Cervical Pessary to Prevent Preterm Birth in Singleton Pregnancies With a Sonographically Measured Short Cervix: an Open-label Randomized Controlled Trial
Phase: NA
Conditions: Premature Birth
Sponsor: Gene Lee, MD

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October 4, 2019 
 
Study Title: Cervical Pessary to Prevent Preterm Birth in Singleton Pregnancies 
With a Sonographically Measured Short Cervix 
 
FDA IDE G140219 
NCT02357394 
 
This study was an open label, randomized controlled trial which was designed to 
determine if the use of the Arabin cervical pessary would reduce the incidence of preterm 
birth.  At the time of conception, our study differed from other studies regarding the 
Arabin cervical pessary in that we allowed the use of vaginal progesterone and/or 
cervical cerclage in the control group.  In essence, our study compared the community 
care standard of practice in our area with the use of the Arabin cervical pessary for an 
ultrasound diagnosed short cervix. 
 
Our study required an FDA IDE application, assigned number G140219, and registration 
on clinicaltrials.gov as NCT02357394.  Our first patient was enrolled 7/1/2015.  Our last 
patient was enrolled 7/4/2016.  Our last data entry occurred in November 2016.  We 
subsequently were unable to enroll any further patients du e to low interest.  We decided 
to close the study formally 4/4/2019.   
 
Results were entered to clinicaltrials.gov on 10/4/2019.   Due to low number of enrolled 
subjects (n=7), only raw data in reported.  No statistical tests were run.   
 
Signed, 
 
Gene Lee MD 
Assistant Professor 
MFM/OBGYN 
The University of Kansas Health System 
 
 

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Sponsor: GENE T. LEE, MD 
 
Clinical Research Protocol 
 
Cervical pessary to prevent preterm birth in singleton pregnancies 
with a songraphically measured short cervix: an open-label 
randomized controlled trial 
 
Protocol Number: 
Cerclage Pessary 
Version Date: 
4/24/2015 
Investigational Device: 
Arabin Pessary 
IDE Number: 
G140219 
Study Phase: 
II 
Sponsor-Investigator: 
Gene T. Lee, MD 
Assistant Professor 
Department of Obstetrics and Gynecology 
University of Kansas Medical Center
Funding Organization: 
Unfunded 
Site Investigator:  
Gene T. Lee, MD 
Assistant Professor 
Department of Obstetrics and Gynecology 
University of Kansas Medical Center 
 
Carl P. Weiner, MD MBA 
KE Krantz Professor and Chair 
Department of Obstetrics and Gynecology 
University of Kansas Medical Center  
 
Eugene Y Chang, MD 
Associate Professor 
Department of Obstetrics and Gynecology 
Medical University of South Carolina
 
 

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This confidential information about an investigational product is provided for the exclusive use of 
investigators of this product and is subject to recall at any time.  The information in this document 
may not be disclosed unless federal or state law or regulations require such disclosure.  Subject to the 
foregoing, this information may be disclosed only to those persons involved in the study who have a 
need to know, with the obligation not to further disseminate this information.   
 

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 TABLE OF CONTENTS 
 
1.0 
PURPOSE OF THE INVESTIGATION…………………………………………………......... 8 
2.0 
CLINICAL PROTOCOL………………………………………………………………………. 10 
3.0 
RISK ANALYSIS……………………………………………………………………………….. 17 
4.0 
DESCRIPTION OF THE INVESTIGATIONAL DEVICE…………………………………. 20 
5.0 
MONITORING PROCEDURES………………………………………………………………. 21 
6.0 
LABELING……………………………………………………………………………………… 22 
7.0  
INFORMED CONSENT……………………………………………………………………….. 23 
8.0  
IRB INFORMATION………………………………………………………………………….. 23 
9.0 
ADDITIONAL RECORDS AND REPORTING…………………………………………….. 24 
10.0 
ADDITION OR REMOVAL OF INVESTIGATORS…………………………………........  25 
 
 

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LIST OF ABBREVIATIONS 
AE 
adverse event 
CFR 
Code of Federal Regulations 
CRF 
case report form 
DMC 
Data Monitoring Committee 
DSMB 
Data Safety Monitoring Board 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HSC 
Human Subjects Committee, KUMC Local IRB 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
QC 
Quality Control 
PI 
Principal Investigator 
UADE 
unanticipated adverse device effect 
 
 
 

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PROTOCOL SYNOPSIS 
TITLE 
Cervical pessary to prevent preterm birth in singleton pregnancies  with a 
songraphically measured short cervix: an open-label randomized controlled 
trial
SPONSOR 
Gene T. Lee, MD 
FUNDING 
ORGANIZATION 
Unfunded 
NUMBER OF SITES 
1; University of Kansas Medical Center 
2. Medical University of South Carolina
RATIONALE 
The Arabin cervical pessary has emerged as a promising treatment for 
cervical insufficiency.  A recent Spanish RCT demonstrated reduced 
preterm births with the use of the Arabin pessary.  The results of this study 
pessary should also be confirmed here in the USA.  
STUDY DESIGN 
Open-label, randomized, controlled trial 
PRIMARY OBJECTIVE 
To determine if the Arabin pessary can reduce preterm birth before 37 
weeks in patients with a short cervix 
SECONDARY 
OBJECTIVES 
To determine if the Arabin pessary can reduce maternal and neonatal 
morbidity   
NUMBER OF 
SUBJECTS 
256 
SUBJECT SELECTION 
CRITERIA 
Inclusion Criteria: 
 
singleton pregnancy 
 
age 18 – 45y  
 
cervical length < 25 mm measured by transvaginal ultrasound prior 
to 23 weeks 0 days 
 Agrees to refrain from sexual intercourse 
 
Exclusion Criteria: 
 
major fetal anomalies 
 
painful regular uterine contractions 
 
active vaginal bleeding 
 
ruptured membranes 
 
evidence of chorioamnionitis or other maternal/fetal infectious 
morbidity 
 
placenta previa 
 
current progesterone therapy 
 
cervical cerclage in situ 
 
visual cervical dilation of 2 cm or greater with visible 
amnion/chorion 
 
significant maternal-fetal complications (insulin dependent diabetes 
mellitus, systemic lupus erythematosus with nephritis, chronic 
hypertension, red cell alloimmunization, drug abuse)
INVESTIGATIONAL 
DEVICE / INTENDED 
USE 
Device: Arabin pessary  
The intended use is to treat women with cervical insufficiency characterized 
by a cervix that is too short for gestation as objectively measured on 
transvaginal ultrasound.  

