Clinical trial NCT02225353
Conditions: Preterm Birth
Keywords: Preterm birth Short cervix Cervical Pessaries Progesterone
Sponsor: Grünenthal GmbH
Start date: 2013-09-02; Completion date: 2017-03-13
Enrollment: 271 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Assess the efficacy of 2 Cervical Pessaries containing 6.3 g and 7.7 g micronized progesterone for the prevention of preterm delivery, established through spontaneous birth before gestation weeks 32 (31 weeks and 6 days) and 34 (33 weeks and 6 days), when the pessary is inserted during weeks 16th and 24th and removed at 36 weeks and 6 days in pregnant women at high risk of premature birth.

Detailed description:
Participant selection will be performed by screening the general population of pregnant women with single fetus monitored by the Hospital Healthcare Network, to investigate by serial transvaginal ultrasound performed between gestation weeks 16 (0 day to 7 days) and 24 (0 day to 7 days) those patients who have a cervical length between 10 mm and 25 mm, and/or women with a single fetus and cervical length ≥10 mm presenting one or more of the following risk factors:

1. preterm birth prior to 35 (34 weeks and 6 days) weeks of gestation;
2. premature rupture of membranes prior to 35 (34 and 6 days) weeks of gestation.

After insertion of the pessary or beginning of the administration with vaginal progesterone capsules and until 28 weeks of gestation, participants in the 3 treatment groups will be monitored every 4 weeks at the most or more often, if the site has established so as a control standard. After 28 weeks, patients should be monitored every 2 weeks.

The proportions of spontaneous preterm delivery before gestation weeks 32 and 34 will be compared between the control group and the 2 groups with the pessaries containing different doses of progesterone.

Arms: arm 1: 90 pregnant women with Progesterone Cervical Pessary arm 2: 90 pregnant women with Progesterone Cervical Pessary arm 3: 90 pregnant women using Progesterone 200 mg vaginal capsules daily
Interventions: intervention 1: Progesterone Cervical Pessary 6.3 g intervention 2: Progesterone 200 mg vaginal capsules intervention 3: Progesterone Cervical Pessary 7.7 g
Intervention descriptions: intervention 1: Progesterone Cervical Pessary low dose intervention 2: Progesterone 200 mg vaginal capsules daily intervention 3: Progesterone Cervical Pessary high dose

Protocol documents:
Prot_000.pdf: 
A Randomized, Open-Label, Controlled, Multi-Center Study on the 
Efficacy of a Sustained Release Progesterone Cerclage Cervical 
Pessary at Doses of 6.3 g or 7.7 g for the Prevention of Preterm Birth 
and a Maximum Duration of 20 Weeks. 
 
NCT Number: 02225353 
Protocol ID: EC12012/10IEI-9339 
Date of Document:  16 May 2016 
 
 


Version 3 -May 16, 2016
Clinical Protocol: PCP 002
A Randomized, Open-Label, Controlled, Multi-Center Study on the 
Efficacy of a Sustained Release Progesterone Cerclage Cervical 
Pessary at Doses of 6.3 g or 7.7 g for the Prevention of Preterm Birth 
and a Maximum Duration of 20 Weeks
Research Sites:
Instituto de Investigación Materno Infantil (IDIMI) –Maternidad Hospital Clínico 
San Borja Arriarán (HCSBA).
UNICERH, South Department of Obstetrics & Gynecology –School of Medicine
UCHHospital Barros Luco-Trudeau.
Centro de Investigación e Innovación en Medicina Materno Fetal (CIMAF) -
Complejo Asistencial Dr. Sótero del Río (CASR)
East Department of Obstetrics & Gynecology –School of Medicine UCH Hospital 
Dr. Luis Tisné Brousse.
Study Phase: II
Sponsor:
Laboratorio Andrómaco S.A.
Avenida Quilín N° 5273, Peñalolén, Santiago




