investigator(s)/institution(s) will permit trial-related monitoring, audits, REC review, and 
regulatory inspection(s), providing direct access to source data/documents. Trial participants 
are informed of this during the informed consent discussion. Participants will consent to 
provide access to their medical notes. 
 
17 Finance 
The trial is partially funded by the Twins and Multiple Births Association (TAMBA), which is 
the largest UK charity providing support to multiple pregnancies. The funding will contribute 
to the salary of a research midwife who will coordinate the trial.  

 
 
 
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18 Insurance and indemnity 
NHS bodies are liable for clinical negligence and other negligent harm to individuals covered 
by their duty of care. NHS Institutions employing researchers are liable for negligent harm 
caused by the design of studies they initiate. 
19 Development policy 
The sponsor, participating sites and all investigators involved in the study shall treat all 
information and data related to the study as confidential and with the proper respect for the 
privacy of each participant. The parties shall equally warrant to not disclose such information 
to third parties or disclose such publicly, but shall use such information solely for the purpose 
of this study. All data shall be coded or de-identified prior to transfer of such data to sponsor. 
Parties have expressly agreed that any and all data collected and prepared in the context of 
the study shall be the property of the sponsor, provided that the participating sites shall 
remain the owner of their source data and may utilise such data as it deems appropriate 
without the approval of sponsor. 
The participating sites and their proper investigators warrant that they shall not perform the 
study without having obtained the proper, written informed consent from each participant, in 
accordance with applicable legislation and as approved by the appropriate ethics 
committee/review board. 
20 Publication policy 
Publication: “Any activity that discloses, outside of the circle of trial investigators, any final or 
interim data or results of the Trial, or any details of the Trial methodology that have not been 
made public by the Sponsor including, for example, presentations at symposia, national or 
regional professional meetings, publications in journals, theses or dissertations.” 
All scientific contributors to the Trial have a responsibility to ensure that results of scientific 
interest arising from Trial are appropriately published and disseminated. The Sponsor has a 
firm commitment to publish the results of the Trial in a transparent and unbiased manner 
without consideration to commercial objectives.  
To maximise the impact and scientific validity of the Trial, data shall be consolidated over the 
duration of the trial, reviewed internally among all investigators and not be submitted for 
publication prematurely.  
 
20.1  Before the official completion of the Trial 
All publications during this period are subject to permission by the Sponsor. If an investigator 
wishes to publish a sub-set of data without permission of the Sponsor during this period, the 
steering committee shall have the final say.  

 
 
 
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20.2  Up to 180 days after the official completion of the Trial  
During this period the Chief Investigator shall liaise with all investigators and strive to 
consolidate data and results, then submit a manuscript for peer review with a view to 
publication in a reputable academic journal or similar outlet as the Main Publication.  
 
The Chief Investigator shall be senior and corresponding author of the Main 
Publication.  
 
Insofar as is compatible with the policies of the publication outlet and good academic 
practice, the other Investigators shall be listed in alphabetic order.  
 
Providers of analytical or technical services shall be acknowledged, but will be listed 
as co-authors only if their services were provided in a non-routine manner as part of 
a scientific collaboration.  
 
Members of the Steering Group shall be acknowledged as co-authors only if they 
also contributed in other capacities. 
 