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CONTROL GROUP OR 
OTHER STUDY ARMS 
(if applicable) 
Device: None 
Patients randomized to the control group will receive standard of care for 
their condition. 
Duration of Subject 
Participation and 
Estimated Total Length of 
Study 
Subjects’ participation in the study will last about 7 months.  
 
Based on the number of patients KUMC and MUSC examine in a year for 
cervical length screening in the 2nd trimester, the study will take 4 years to 
complete with 80% accrual.  We expect a loss to follow up rate of 5%. 
PRIMARY ENDPOINT 
 
Preterm birth less than 37 weeks 0 days gestation 
SECONDARY 
ENDPOINTS 
 
Neonatal composite morbidity – fetal or neonatal death, respiratory 
distress syndrome (RDS), chronic lung disease, periventricular lucency, 
periventricular leukomalacia, intraventricular hemorrhage grade 3 or 4, 
necrotizing enterocolitis, early-onset-culture-proven sepsis 
 
Neonatal length of stay 
 
Neonatal NICU admission 
 
Total NICU days 
 
Duration of ventilator support  
 
retinopathy of prematurity (ROP) requiring treatment 
 
birthweight < 1500g and < 2500g 
 
preterm birth < 34 weeks 
 
gestational age at delivery  
 
use of tocolysis 
 
use of antenatal steroids  
 
chorioamnionitis  
 
vaginal bleeding 
 
preterm premature rupture of membranes 

cesarean delivery
OTHER EVALUATIONS 
Maternal age, body mass index, obstetric history, smoking history, 
gestational age at randomization, cervical length at randomization, sludge at 
randomization
SAFETY 
EVALUATIONS 
Patients randomized to the pessary group will be examined for vaginal and 
cervical infections.  Any found infections are treated, and pessary insertion 
is delayed a week.  After insertion, patients are examined for urinary 
retention.  If found, a smaller pessary is inserted.  Patients are seen in clinic 
every 2 weeks, vaginal swabs are examined if symptoms of infection are 
present, and a questionnaire about symptoms is completed.  Pessaries are 
removed if there is active vaginal bleeding, risk of preterm labor with 
persistent contractions, or severe patient discomfort.   
PLANNED INTERIM 
ANALYSES  
The data will be reviewed every 6 months by the designated medical 
monitor for the study, Vishal Pandey MD (neonatologist).  The medical 
monitor is specifically chosen outside of the department of OBGYN to 
allow for objectivity.  Adverse events which would requires immediate 
suspension of study for review would include an excess of 1 maternal death, 
1 maternal ICU admission for sepsis, or  2 perinatal deaths in the pessary 
group.  Unanticipated adverse events will be reported immediately to the 
Human Subjects Committee (HSC) and the FDA, and its recommendations 
for temporary cessation or continuation of the study will be followed.  If an 
excess of 4 perinatal deaths occur in the pessary group, the study should be 
concluded.   

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STATISTICS 
Primary Analysis Plan 
The Research hypothesis is that proportion of preterm deliveries before 37 
weeks 0 days gestation is reduced in the pessary group as compared to the 
control group. The primary endpoint and the categorical outcomes that are 
part of the secondary endpoints will be reported using frequency counts and 
proportions. For the secondary endpoints that are continuous variables, 
summary statistics such as mean and standard deviation, or median and 
inter-quartile range will be reported based on whether the assumption of 
normality is justified. A chi-square test (or a Fisher’s exact test) will be used 
to perform statistical comparison of proportions across the two groups. 
Likewise, comparisons for continuous outcomes will be done using a two-
sample t-test (or Wilcoxon Rank Sum test) as will be deemed necessary.   
For gestational age, we will also compare the Kaplan Meier survival curves 
of the two groups (control and pessary) using the logrank test. 
Level of significance for all statistical tests will be set at 0.05.
Rationale for Number of 
Subjects 
Based on KUMC and MUSC hospital data, the proportion of preterm births 
before 37 weeks 0 days gestation in patients with short cervices is 30%.  In 
order to detect a reduction in half to 15%, a sample size of 242 will be 
required to have power of 80% using a two-sided z-test assuming pooled 
variances.  Level of significance is set at 0.05.  We anticipate a loss to 
follow up rate of 5%.  We expect to enroll 256 subjects.  
 
 
 
 

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1.0 PURPOSE OF THE INVESTIGATION 
1.1  
Name of investigational device 
Device Name: Arabin pessary 
Company/Manufacturer: Dr. Arabin GmbH & Co. KG 
Address: Alfred-Herrhausen-Str. 44 – 58455 Witten 
1.2       Intended use of the investigational device 
The intended use is to treat women with cervical insufficiency characterized by a cervix 
that is too short for gestation as objectively measured on transvaginal ultrasound.   
1.3 Report of Prior Investigations 
1.3.1 General  
The report of prior investigations shall include reports of all prior clinical, animal, and 
laboratory testing of the device and shall be comprehensive and adequate to justify the proposed 
investigation.  
 
The Arabin pessary was first described clinically for the treatment of cervical insufficiency in a 
1990 article published in German (6).  Although good outcomes were obtained, it would be 13 
more years before another study reintroduced the Arabin pessary for the treatment of cervical 
insufficiency (2).   This 2003 pilot project consisting of 46 at risk patients again demonstrated 
improved outcomes characterized by a 32 day prolongation of gestation in singletons and an 18 
day prolongation of gestation in twins compared to patients without pessary. The authors 
acknowledged a larger RCT needed to be done.  In 2012, a large RCT including 385 singleton 
pregnancies was concluded demonstrating the Arabin pessary prolonged pregnancy and reduced 
the rate of preterm birth in women with a singleton and a sonographically short cervix (2).   For 
patients with a cervical length < 25 mm at 20-23 weeks gestation, the pessary reduced the 
prevalence of preterm birth < 34 weeks from 27% to 6%.  Three other cohort studies, 2 
retrospective and 1 prospective, provide supportive evidence of prolongation of pregnancy when 
the pessary is used (1,3,4).  One study investigated a particularly high-risk population consisting 
of twin pregnancies complicated by twin-to-twin transfusion syndrome and a sonographically 
short cervix.  In 2013, a large RCT of 808 multiples (ProTWIN) did not find evidence of benefit 
in the pessary group.  This trial did not require an inclusion criteria of a short cervix, and a 
significant number of patients in the pessary group either did not receive the pessary (6%) or had 
the pessary removed prior to  28 weeks (57 patients, 14%).  Some of the reasons for removal 
suggest poor insertion or provider anxiety (lost pessary 7, contractions 5, pain 17).  A subgroup 
analysis suggested that there was benefit for multiple gestations where the cervical length was at 
the 25th percentile (38mm).   
 