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SYNOPSIS
Protocol Number
PCP 002
Title
A Randomized, Open-Label, Controlled, Multi-Center Study on 
the Efficacy of a Sustained Release Progesterone Cerclage 
Cervical Pessary at Doses of 6.3 g or 7.7 g for the Prevention of 
Preterm Birth and a Maximum Duration of 20 Weeks
Sponsor and Phase
Andrómaco -Phase II
Type of Investigation 
Medical Device
Type of Study
Interventional
Study location
1. Instituto de Investigación Materno Infantil (IDIMI) –
Maternidad Hospital Clínico San Borja Arriarán (HCSBA).
2. UNICERH, South Department of Obstetrics &Gynecology –
School of Medicine UCHHospital Barros Luco
3. Centro de Investigación e Innovación en Medicina Materno 
Fetal (CIMAF) -Complejo Asistencial Dr. Sótero del Río (CASR).
4. East Department of Obstetrics & Gynecology –School of 
Medicine UCH Hospital Dr. Luis Tisné Brousse.
Primary Objective of 
the Study
To assess the efficacy of Cerclage Pessaries containing 6.3 g or 
7.7g of micronized progesterone for the Prevention of Preterm 
Birth, established through spontaneous parturition before 
gestation weeks 32 (31 6/7) and 34 (33 6/7), when the pessary is 
inserted between weeks 16 and 24 and removed at 36 6/7 weeks 
of gestation in pregnant women at risk of preterm birth.
Secondary Objectives of 
the Study
To record the occurrence of premature rupture of membranes 
before gestation weeks 32 (31 6/7) and 34 (33 6/7).
To assess anatomical cervix features in pregnant women: 
position and length.
To establish the acceptability and tolerance of the use of the 
Cerclage Pessary by pregnant women.
To evaluate local and systemic safety in pregnant women 
using the Cerclage Pessary.
Study Design
Randomized, open-label, controlled clinical study of efficacy.
Study population
Inclusion Criteria
Exclusion Criteria
Voluntary patients:
1.Women with single pregnancy and a cervical length of 10 mm -
25 mm between 16 and 24 weeks of gestation, without any 
previous risk factors.
2.Women with single pregnancy and a cervical length ≥ 10 mm 
between 16 and 24 weeks of gestation, and pre-existing risk 
factors for preterm birth:
Previous preterm birth before week 35.
Previous rupture of membranes before week 35.
1. Pregnancies with:
Major fetal abnormalities, such as lethal malformations 
or malformations requiring pre-or post-natal surgery, 
and fetal death before randomization.
History of rupture of membranes or prophylactic 


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cerclage in the current pregnancy before inclusion into 
the study.
Planned number of 
participants
2. Cervical or vaginal injuries prior to insertion of the pessary 
(e.g. cervical erosion secondary to trauma, infection or carcinoma, 
vesicovaginal or rectovaginal fistulas).
3.Unconscious, severely ill, mentally disabled patients, or under 16 
years of age.
4. Patients for whom use of progesterone is contraindicated.
5. Patients with history of thrombosis.
A sample consisting of 270 pregnant women at risk of preterm 
birth, with useful information for the analysis and recruited in the 
4 participating sites. This population will be divided into 3 groups 
of treatment, with 90 participants each.
The 3 groups of the clinical trial are: One control group with 
progesterone 200 mg vaginal capsules and 2 study groups with 2 
different doses of progesterone in the pessaries.
Investigational Product
Cerclage pessaries containing 6.3 g or 7.7g of sustained-release 
micronized progesterone each.
Outcomes to be 
evaluated
Primary
Secondary
Determination of the effective dose of progesterone in the 
cerclage pessary through the occurrence of spontaneous birth 
before 32 (31 6/7) and 34 (33 6/7) weeks of gestation.
Occurrence of rupture of membranes:
Premature rupture of membranes before 32 (31 6/7) and 34 
(33 6/7) weeks of gestation.
Cervical anatomic changes
1. Cervical length and internal cervical os dilation before and after 
inserting the pessary.
2. Cervical position in relation to the uterus longitudinal axis 
before and after inserting the medicated pessary.
Acceptability:
1. Ease of insertion
2. Pain of the patient at the time of insertion
3. Assessment based on the VAS during use
4. Spontaneous expulsion of the pessary
5. Request for early removal of the pessary
6. Subjective changes of vaginal discharge
Local safety:
Major maternal complications attributable to the pessary 
(chorioamnionitis, severe vaginal or cervical trauma).
Length of the Study 
21 –48 months 