If there are disagreements about the substance, content, style, conclusions, or author 
list of the Main Publication, the Chief Investigator shall ask the Steering Group to 
arbitrate.     
20.3  Beyond 180 days after the official completion of the Trial  
After the Main Publication or after 180 days from Trial end date, any Investigator or group of 
investigators may prepare further publications.  In order to ensure that the Sponsor will be 
able to make comments and suggestions where pertinent, material for public dissemination 
will be submitted to the Sponsor for review at least sixty (60) days prior to submission for 
publication, public dissemination, or review by a publication committee. Sponsor’s 
reasonable comments shall be reflected. All publications related to the Trial shall credit the 
Chief and Co-Investigators as co-authors where this would be in accordance with normal 
academic practice and shall acknowledge the Sponsor and the Funders.    
21 Statement of Compliance 
The trial will be conducted in compliance with the protocol, Sponsor’s Standard Operating 
Procedures (SOPs), GCP and the applicable regulatory requirement(s). 
The study conduct shall comply with all relevant laws of the EU if directly applicable or of 
direct effect and all relevant laws and statutes of the country in which the study site is 
located, including but not limited to the Human Rights Act 1998, the Data Protection Act 
1998, the Human Medicines Regulations 2012, ICH GCP, the World Medical Association 
Declaration of Helsinki entitled 'Ethical Principles for Medical Research Involving Human 
Subjects' (2008 Version), the NHS Research Governance Framework for Health and Social 
Care (Version 2, April 2005).    

 
 
 
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This study will be conducted in compliance with the protocol approved by the REC and 
according to GCP standards. No deviation from the protocol will be implemented without the 
prior review and approval of the Sponsor and REC except where it may be necessary to 
eliminate an immediate hazard to a research subject.  In such case, the deviation will be 
reported to the Sponsor and REC as soon as possible. 
22    List of Protocol appendices 
Appendix 1 Study flow chart  
Appendix 2 Summary table of study assessments 
Appendix 3 Timeline of the proposed pilot study 
Appendix 4 Protocol Amendment/Revision History (chronological order) or a statement 
“There are currently no amendments” 
 
23    References 
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birth. Lancet 2008;371:75–84. 
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3. Miller J, Chauhan SP, Abuhamad AZ. Discordant twins: diagnosis, evaluation and 
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4. D'Antonio F, Khalil A, Dias T, Thilaganathan B; Southwest Thames Obstetric Research 
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the Southwest Thames Obstetric Research Collaborative (STORK) multiple pregnancy 
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5. D'Antonio F, Khalil A, Dias T, Thilaganathan B; Southwest Thames Obstetric Research 
Collaborative (STORK). Early fetal loss in monochorionic and dichorionic twin 
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9. To MS, Fonseca EB, Molina FS, Cacho AM, Nicolaides KH. Maternal characteristics 
and cervical length in the prediction of spontaneous early preterm delivery in twins. Am 
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Fonseca E, Creasy GW, Klein K, Rode L, Soma-Pillay P, Fusey S, Cam C, Alfirevic Z, 
Hassan SS. Vaginal progesterone in women with an asymptomatic sonographic short 
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12. Hassan SS, Romero R, Vidyadhari D, Fusey S, Baxter JK, Khandelwal M, 
Vijayaraghavan J, Trivedi Y, Soma-Pillay P, Sambarey P, Dayal A, Potapov V, O'Brien 
J, Astakhov V, Yuzko O, Kinzler W, Dattel B, Sehdev H, Mazheika L, Manchulenko D, 
Gervasi MT, Sullivan L, Conde-Agudelo A, Phillips JA, Creasy GW; PREGNANT Trial. 
Vaginal progesterone reduces the rate of preterm birth in women with a sonographic 
short cervix: a multicenter, randomized, double-blind, placebo-controlled trial. 
Ultrasound Obstet Gynecol 2011;38:18-31. 
13. Fonseca EB, Celik E, Parra M, Singh M, Nicolaides KH; Fetal Medicine Foundation 
Second Trimester Screening Group. Progesterone and the risk of preterm birth among 
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ultrasonography in women with singleton gestations and previous preterm birth: a meta-
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15. Althuisius SM, Dekker GA, Hummel P, Bekedam DJ, van Geijn HP. Final results of the 
Cervical Incompetence Prevention Randomized Cerclage Trial (CIPRACT): therapeutic 
cerclage with bed rest versus bed rest alone. Am J Obstet Gynecol 2001;185:1106–
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16. Crowther CA, Neilson JP, Verkuyl DA, Bannerman C, Ashurst HM. Preterm labour 
in twin pregnancies: can it be prevented by hospital admission? BJOG 1989;96:850-
853. 
17. Roman AS, Saltzman DH, Fox N, Klauser CK, Istwan N, Rhea D, Rebarber A. 
Prophylactic cerclage in the management of twin pregnancies. Am J Perinatol 
2013;30:751-754. 
18. Senat MV, Porcher R, Winer N, Vayssière C, Deruelle P, Capelle M, Bretelle F, Perrotin 
F, Laurent Y, Connan L, Langer B, Mantel A, Azimi S, Rozenberg P; Groupe de 
Recherche en Obstétrique et Gynécologie. Prevention of preterm delivery by 17 alpha-
hydroxyprogesterone caproate in asymptomatic twin pregnancies with a short cervix: a 
randomized controlled trial. Am J Obstet Gynecol 2013;208:194.e1-8. 
19. Norman JE1, Mackenzie F, Owen P, Mactier H, Hanretty K, Cooper S, Calder A, Mires 
G, Danielian P, Sturgiss S, MacLennan G, Tydeman G, Thornton S, Martin B, Thornton 
JG, Neilson JP, Norrie J. Progesterone for the prevention of preterm birth in twin 
pregnancy (STOPPIT): a randomised, double-blind, placebo-controlled study and meta-
analysis. Lancet. 2009 ;373(9680):2034-2040.  