1.3.2 Specific Content  
a)  A bibliography of all publications, whether adverse of supportive, that are relevant to 
an evaluation of the safety or effectiveness of the device, copies of all published and 
unpublished adverse information, and, if requested by an IRB or FDA, copies of other 
significant publications.  
 

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1: Carreras E, Arevalo S, Bello-Munoz JC, Goya M, Rodo C, Sanchez-Duran MA, Peiro 
JL, Cabero L. Arabin cervical pessary to prevent preterm birth in severe 
twin-to-twin transfusion syndrome treated by laser surgery. Prenat Diagn. 2012 
Dec;32(12):1181-5. doi: 10.1002/pd.3982. Epub 2012 Oct 11. PubMed PMID: 23055333. 
 
2: Goya M, Pratcorona L, Merced C, Rodo C, Valle L, Romero A, Juan M, Rodriguez 
A, Munoz B, Santacruz B, Bello-Munoz JC, Llurba E, Higueras T, Cabero L, Carreras 
E; Pesario Cervical para Evitar Prematuridad (PECEP) Trial Group. Cervical 
pessary in pregnant women with a short cervix (PECEP): an open-label randomised 
controlled trial. Lancet. 2012 May 12;379(9828):1800-6. Epub 2012 Apr 3. Erratum  
in: Lancet. 2012 May 12;379(9828):1790. PubMed PMID: 22475493. 
 
3: Ting YH, Lao TT, Law LW, Hui SY, Chor CM, Lau TK, Leung TY. Arabin cerclage 
pessary in the management of cervical insufficiency. J Matern Fetal Neonatal Med. 
2012 Aug 22. [Epub ahead of print] PubMed PMID: 22871155. 
 
 
4: Sieroszewski P, Jasinski A, Perenc M, Banach R, Oszukowski P. The Arabin 
pessary for the treatment of threatened mid-trimester miscarriage or premature 
labour and miscarriage: a case series. J Matern Fetal Neonatal Med. 2009 
Jun;22(6):469-72. PubMed PMID: 19530009. 
 
5: Arabin B, Halbesma JR, Vork F, Hubener M, van Eyck J. Is treatment with 
vaginal pessaries an option in patients with a sonographically detected short 
cervix? J Perinat Med. 2003;31(2):122-33. PubMed PMID: 12747228. 
 
6: Quaas L, Hillemanns HG, du Bois A, Schillinger H. [The Arabin cerclage 
pessary--an alternative to surgical cerclage]. Geburtshilfe Frauenheilkd. 1990 
Jun;50(6):429-33. German. PubMed PMID: 2198191. 
 
7. Liem S, Schuit E, Hegeman M, Bais J, de Boer K, Bloemenkamp K, Brons J, 
Duvekot H, Bijvank BN, Franssen M, Gaugler I, de Graaf I, Oudijk M, Papatsonis D, 
Pernet P, Porath M, Scheepers L, Sikkema M, Sporken J, Visser H, van Wijngaarden  
W, Woiski M, van Pampus M, Mol BW, Bekedam D. Cervical pessaries for prevention 
of preterm birth in women with a multiple pregnancy (ProTWIN): a multicentre, 
open-label randomised controlled trial. Lancet. 2013 Oct 19;382(9901):1341-9. 
doi: 10.1016/S0140-6736(13)61408-7. Epub 2013 Aug 5. PubMed PMID: 23924878. 
 
 
8. Liem SM, van Baaren GJ, Delemarre FM, Evers IM, Kleiverda G, van Loon AJ, 
Langenveld J, Schuitemaker N, Sikkema JM, Opmeer BC, van Pampus MG, Mol BW, 
Bekedam DJ. Economic analysis of use of pessary to prevent preterm birth in women 
with multiple pregnancy (ProTWIN trial). Ultrasound Obstet Gynecol. 2014 
Sep;44(3):338-45. doi: 10.1002/uog.13432. Epub 2014 Aug 7. PubMed PMID: 24898103. 
1.4  
Objectives of the clinical investigation 
1.4.1  Primary objective 
 
Frequency of preterm deliveries < 37 weeks 0 days gestation 

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1.4.2 
Secondary Objectives 
 Neonatal composite morbidity – fetal or neonatal death, respiratory distress 
syndrome (RDS), chronic lung disease, periventricular lucency, 
periventricular leukomalacia, intraventricular hemorrhage grade 3 or 4, 
necrotizing enterocolitis, early-onset-culture-proven sepsis 
 Neonatal length of stay 
 Neonatal NICU admission 
 Total NICU days 
 Duration of ventilator support  
 retinopathy of prematurity (ROP) requiring treatment 
 birthweight < 1500g and < 2500g 
 preterm birth < 34 weeks 
 gestational age at delivery  
 use of tocolysis 
 use of antenatal steroids  
 chorioamnionitis  
 vaginal bleeding 
 preterm premature rupture of membranes 
 cesarean delivery 
 
1.5  
Anticipated duration of the clinical investigation 
 
KUMC examines approximately 1900 patients in a year for cervical length screening in 
the 2nd trimester (our standard of care for more than 6 years).  Approximately 45 patients 
a year have cervical lengths < 25 mm.  
 
MUSC examines approximately  2-3 thousand patients per year with cervical length 
screening.  Approximately 60 patients a year have cervical lengths <25 mm. 
 