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2
RATIONALE
Nowadays, prematurity is a central issue both for obstetrics as well as for public 
health worldwide, as it is a highly incident clinical situation (affecting approximately 7% to 
10% of births), and is involved in around 50 -75% of neonatal morbidities and mortalities, 
mainly in neonates born before 32 weeks of gestation. Sequelae in premature neonates also 
impact on the increase of healthcare costs and infant mortality during the first year of life 
(1).
The rate of preterm births has not declined over the last 20 years, and in most 
developed countries it remains high despite advances in the knowledge about risk factors 
and mechanisms related to preterm births (2). Essentially, there are two reasons that explain 
the failure to reduce preterm births: first, the absence of a screening method effective for the 
identification of women at high risk for this event; and second, the lack of effective 
intervention to prevent this complication.
The most commonly adopted approach for identification of pregnancies at high risk 
for preterm birth has been the use of obstetrical history and mother’s demographics.
In published screening studies where over 60,000 women with single pregnancies 
were included, the preterm birth rate by week 34 in England was 1.8%, very similar to that 
found in our country (1.3%). Preterm births were spontaneous in two-thirds of the cases 
(1.2% of the total), whereas one-third were iatrogenic. Only in 3% of cases, the patients had 
a history of preterm birth and this group accounted for 15% of the total number of 
spontaneous deliveries by week 34 only. This demonstrates that identification of patients at 
risk of delivery before week 34 based on obstetric history leaves most of these patients 
outside of the risk group, and therefore, not covered by preventive measures.
An effective method for prenatal screening to detect the risk of preterm birth is the 
measurement of the cervical length by ultrasound between gestation weeks 20 and 25. The 
risk of preterm birth both for single-fetus as well as for twin pregnancies is inversely related 
to the cervical length. Therefore, a woman with a cervical length (CL) between 1-10 mm 
has a risk of preterm birth of 44%, whereas a woman with a CL between 26-30 mm has a 
risk of 1.3%. The group with cervix measures of 1 to 15mm corresponded to 28% of all 
spontaneous deliveries before week 34, and the group with a cervix measure of 16 to 25 
mm corresponded to 21% (3).
In addition to the myriad of scientific evidence available from the studies above, they 
allow to state that the lower a certain cervical length in the second trimester of pregnancy, 
the higher the risk of spontaneous preterm birth both in single and twin pregnancies (4). 
However, there is still no consensus on the accurate definition for "short cervix" during 
gestation related to preterm birth risk prediction. Almost every women before 14 weeks of 
gestation including those at increased risk of preterm birth will have a normal cervical 
length (CL). A CL of 25 mm at this gestational age is only seen in women with a history of 
miscarriage in the second trimester, or who have undergone cervical surgery (cone). A CL 
in the range of 25-50 mm is normal between 14 and 24 weeks in all pregnant women. In 
women at low risk of preterm birth, the mean CL between 14-30 weeks of gestation is 35-
40 mm, and the 10th percentile is 25 mm, while the 90th percentile lies in 50 mm. The 
optimal timing for measurement of the CL by transvaginal ultrasound should be accurately 
established since, if performed before 14 weeks, a separate visualization of the cervix from 
the lower uterine segment may be very difficult. In addition, after week 30, the cervix is 