 
 
 
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20. Rafael TJ, Berghella V, Alfirevic Z. Cervical stitch (cerclage) for preventing preterm birth 
in multiple pregnancy. Cochrane Database Syst Rev. 2014 Sep 10;9:CD009166. doi: 
10.1002/14651858.CD009166.pub2. 
21. Althuisius SM, Dekker GA, Hummel P, van Geijn HP; Cervical incompetence prevention 
randomized cerclage trial. Cervical incompetence prevention randomized cerclage trial: 
emergency cerclage with bed rest versus bed rest alone. Am J Obstet Gynecol 
2003;189:907–910. 
22. Pereira L, Cotter A, Gómez R, et al. Expectant management compared with physical 
examination-indicated cerclage (EMPEC) in selected women with a dilated cervix at 
14(0/7)-25(6/7) weeks: results from the EM-PEC international cohort study. Am J Obstet 
Gynecol 2007;197:483, e1–e8 
23. Stupin JH, David M, Siedentopf JP, Dudenhausen JW. Emergency cerclage versus bed 
rest for amniotic sac prolapse before 27 gestational weeks. A retrospective, comparative 
study of 161 women. Eur J Obstet Gynecol Reprod Biol 2008;139:32–37 
24. Ventolini G, Genrich TJ, Roth J, Neiger R. Pregnancy outcome after placement of 
“rescue” Shirodkar cerclage. J Perinatol 2009;29:276–279 
25. Daskalakis G, Papantoniou N, Mesogitis S, Antsaklis A. Management of cervical 
insufficiency and bulging fetal membranes. Obstet Gynecol 2006;107(2 Pt 1):221–226 
26. Namouz S, Porat S, Okun N, Windrim R, Farine D. Emergency cerclage: literature 
review. Obstet Gynecol Surv 2013;68:379-88. 
27. Gupta M, Emary K, Impey L. Emergency cervical cerclage: predictors of success. J 
Matern Fetal Neonatal Med 2010;23:670–674 
28. Diago Almela VJ, Martínez-Varea A, Perales-Puchalt A, Alonso-Díaz R, Perales A. 
Good prognosis of cerclage in cases of cervical insufficiency when intra-amniotic 
inflammation/infection is ruled out. J Matern Fetal Neonatal Med 2014:1-6. [Epub ahead 
of print] 
29. Levin I, Salzer L, Maslovitz S, Avni A, Lessing JB, Groutz A, Almog B. Outcomes of mid-
trimester emergency cerclage in twin pregnancies. Fetal Diagn Ther 2012;32:246-50.  
30. Aguilera M, Ramin K, Nguyen R, Giacobbe L, Swartout J. Emergency cerclage 
placement in multifetal pregnancies with a dilated cervix and exposed membranes: case 
series. AJP Rep 2013;3:1-4.  
31. Roman A, Rochelson B, Martinelli P, Saccone G, Harris K, Zork N, Spiel M, O'Brien K, 
Calluzzo I, Palomares K, Rosen T, Berghella V, Fleischer A. Cerclage in twin pregnancy 
with dilated cervix between 16 to 24 weeks of gestation: retrospective cohort study. Am 
J Obstet Gynecol 2016;215:98.e1-98.e11 
32. Senat MV, Deprest J, Boulvain M, et al. 2004. Endoscopic laser surgery versus serial 
amnioreduction for severe twin-to-twin transfusion syndrome. N Engl J Med 351: 136–
44. 
33. Robyr R, Boulvain M, Lewi L, et al. 2005. Cervical length as a prognostic factor for 
preterm delivery in twin-to-twin transfusion syndrome treated by fetoscopic laser 
coagulation of chorionic plate anastomoses. Ultrasound Obstet Gynecol 25: 37–41. 
34. Salomon LJ, Nasr B, Nizard J, Bernard JP, Essaoui M, Bussieres L, Ville Y. 
Emergency cerclage in cases of twin-to-twin transfusion syndrome with a short cervix at 
the time of surgery and relationship to perinatal outcome. Prenat Diagn 2008;28:1256-
61. 
35. Saunders NJ, Snijders RJ, Nicolaides KH. 1992. Therapeutic amniocentesis in twin-twin 
transfusion syndrome appearing in the second trimester of pregnancy. Am J Obstet 
Gynecol 166: 820–4. 
36. Ville Y, Sideris I, Nicolaides KH 1996. Amniotic ﬂuid pressure in twin-to-twin transfusion 
syndrome: an objective prognostic factor. Fetal Diagn Ther 11: 176–80. 
37. Papanna R, Habli M, Baschat AA, Bebbington M, Mann LK, Johnson A, Ryan G, Walker 
M, Lewis D, Harman C, Crombleholme T, Moise KJ Jr. Cerclage for cervical shortening 