We expect 80% accrual rate into the study.  The expected duration of the study is ~ 4 
years. 
2.0 
CLINICAL PROTOCOL 
2.1 
Protocol number  
KUOBGYN001: Can the Arabin pessary prevent preterm birth in singleton pregnancies 
that have a short cervix? 
2.2 
Protocol version number and date  
April 24, 2015 

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2.3 
Study design 
2.3.1 
General study design 
This study is a randomized controlled trial.  It is not blinded to either investigator or 
patient.   
2.4 
Subject selection 
2.4.1 
General characteristics of the proposed subject population(s) 
The patients enrolled into this study are < 23 weeks 0 days pregnant and will have a 
cervical length < 25 mm detected by transvaginal ultrasound performed during universal 
screening at each institution participating in this trial.  These patients are seeking care at a 
tertiary care center, and in general have a higher risk profile compared to the community 
due to presence of maternal disease such as diabetes or hypertension or obstetric history 
such as prior preterm birth.  
The Arabin pessary is designed to reduce preterm birth in pregnant patients with a short 
cervix.  The suggested patients for this clinical trial exactly match the type of patients 
treated by the Arabin pessary.   
2.4.2 
Anticipated number of research subjects 
We plan to enroll 256 subjects in this study on a 1:1 basis.  Our research hypothesis is the 
proportion of preterm deliveries before 37 weeks 0 days gestation is reduced in the 
pessary group as compared to the control group.  Based on records of patients currently 
treated for short cervices here at KUMC and MUSC over the past year, the number of 
preterm birth before 37 weeks gestation is 30%.  In order to detect a reduction in half to 
15%, we require a  sample size of 242 subjects for analysis.  We experience about a 5% 
loss to follow up rate. We will use an intent-to-treat principle for analyzing the outcomes 
of the trial.  All enrolled patients will provide informed consent for study participation.  
 
2.4.3 
Inclusion criteria 
 
 Singleton pregnancy 
 Age 18 – 45y  
 Cervical length < 25 mm measured by transvaginal ultrasound prior to 23 weeks 0 
days 
 Agrees to refrain from sexual intercourse 
 
2.4.4  Exclusion criteria 
  
 Major fetal anomalies 
 Painful regular uterine contractions 
 Active vaginal bleeding 
 Ruptured membranes 

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 Evidence of chorioamnionitis or other serious maternal/fetal infectious morbidity 
 Placenta previa 
 Current progesterone therapy 
 Cervical cerclage in situ 
 Visual cervical dilation of 2 cm or greater with visible amnion/chorion 
 Significant maternal-fetal complications (insulin dependent diabetes mellitus, 
systemic lupus erythematosus patients with nephritis, chronic hypertension, red 
cell alloimmunization, drug abuse) 
 
The PECEP trial (Goya et al 2012) excluded patients with a history of prior cone biopsy.  
We feel that a history of prior cone biopsy is exactly the type of patient the pessary was 
designed to treat, a pregnancy at increased risk of preterm delivery due to a shortened 
cervix.  Anatomically, prior cone surgery can lead to a shortened cervix anatomically, 
which would preclude successful placement of the pessary.  Clearly, if a pessary cannot 
be placed, it will have no effect on outcomes.  On the other hand, if the cone surgery has 
not precluded the placement of the pessary due to anatomy, then we feel that these 
patients should be included in the study.  
 
Significant maternal-fetal complications are listed as an exclusion since they have 
increased risk of iatrogenic preterm delivery for reasons that have no relationship with 
the presence or absence of the pessary.  Insulin dependent diabetes with significant 
proteinuria, lupus patients with nephritis, chronic hypertensives with proteinuria all have 
increased risks for preeclampsia, intrauterine growth restriction, placental abruption and 
stillbirth which would impact the outcomes recorded in this study.  
 
 

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2.5 
Study procedures 
2.5.1 
Screening procedures 
 
Patients are identified for the study by universal cervical length screening performed by 
ultrasound during the 2nd trimester.  Once identified, patients are approached by study 
investigators who are authorized to obtain informed consent.  The counseling will take 
place in the privacy of the ultrasound suite or a private clinic room.  Both a medical 
history and physical exam are performed to verify if a patient meets criteria for 
enrollment in the study.  The physical exam includes a sterile speculum exam which 
investigates for vaginal or cervical infections in symptomatic patients.   
 
 
2.5.2 
Study treatment or diagnostic product procedures 
 
The treatment proposed in this study is the placement of the Arabin pessary around the 
cervix.  This device currently does not have FDA approval.  The company which 
manufactures the device in Europe has applied for FDA license.  A consultant report by 
NAMSA which describes the device, classification, safety, toxicity, and testing is 
included in this application.   
 
Patients in the experimental arm will have the Arabin pessary placed at time of 
enrollment.  First, they are assessed for uterine contractions by tocodynamometer.  To 
repeat, if symptoms of genital infection are present, the investigator will perfrom a sterile 
speculum exam and a wet mount and cervical cultures for gonorrhea/chlamydia will be 
obtained.  Any symptomatic infections are treated, and the pessary insertion is delayed a 
week.  Any infections resulting after pessary infection will also be treated.  When the 
pessary is placed, a sterile vaginal examination gel (non-antibiotic) will be used.  Once 
the pessary is placed, patients will return to clinic every 2 weeks for an evaluation.  A 
questionnaire will be filled out for symptoms, and a speculum exam performed to search 
for infections if the patient is symptomatic.  Fetal biometry will be performed monthly, 
and a transvaginal cervical length will be measured every 2 weeks.  The pessary will be 
removed if there are signs of tissue erosion of the cervix or vagina, intractable pain, or 
labor.  Otherwise, the pessary is removed at 37 weeks. 
 
The control arm will be followed with serial transvaginal ultrasounds to measure cervical 
length.  If the length decreases to less than 20 mm, then vaginal progesterone 200 mg will 
be prescribed from a local pharmacy.  If the cervical length continues to shorten such that 
membranes are visible at the os, then an emergent cerclage will be offered.  Treatments 
will not be offered after 24 weeks gestation.  Similar to the experimental group, patients 
will return to clinic every 2 weeks for an evaluation.  A questionnaire will be filled out 
for symptoms, and a speculum exam performed to search for infections if the patient is 
symptomatic. Fetal biometry will be performed monthly, and a transvaginal cervical 
length will be measured every 2 weeks.  
 