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progressively shortened in preparation for a full-term delivery, so in asymptomatic women, 
a CL <25 mm after 30 weeks is physiological and indicative of a non-preterm birth (5).
Most women who have a preterm birth display a shortened neck for the first time 
approximately between 18-22 weeks of gestation, so the initial examination should be 
conducted at least within that period. Besides the already established inverse relationship 
between CL and the risk of preterm birth, the earlier the cervix is shortened during 
gestation, the higher the likelihood of a preterm birth. In women at higher risk, a CL <25 
mm has apositive predictive value of 70% for preterm birth before 35 weeks when detected 
at 14-18 weeks, and 40% when detected at 18-22 weeks (5). In the same line of evidence, 
Vaisbuch et al. (4) recently demonstrated an approximate two-fold risk of delivery before 
28 or 32 weeks if CL is ≤15 mm before 20 weeks (76.9% and 80.8%) versus 20-24 weeks 
(30.9% and 48.1%). Overall, this evidence suggests that starting the screening of patients 
with cervix measurements earlier than week 18 and using a 25-mm CL limit to determine 
the need for an intervention as discussed in this clinical study might entail a greater 
advantage.
Preventing the Preterm Birth
The traditional practice for prevention of preterm birth is the administration of 
tocolytics to patients threatened to, or into premature labor. Although tocolytics 
administration has been used for several decades, systematic reviews of randomized studies 
have reported no improvement in the neonatal outcome with the administration of such 
agents or a decrease in the frequency of preterm births (7). Prophylactic administration of 
progesterone to women with a history of preterm birth and to those with short cervix and 
single-fetus pregnancy in mid-gestation has shown to significantly reduce the rate of 
spontaneous preterm birth (about 40-45% less) before week 33-34. However, there are 55-
60% of patients remaining with shortened cervix who likewise and despite progesterone 
administration, gave birth by week 34 (8-10), which is in line with the multi-causal nature 
of this condition in humans.
Progesterone mechanism of action to prevent preterm births seems to be related in 
part with a local anti-inflammatory effect that stops or slows-down the pathway of 
biochemical events involved in cervical maturation and, on the other hand, by means of a 
mild inhibitory effect of uterine contractions (13).
The cervical cerclage surgical procedure has also been proposed as a prevention 
alternative in pregnant patients with single-fetus and short cervix. However, results in 
patients without previous history of cervical incompetence are still controversial. A recent 
publication shows that results in the prevention of preterm birthusing cerclage for the 
indication of short cervix are similar in the group in which cerclage is indicated on the basis 
of the obstetric history. Thus, there would not be a rationale for expecting the cervical 
shortening to occur in order to perform the procedure (14). On the other hand, multiple 
observational studies and a recent randomized clinical study in patients with short cervix 
before 24 weeks of gestation show that the placement of a cerclage pessary (without 
surgery) significantly reduces the riskof preterm birth as compared to control patients (15-
17). Previous evidence suggests that a mechanical factor—probably a cervical distension 
and/or pressure on the inner cervical os—seems to be also related to early cervical maturity 
and the risk of preterm birth.


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Under normal conditions, an immature cervix in a pregnant woman is displaced 
posteriorly toward the sacrum, whereby the intrauterine and fetal presentation pressure are 
exerted on the uterine segment and not on the inner cervical os
(18), thus preventing early dilatation.
Cerclage Pessary without Drug Substance
The cerclage pessary mechanism of action in the prevention of preterm birth has not 
been fully elucidated. Theoretically, the effect of the pessary is based on its mechanical 
capability to displace the cervix posteriorly, hence slightly increasing the cervix length and 
changing the angle of the cervical uterus. All these variations not only reinforce the cervical 
canal, but also reduce the likelihood for membranes to make contact with the vaginal 
environment, thus contributing to preserve its integrity (20). An additional benefit of the 
cerclage pessary may be that it contributes to maintain the immunological barrier between 
the extraovular chorio-amniotic space and the microbiology flora in the vagina–a 
mechanism similar to that postulated for surgical cerclage.
 
 
In a paired-analysis, retrospective study on women with twin 
pregnancies and a cervical length below the 10th percentile by routine ultrasound, 23 cases 
were treated with the pessary and 23 received expectant management. The spontaneous 
delivery rate before week 32 was 0% in the group with pessary and 30% in the control 
group (p <0.001). In the same study, 12 women with single pregnancies were treated with 
the pessary and other 12 were treated with expectant management. The spontaneous preterm 
birth rate before week 36 was 0% in the group with pessary and 50% in the control group (p 
<0.001) (16). There are many other observational or case-control studies about the use of 
pessaries for preventing preterm birth. These studies date back to 1959 and have resulted in 
a promising absence of severe adverse effects (23).
A recent study that included 385 patients with single-fetus pregnancies and shortened 
cervix confirms the findings above, even though the magnitude of reduction in the 
prematurity rate for the control group appears to be disproportionately high (17, 20).
 