 
 
 
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at fetoscopic laser photocoagulation in twin-twin transfusion syndrome. Am J Obstet 
Gynecol 2012;206:425.e1-7. 
38. Greenberg MB, Anderson BL, Schulkin J, Norton ME, Aziz N. A first look at 
chorioamnionitis management practice variation among US obstetricians. Infect Dis 
Obstet Gynecol 2012;2012:628362.  
39. Romero R, Yoon BH, Mazor M, et al. A comparative study of the diagnostic 
performance of amniotic fluid glucose, white blood cell count, interleukin-6, and Gram 
stain in the detection of microbial invasion in patients with preterm premature rupture of 
membranes. Am J Obstet Gynecol 1993;169:839-51. 
40. Papile LA, Burstein J, Burstein R, Koﬄ  er H. Incidence and evolution of subependymal 
and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 
gm. J Pediatr 1978; 92: 529–34. 
41. International Committee for the Classification of Retinopathy of Prematurity. The 
International Classification of Retinopathy of Prematurity revisited. Arch Ophthalmol 
2005;123:991-9. 
42. Bell MJ, Ternberg JL, Feigin RD, et al. Neonatal necrotizing enterocolitis: therapeutic 
decisions based upon clinical staging. Ann Surg 1978; 187: 1–7. 
 
 

 
 