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All patients enrolled in the study are seen at the high risk pregnancy clinic at the 
participating institutions for evaluation.  The visit will be recorded in the electronic 
medical record.  The visit will include prenatal care.  Results are communicated back to 
the primary obstetrician by sending a copy of the clinic note back to the inbox of the 
primary obstetrician.   
2.5.3 
Allocation to treatment 
 
Patients will be assigned to their group based on a randomization scheme generated by a 
computer.  Randomization is first stratified by location of the institution, then by random 
blocks within each institution.  Once the assignment list is generated for each institution, 
the assignments are then placed in sealed, numbered, envelopes.   The patients are 
assigned on a 1:1 basis between the two groups.  
2.5.4 
Treatment adherence  
 
Patients are asked to return to clinic at frequent intervals for an evaluation that includes 
history, transvaginal ultrasounds, and physical exam if needed.  The pessary patients will 
return every 2 weeks after the pessary is placed.  The control patients will have a weekly 
transvaginal ultrasound up to 24 weeks, then a clinic visit every 2 weeks.   
2.5.5 
Withdrawal of subjects due to non-compliance 
 
An intent-to-treat analysis will be used for analyzing study results.  In the pessary group, 
if a patient removes the pessary, their outcomes will still be analyzed in the pessary 
group.  In the control group, if patients do not use vaginal progesterone, their results are 
still analyzed in the control group.  Patients who receive emergency cerclages are 100% 
compliant.   
 
If patients do not return for their clinic visits or their delivery information is lost, their 
data cannot be analyzed.  The investigators will call a minimum of 2 times, separated by 
a week, to ensure follow up.  If unsuccessful, a letter will be mailed to the address of 
record requesting follow up.  With regards to the primary outcome of preterm delivery, 
they will be assumed as having delivered the pregnancy at the gestational age they were 
lost to follow up.   
2.5.6 
Procedures to assess efficacy 
 
Patients are brought back to clinic for evaluation every 2 weeks.  They will fill out a 
questionnaire reviewing their symptoms, fetal biometry will be performed, and the 
cervical length will be measured by transvaginal ultrasound. A physical exam (including 
a sterile speculum exam) will search for cervical and vaginal infections if patients are 
symptomatic.  This information is recorded on the web-based case report form (CRF) 
built and stored by REDCap (www.project-redcap.org).  
 

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2.5.7 
Procedures to assess safety 
 
Patients are brought back to clinic for evaluation every 2 weeks.  They will fill out a 
questionnaire reviewing their symptoms, fetal biometry will be performed, and the 
cervical length will be measured by transvaginal ultrasound.  A physical exam (including 
a sterile speculum exam) will search for cervical and vaginal infections if patients are 
symptomatic.  This information is recorded on the REDCap CRF.  
 
2.5.8 
Schedule of study visits 
 
+ assume enrollment at 20 weeks 
* if needed 
 
+ assume enrollment at 20 weeks 
Schedule of 
Events for 
Pessary group+ 
Screening Visit 
Study Visits 
Visit 1,  
Day 0 
Visit 2, 
Day 7* 
Visit 3, 
Day 14 
Visit 4, 
Day 28 
Visit 5, 
Day 42 
Visit 6, 
Day 56 
Visit 7, 
day 70 
Visit 8, 
Day 84 
Visit 9, 
Day 98 
Visit 10, 
Day 112 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Medical history, 
demographics, and general 
health 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
Review of current 
medications 
X 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fetal biometry 
X 
 
 
X 
 
X 
 
X 
 
X 
TVCL 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Schedule of 
Events for  
Non-Pessary 
group+ 
Screening 
Visit 
 
Study Visits 
Visit 1,  
Day 0 
Visit 2, 
D 7* 
Visit 3, 
D 14 
Visit 4, 
D 21* 
Visit 5, 
D 28 
Visit 6, 
D 42 
 
Visit 7, 
D 56 
 
Visit 8, 
D 70 
 
Visit 9, 
D 84 
 
Visit 10 
D 98 
Visit 
11, D 
112 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Medical history, 
demographics, and 
general health 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review of current 
medications 
X 
 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fetal biometry 
X 
 
 
 
X 
 
X 
 
X 
 
X 
TVCL 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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* if needed 
 
2.6 
Study outcome evaluations 
2.6.1 
Study endpoints 
 
These are listed in sections 1.4.1 and 1.4.2.  To repeat, the primary outcome is a preterm 
delivery less than 37 weeks 0 days.   
2.6.2 
Sample size determination 
 
Based on KUMC hospital data, the number of preterm births < 37 weeks 0 days gestation 
in patients with short cervices (< 25 mm) is 30%.  In order to detect a reduction in half to 
15%, a sample size of 242 will be required to have power of 80% using a two-sided z-test 
assuming pooled variances.  Level of significance is set at 0.05. 
Based on records of patients currently treated for short cervices here at KUMC over the 
past year, we experience about a 5% loss to follow up rate.  Our sample size 
determination requires 242 subjects for analysis.  We plan to enroll a total of 256 
patients.  We will use an intent-to-treat principle for analyzing the outcomes of the trial.  
All enrolled patients will provide informed consent for study participation.  
2.6.3 
Outcome data and data analysis 
 
When patients are admitted to the hospital for delivery of the fetus, the research team will 
record the information listed on the REDCap CRF.  Both the mother and newborn 
hospital charts will be reviewed for the primary and secondary outcomes listed in 
sections 1.4.1 and 1.4.2.  If patients deliver at another hospital, those records will be 
obtained with the patient’s consent.   
 
De-identified data from each institution will be stored on the REDCap website.  That data 
will be downloaded into either Excel or SAS format for analysis.  This file will be stored 
in the folder of Gene Lee MD, on the network server named “Sydney”.  This drive is 
password protected.  Only members of the research team will be given access to the 
stored data.   
 
The primary endpoint and the categorical outcomes that are part of the secondary 
endpoints will be reported using frequency counts and proportions. For the secondary 
endpoints that are continuous variables, summary statistics such as mean and standard 
deviation, or median and inter-quartile range will be reported based on whether the 
assumption of normality is justified. A chi-square test (or a Fisher’s exact test) will be 
used to perform statistical comparison of proportions across the two groups. Likewise, 
comparisons for continuous outcomes will be done using a two-sample t-test (or 
Wilcoxon Rank Sum test) as will be deemed necessary.  For gestational age, we will also 
compare the Kaplan Meier survival curves of the two groups (control and pessary) using 
the logrank test.  Level of significance for all statistical tests will be set at 0.05. 