 
 
 
Development of a Cerclage Pessary containing Sustained-Release Progesterone
 
 
 
 
 
 
 
 


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On the basis of the same principle, the development of a cerclage pessary containing 
progesterone, which is released in a sustained manner upon implantation around the cervix, 
has been initiated. 
 
 
Characteristics of the Cerclage Pessary with Sustained-Release Progesterone
 
 
 
 
 
 
3
STUDY OBJECTIVES
Primary Objective:This is a Phase II clinical study to assess the efficacy of two cerclage 
pessaries containing 6.3g and 7.7g of sustained-release micronized progesterone for the 
prevention of preterm birth, established by spontaneous delivery before gestation weeks 32 
(31 6/7) and 34 (33 6/7) when the pessary is inserted between weeks 16 and 24 and 
removed in gestation week 36 6/7, in pregnant women at risk of preterm birth.
Secondary Objectives:
•
To record occurrence of premature rupture of membranes before gestation weeks 32 
and 34.
•
To assess anatomical cervix features in pregnant women: position and length.
•
To establish acceptability and tolerance in pregnant women using the Cerclage 
Pessary.
•
To evaluate local and systemic safety in pregnant women using the Cerclage Pessary.


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4
STUDY DESIGN
The study will be conducted in compliance with the protocol, the good clinical 
practice standards, and the provisions of the corresponding ethics committee.
This will be a randomized, open-label, controlled, multicenter, exploratory Phase II 
study of efficacy. Pregnant patients with a single fetus who after reading the informed 
consent voluntarily agree to participate in the study will be included.
For secondary outcomes, patients will be their own controls on the following 
endpoints to be tested: cervix anatomical features—position and length—; plasma and 
endometrial progesterone concentrations in non-pregnant menopausal women; surveys on 
pregnant women to establish the acceptability and tolerance of the intervention; and local 
and systemic safety issues.
4.1. Pregnant Volunteers: 270 + 10% pregnant women at risk of preterm birth from the 4 
participating sites will be recruited. This population will be divided into 3 treatment groups 
with 90 participants each.
They will be informed and invited to participate in the study at prenatal and/or ultrasound 
control between 16 and 24 weeks of gestation. Volunteers will be included in all cases up to 
24 (0/0) weeks of gestation. Volunteers will be selected on the basis of their clinical history 
and by transvaginal ultrasound performed between weeks 16 and 24. All volunteers with a 
single pregnancy and cervical length ≤25 mm but ≥10 mm will be invited to participate in 
the study. Prior to inclusion in the study, fetal vitality or other exclusion factors discussed in 
detail below will be confirmed. Those patients who do not agree to participate in the study 
will receive the current standard care at each participating site depending on their condition.
4.1.1. Inclusion criteria in pregnant volunteers:
Pregnant women with a single fetus with a cervical length of 10-25 mm between 
16 and 24 weeks of gestation with no pre-existing risk factors.
Women with ongoing pregnancy between 16 and 24 weeks of gestation with a 
single fetus and cervical length ≥10mm, and having pre-existing risk factors in 
the immediately previous pregnancy characterized by:
-
Preterm birth before week 35 (with a viable fetus).
-
Premature rupture of membranes before week 35 (with a viable fetus).
4.1.2. Exclusion criteria in pregnant volunteers

Pregnancies with:
-
Major fetal abnormalities in the current pregnancy such as: lethal 
malformations, or requiring pre-or post-natal surgery; and fetal death prior 
to randomization.
-
History of rupture of membranes or prophylactic cerclage in the current 
pregnancy before inclusion into the study.