 
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Table 1. Summary of studies on cerclage in twin pregnancy with dilated cervix. 
First 
author and 
year 
Study  
design 
Cerclage 
Controls 
(no 
cerclage) 
GA  
Amniocentesis 
Antibiotics 
Tocolysis 
Time 
interval 
until 
delivery 
(days) 
PTB <28 
weeks 
PTB 
<32 
weeks 
PTB 
<34 
weeks 
PPROM 
Neonatal 
survival 
Althuisius 
2003 
RCT 
3 
4 
<27 
No 
No 
No 
No data 
No data 
No data 
No data 
No data 
No data 
Parilla 2003 
RC 
11 
Not 
specified 
21.4±2.
2 
No 
N/A 
N/A 
No data 
No data 
No data 
No data 
No data 
No data 
Gupta 2010 
RC 
11 
0 
<27 
No 
Yes, not 
specified 
Yes, not 
specified 
No data 
No data 
No data 
No data 
No data 
No data 
Levin 2012 
RC 
14 
0 
20.1±2.
5 
No 
All 
No 
71.1±44.6 
2 
(14.3%) 
N/A 
N/A 
2 (14.3) 
16/20 
(80%) 
Rebarber 
2013 
RC 
12 
0 
14-23.8 
12 (100%) 
12 (100) 
12 (100) 
92        
(26-145) 
2 
(16.6%) 
3 (25%) 
7 
(58.3%) 
2 
(16.6%) 
20/24 
(83%) 
Zanardini 
20131 
RC 
14 
0 
16-26 
No 
14 (100) 
14 (100) 
69 (2-125) 
3 (21%) 
7 (50%) 
7 (50%) 
4 (29%) 
24/28 
(86%) 
Miller 2014 
RC 
104 
0 
16-23.8 
Not routinely 
used 
56 (54.3) 
69 (57.3) 
69 (21-99) 
35 
(33.7%) 
54 
(51.9%) 
N/A 
35 
(33.7%) 
No data 
Barnabeu 
2015 
RC 
7 
0 
19.6±4.
0 
7 (100%) 
7 (100) 
7 (100) 
12.1 (4-16) 
2 (28%) 
No data 
3 
(42.8%) 
1 
(14.2%) 
14/14 
(100%) 
Roman 
2016 
RC 
38 
38 
16-24 
30 (79%) 
36 (94%) 
29 (76%) 
73±39 
12 
(31.6%) 
17 
(44.7%) 
20(52.6
%) 
8 (21%) 
50/76 
(65.8) 
RCT: randomised controlled trial; RC: retrospective cohort; GA: gestational age in weeks; PTB: preterm birth; PPROM: preterm pre-labour 
rupture of membranes. 

 
 
 
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Appendix 1 
Study flow chart  
 

 
 
 
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Appendix 2. Summary table of study assessments. 
 
 
Study Procedures 
Screening 
Treatment 
Follow-up  
(neonatal 
discharge) 
Informed consent 
√ 
 
 
Inclusion/exclusion criteria 
√ 
 
 
Data collection 
√ 
 
 
Demographics 
√ 
 
 
Baseline 
√ 
 
 
Screening  
√ 
 
 
Ultrasound 
√ 
 
 
Intervention 
 
√ 
 
Data collection/Telephone call 
 
 
√ 

 
 
 
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Appendix 3. Timeline of the proposed pilot study 
 
Calendar year 
2017   
  
  
  
  
  
  
  
  
2018   
Calendar month 
March 
April 
May  
June 
July 
August 
Sept 
Oct 
Nov 
Dec 
Jan 
Feb 
Ethics approval 
  
  
  
  
  
  
  
  
  
  
  
  
Database design 
  
  
  
  
  
  
  
  
  
  
  
  
Project set-up 
  
  
  
  
  
  
  
  
  
  
  
  
Co-ordination 
among the 
participating 
centres 
  
  
  
  
  
  
  
  
  
  
  
  
Recruitment 
  
  
  
  
  
  
  
  
  
  
  
  
Data collection 
  
  
  
  
  
  
  
  
  
  
  
  
Preliminary data 
analysis, literature 
review for a peer-
reviewed paper 
  
  
  
  
  
  
  
  
  
  
  
  
Statistical analysis 
  
  
  
  
  
  
  
  
  
  
  
  
Writing and 
submission of a 
peer-reviewed 
paper and report to 
the funder 
  
  
  
  
  
  
  
  
  
  
  
  

 
 
 
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Appendix 4 
Protocol amendment /Revision History 
 
Protocol Version and 
Date 
 
New text