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As mentioned before, subjects lost to follow up will have the gestational age at delivery 
set at the point data was lost.  An intent to treat analysis will then be performed.  A 
sensitivity analysis will be conducted by omitting the incomplete data and recalculating 
the differences between the pessary and control groups.  The changes in results will then 
be compared.  
 
The Arabin pessary will be considered a success if the following conditions are met: 1) a 
statistically significant reduction of preterm birth is found in the group treated with the 
Arabin pessary, 2) the number of patients with incomplete data does not exceed 10%.  If 
a statistically significant difference is observed, but missing data is equal or greater than 
10%, then additional study with a larger sample size is warranted.    
 
3.0 
RISK ANALYSIS 
3.1 
Anticipated risks 
The primary physical risks of this study are  
1) the pessary fails to reduce preterm birth 
2) cervical amputation due to tight pessary constriction of the cervix 
3) erosion of maternal tissue 
4) maternal discomfort  
5) vaginal infections 
6) vaginal discharge, which may be mistaken for rupture of membranes 
7) pain at insertion and/or removal 
8) improper pessary placement 
The risks are minimized by  
1) This clinical trial is conducted after a large Spanish RCT suggested that the 
pessary is a better treatment than any current therapy.  Rather than testing the 
pessary for the first time, our trial has the goal of confirming the prior Spanish 
results in a Midwest USA regional setting.  
2) Patients are evaluated every 2 weeks for symptoms of pain, abnormal vaginal 
discharge, and infections.  A questionnaire is completed, and a speculum exam to 
directly assess the cervical and vaginal tissue is performed as needed.  Nitrazine, 
ferning, and pooling will be performed as needed to diagnosed rupture of 
membranes correctly.  The pessary is removed if there are concerning signs of 
trauma, erosion, intractable pain, and bleeding.  The NAMSA report reiterates the 
known safety of silicone pessaries (p8-9, 10-11).  
3) Providers are taught how to insert and remove the pessary by instructional videos 
sponsored by Dr. Birgit Arabin, the inventor of the device.  In addition, pain 

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experienced at insertion and/or removal will be treated with narcotic 
administration as needed.   
Risk benefit analysis:  
This study is conducted to confirm results of a larger RCT already concluded 
internationally.  Those results strongly suggest that the pessary is more effective than any 
current therapy.  These potential benefits outweigh the concerns for untreated short 
cervix with resulting preterm birth.  The concern of tissue erosion is extremely low 
(please reference NAMSA report, p8-9, 10-11). These benefits accrue directly to the 
individual, and in aggregate, to society as a result. 
3.2 
Adverse event reporting  
3.2.1 
Adverse event definitions 
Unanticipated adverse device effect (UADE): Any serious adverse effect on health or 
safety or any life-threatening problem or death caused by, or associated with, a device, if 
that effect, problem, or death was not previously identified in nature, severity, or degree 
of incidence in the investigational plan or IDE application (including a supplementary 
plan or application), or any other unanticipated serious problem associated with a device 
that relates to the rights, safety, or welfare of subjects. 
Associated with the investigational device: There is a reasonable possibility that the 
adverse effect may have been caused by the investigational device. 
Life-threatening adverse effect: Any adverse effect that places the subject, in the view 
of either the investigator or the sponsor, at immediate risk of death from the effect as it 
occurred.  It does not include a reaction that, had it occurred in a more severe form, 
might have caused death. 
Serious adverse effect: An adverse effect is considered “serious” if, in the view of either 
the investigator or the sponsor, it results in any of the following outcomes:  
 death  
 a life-threatening AE 
 inpatient hospitalization or prolongation of existing hospitalization 
 a persistent or significant disability/incapacity 
 a congenital anomaly/birth defect. 
Unanticipated adverse effect: Any adverse effect, the nature, specificity, severity, or 
frequency of which is not consistent with the risk information in the clinical study 
protocol or elsewhere in the current IDE application. 
3.2.2  Eliciting adverse effect information 
Clinical study subjects will be routinely questioned about adverse effects at study visits. 
3.2.3  Recording and assessment of adverse effects 
All observed or volunteered adverse effects (serious or non-serious) and abnormal test 
findings, regardless of treatment group, if applicable, or suspected causal relationship to 

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the investigational device or, if applicable, other study treatment or diagnostic product(s) 
will be recorded in the subjects’ case histories.  For all adverse effects, sufficient 
information will be pursued and/or obtained so as to permit 1) an adequate determination 
of the outcome of the effect (i.e., whether the effect should be classified as a serious 
adverse effect) and; 2) an assessment of the casual relationship between the adverse effect 
and the investigational device or, if applicable, the other study treatment or diagnostic 
product(s).    
Adverse effects or abnormal test findings felt to be associated with the investigational 
device or, if applicable, other study treatment or diagnostic product(s) will be followed 
until the effect (or its sequelae) or the abnormal test finding resolves or stabilizes at a 
level acceptable to the sponsor-investigator. 
3.2.4 
Abnormal test findings 
An abnormal test finding will be classified as an adverse effect if one or more of the 
following criteria are met: 
 The test finding is accompanied by clinical symptoms 
 The test finding necessitates additional diagnostic evaluation(s) or medical/surgical 
intervention; including significant additional concomitant drug or other therapy  
(Note: simply repeating a test finding, in the absence of any of the other listed 
criteria, does not constitute an adverse effect.) 
 The test finding leads to a change in study dosing or exposure or discontinuation of 
subject participation in the clinical study 
 The test finding is considered an adverse effect by the sponsor-investigator 
 
3.2.5 
Causality and severity assessment 
The sponsor-investigator will promptly review documented adverse effects and abnormal 
test findings to determine 1) if the abnormal test finding should be classified as an 
adverse effect; 2) if there is a reasonable possibility that the adverse effect was caused by 
the investigational device or other study treatments; and 3) if the adverse effect meets the 
criteria for a serious adverse effect. 
If the sponsor-investigator’s final determination of causality is “unknown and of 
questionable relationship to the investigational device or other study treatments,” the 
adverse effect will be classified as associated with the use of the investigational device or 
other study treatments for reporting purposes.  If the sponsor-investigator’s final 
determination of causality is “unknown but not related to the investigational device or 
other study treatments,” this determination and the rationale for the determination will be 
documented in the respective subject’s case history.  
3.2.6 
Reporting adverse effects to the FDA 
For any observed or volunteered adverse event that is determined to be a UADE, the 
sponsor-investigator will submit an expedited safety report to the FDA’s Center for 
Devices and Radiological Health.  The expedited safety report will consist of: 
 a completed Form FDA 3500A  

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 a cover letter analyzing the significance of the event   
A copy of this safety report will be provided to all participating study investigators.   
The completed Form FDA 3500A and cover letter will be submitted to the FDA as soon 
as possible and, in no event, later than 10 working days after the sponsor-investigator first 
receives notice of the adverse effect. 
If, following receipt and investigation of follow-up information regarding an adverse 
effect that was previously determined not to be a UADE, the sponsor-investigator 
determines that the event does meet the requirements for expedited reporting, the 
sponsor-investigator will submit a completed Form FDA 3500A and cover letter as soon 
as possible, but in no event later than 10 working days, after the determination is made. 
Subsequent to the initial submission of a completed FDA Form 3500A, the sponsor-
investigator will submit additional information concerning the reported adverse effect as 
requested by the FDA. 
3.2.5 
Reporting adverse effects to the responsible IRB 
For any adverse event determined to be a UADE, the sponsor-investigator will submit the 
completed Form FDA 3500A and cover letter to the IRB as soon as possible and, in no 
event, later than 10 working days after the sponsor-investigator first receives notice of the 
adverse effect. 
Follow-up information to reported adverse effects will be submitted to the IRB as soon as 
the relevant information is available.   
3.3 
Withdrawal of subjects due to adverse effects 
Patients are evaluated every 2 weeks for symptoms of pain, abnormal vaginal discharge, 
and infections.  A questionnaire is completed, and a speculum exam to directly assess the 
cervical and vaginal tissue is performed as needed.  Nitrazine, ferning, and pooling will 
be performed as needed to diagnosed rupture of membranes correctly.  The pessary is 
removed if there are concerning signs of trauma, erosion, intractable pain, and bleeding.   
 
Patients whose pessaries are removed are still analyzed in their assigned group according 
to an intent-to-treat analysis.  Their outcomes and complications are recorded similar to 
other subjects.  They are not replaced.  
4.0 
DESCRIPTION OF THE INVESTIGATIONAL DEVICE 
 
Please see NAMSA report for description of cytotoxicity, sensitization, irritation, acute 
systemic toxicity, subchronic systemic toxicity, genotoxicity, implantation, chronic 
systemic toxicity in detail.  
 
In this study, the Arabin pessary will be for single patient use only. Each enrolled patient 
will be given their own new pessary. The patient will use the same pessary throughout the 
length of the study.    

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Please see MEDCERT certificates for information regarding manufacturing, quality 
management, and distribution. Pessaries are stored at room temperature and do not 
require special packaging.  The principal investigators “install” the pessaries after they 
are appropriately trained by a video tutorial.   
 
The following description is modified from http://www.dr-arabin.de/e/cerclage/html 
 
The Arabin pessary is a ring manufactured from medical grade silicone. It has outer and 
inner diameters that vary, a height when laid flat, and a curvature to one side of the 
pessary.  The width of the outer and inner diameters are chosen depending on the 
individual constitution of the pregnancy patient.  The curvature of the pessary is upwards 
so that the pelvic floor supports the larger diameter.  The smaller, inner diameter 
encompasses the cervix.  After application the pessary changes the inclination of the 
cervical canal, directing it more posteriorly (figure 1). Thus the weight of the pregnancy 
is more on the anterior lower segment, as can be observed by TVS in selected cases. The 
use of a spreading gliding compound facilitates pessary insertion.  The silicone material 
is inert and does not react with the vaginal epithelium or cervical epithelium.  The 
silicone pessary does not change during its placement in the vaginal canal.  In general, 
singleton pregnancies require a pessary height of 21-25 mm, and multiple pregnancies 
require a pessary height of 25-30 mm.  
 
There are 13 sizes of the Arabin cervical pessary, differing by their outer diameter, inner 
diameter, and height.  The investigators will be appropriately trained according to 
instructional videos.  If insufficient, there are provision plans to be trained in person by 
the manufacturer.  The pessary size will be selected based on a best fit to the patient’s 
anatomy.  This proper fit will help obviate the risk of cervical amputation.   
 
 
 
 
Figure 1 
  
5.0 
MONITORING PROCEDURES 
 

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Independent monitoring of the study for compliance with the clinical protocol and with 
IDE regulations will be conducted periodically by qualified staff of the University of 
Kansas Medical Center.  The data from both sites will be reviewed every 6 months by the 
designated medical monitor for the study, Vishal Pandey MD.  Dr. Pandey will not be 
blinded as he is searching for adverse events occurring in the pessary group.  In addition, 
Gene Lee MD and John Moore RN, a research coordinator assigned to the study,  will 
conduct monthly chart audits at KUMC to compare clinic, hospital, and research records 
for accuracy of data entry.  Eugene Chang MD will conduct monthly chart audits at 
MUSC.  If an adverse event is encountered, reporting to the Human Subjects Committee 
(HSC) at KUMC and the FDA will occur as detailed in section 3.2.  Principal 
investigators who are notified of possible adverse events will also proceed as detailed in 
section 3.2. 
 
Medical Monitor Contact Information: 
Vishal Pandey, MD 
Neonatologist 
University of Kansas Medical Center 
3901 Rainbow Boulevard 
Kansas City, KS 66160 
Phone: 913-588-6337 
Email: vpandey@kumc.edu 
Fax: 913-588-6317 
 
The medical monitor is specifically chosen outside of the department of OBGYN to 
allow for objectivity.  
 
Adverse events which would require immediate suspension of study for review would 
include an excess of 1 maternal death, 1 maternal ICU admission for sepsis, or  2 
perinatal deaths in the pessary group.   
 
Unanticipated adverse events will be reported immediately to the HSC, and its 
recommendations for temporary cessation or continuation of the study will be followed.  
If an excess of 4 perinatal deaths occur in the pessary group, the study should be 
concluded.   
6.0 
LABELING 
 
The investigators will attach a label to the outside of the package containing the pessary.   
 
The labeling will contain the statement "CAUTION - Investigational Device.  Limited by 
Federal (or United States) Law to Investigational Use.  This device is for single patient 
use only" [§ 812.5(a))].  
 
Copies of the labels are provided in this submission. Refer to label for more information. 

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7.0 
INFORMED CONSENT 
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH 
GCP, US Code of Federal Regulations for Protection of Human Subjects (21 CFR 
50.25[a,b], CFR 50.27, and CFR Part 56, Subpart A), the Health Insurance Portability 
and Accountability Act (HIPAA, if applicable), and local regulations. 
 
The Sponsor-Investigator will prepare the informed consent form and provide the 
documents to IRB for approval.  The written consent document will embody the elements 
of informed consent as described in the International Conference on Harmonisation and 
will also comply with local regulations. The Sponsor-Investigator will retain an IRB-
approved copy of the Informed Consent Form in the study master file. 
 
A properly executed, written, informed consent will be obtained from each subject prior 
to entering the subject into the trial.  Information should be given in both oral and written 
form and subjects must be given ample opportunity to inquire about details of the study.  
A copy of the signed consent form will be given to the subject and the original will be 
maintained with the subject’s records. 
8.0 
IRB INFORMATION 
The study will be submitted and reviewed by the Human Subjects Committee (IRB) at 
the University of Kansas Medical Center and Medical University of South Carolina prior 
to starting any study activities.  UADEs will be reported to the IRB in accordance with 
the standard operating procedures and policies of the IRB, and the Sponsor-Investigator 
will keep the IRB informed as to the progress of the study.  The Investigator will obtain 
assurance of IRB compliance with regulations. 
Any documents that the IRB may need to fulfill its responsibilities (such as protocol, 
protocol amendments, device information, consent forms, information concerning patient 
recruitment, payment or compensation procedures, or other pertinent information) will be 
submitted to the IRB.  The IRB’s written approval of the study protocol and the informed 
consent form will be in the possession of the Investigator before the study is initiated.   
Protocol and/or informed consent modifications or changes may not be initiated without 
prior written IRB approval except when necessary to eliminate immediate hazards to the 
patients or when the change(s) involves only logistical or administrative aspects of the 
study.  Such modifications will be submitted to the IRB and written verification that the 
modification was submitted and subsequently approved should be obtained.   
The IRB must be informed of revisions to other documents originally submitted for 
review; new information that may affect adversely the safety of the patients of the 
conduct of the study; an annual update and/or request for re-approval; and when the study 
has been completed. 

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9.0 
ADDITIONAL RECORDS AND REPORTS   
9.1 
Data handling and record-keeping 
Case report forms (copies of the CRFs are provided as attachment) will be completed for 
each subject enrolled into the clinical study.  The sponsor-investigator will review, 
approve and sign/date each completed CRF; the sponsor-investigator’s signature serving 
as attestation of the sponsor-investigator’s responsibility for ensuring that all clinical and 
laboratory data entered on the CRF are complete, accurate and authentic.   
 
Source Data are the clinical findings and observations, laboratory and test data, and other 
information contained in Source Documents.  Source Documents are the original records 
(and certified copies of original records); including, but not limited to, hospital medical 
records, physician or office charts, physician or nursing notes, subject diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, x-rays, etc.  When applicable, information recorded on the CRF shall match 
the Source Data recorded on the Source Documents.   
 
Case reports forms were created using REDCap. REDCap is a secure, web-based 
application for building and managing online surveys and databases. Data will be entered 
and maintained in the REDCap system. Access to the system will be limited to only 
persons on the study team that are involved in the collection and management of study 
data. 
 
9.2 
Record maintenance and retention  
The sponsor-investigator will maintain records in accordance with 21 CFR 812, Subpart 
G, to include: 
 
FDA correspondence related to the IDE application and Investigational Plan; 
including copies of submitted Form FDA 3500A, supplemental IDE applications, 
current investigator lists, progress reports, notice of device recall or disposition, and 
failure to obtain informed consent reports 
 
IRB correspondence (including approval notifications) related to the clinical 
protocol; including copies of adverse event reports and annual or interim reports 
 
Current and past versions of the IRB-approved clinical protocol and corresponding 
IRB-approved consent form(s) and, if applicable, subject recruitment 
advertisements 
 
Signed Investigator’s Agreements and Certifications of Financial Interests of 
Clinical Investigators 
 
Curriculum vitae (sponsor-investigator and clinical protocol sub-investigators) 
 
Certificates of required training (e.g., human subject protections, Good Clinical 
Practice, etc.) for sponsor-investigator and listed sub-investigators 
 
Normal value(s)/range(s) for medical/laboratory/technical procedures or tests 
included in the clinical protocol 
 
Laboratory certification information 

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 
Instructions for on-site preparation and handling of the investigational device and/or 
study treatment or diagnostic product(s), and other study-related materials (i.e., if 
not addressed in the clinical protocol) 
 
Master randomization list  
 
Signed informed consent forms 
 
Completed Case Report Forms, signed and dated by sponsor-investigator 
 
Source Documents or certified copies of Source Documents 
 
Monitoring visit reports 
 
Copies of sponsor-investigator correspondence to sub-investigators, including 
notifications of adverse effect information 
 
Subject screening and enrollment logs 
 
Subject identification code list 
 
Investigational device accountability records, including documentation of device 
disposal 
 
Interim data analysis report(s) 
 
Final clinical study report. 
 
The sponsor-investigator will retain the specified records and reports for up to two years 
after the marketing application is approved for the investigational device; or, if a 
marketing application is not submitted or approved for the investigational device, until 
two years after investigations under the IDE have been discontinued and the FDA so 
notified. 
 
10.0  Addition or removal of investigators 
Any investigators added to the protocol must sign the investigator agreement prior to 
inclusion as a member of the study team.  Investigators can be removed from the study 
team as needed.