Cervical and/or vaginal injuries prior to insertion of the pessary (e.g., 
cervical erosion secondary to trauma, infection or carcinoma, 
vesicovaginal or rectovaginal fistulas).

Unconscious, severely ill, mentally disabled patients, or under 16 years 
of age.

Patients for whom use of progesterone is contraindicated.

Participants with history of thrombosis.


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5
PROCEDURES
5.1. Recruitment and Screening
Patients will participate voluntarily and under informed consent. Participant selection 
will be performed by screening the general population of pregnant women with single fetus 
monitored by the Hospital Healthcare Network, to investigate by serial transvaginal 
ultrasound performed between gestation weeks 16 (0/7) and 24 (0/7) those patients who 
have a cervical length between 10 mm and 25 mm, and/or women with a single fetus and 
cervical length ≥10 mm presenting one or more of the following risk factors: a) preterm 
birth prior to 35 (34 6/7) weeks of gestation; b) premature rupture of membranes prior to 35 
(34 6/7) weeks of gestation.
Gestational age will be determined by the last menstruation date and will be 
confirmed by measurement of the craniocaudal length obtained in the first trimester 
ultrasound, or by measurement of the cephalic circumference in the second trimester 
ultrasound predominating the actual date of the last menstrual period (LMPad).
The selected volunteers will be examined and those with vaginal discharge will 
undergo clinical examination and/or bacteriological investigation and if confirmed for 
infection, this will be treated with the appropriate antibiotic. In these cases, insertion of the 
sustained-release progesterone cerclage pessary will be performed subsequent to the end of 
treatment although before 24 (0/1) weeks of gestation.
5.2. Study groups
Patients will be randomly assigned to the following 3 study groups:
-Control study group: They will be instructed to administer a micronized progesterone 
200mg capsule by vaginal route on a daily basis.
-Pessary study group A: They will have a pessary with 6.3g of sustained-release 
progesterone inserted for a period of about 4 to 5 months. This procedure will be 
performed by a professional qualified and trained for these purposes.
-Pessary study group B: They will have apessary with 7.7 g of sustained-release 
progesterone inserted for a period of about 4 to 5 months. This procedure will be 
performed by a professional qualified and trained for these purposes.
5.3. Randomization
The randomization program will be generated by an independent statistician. This 
program will be linked in sequential numbers with the treatment code randomly assigned. 
The randomization plan will be kept by a qualified person from Laboratorio Andromaco 
until the database is clean and ready for analysis. Treatment will be dispensed according to 
the randomization plan. Women with single pregnancy chosen will be randomized to 
receive one of the vaginal formulations of the study. For the next volunteer, the Site will 
have the next randomized number available. Each woman will receive only the formulation 
corresponding to their randomization number. The investigator will record on the file the 
randomization number and the code printed on every formulation container. The 
coordinator of each site will assignthe randomization code to the volunteers.


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5.4. Intervention and follow-up
The intervention and follow-up of participants will begin after the conditions eligible 
to participate in the study are verified, proceeding as follows:
5.4.1. For selected participants with pre-existing risk factors, these are: immediately 
previous pregnancy terminated prematurely with preterm birth, or premature rupture 
of membranes before 35 weeks of gestation; placement of a progesterone cerclage 
pessary, or treatment with progesterone capsules will start at week 16 (0/7) but not 
beyond 24 (0/7) weeks of gestation. These participants will have a transvaginal 
ultrasound performed to document the length (≥10 mm) and position of the cervix at 
the placement of the pessary or the start of treatment with vaginal progesterone 
capsules.
5.4.2. For pregnant patients with a single fetus, selected for the presence of a 
shortened cervix (between 10 mm and 25 mm), the pessary will be inserted or the 
vaginal administration of progesterone capsules will be started at the time of the 
investigation, but not before 16 (0/7) weeks of gestation and not after 24 (0/7) weeks 
of gestation. The cervix angulation relative to the uterus body using the intersection 
of the uterus posterior wall longitudinal axis with the cervical canal axis in addition 
to a measurement of the cervical length will be performed on 60% of the study 
participants assigned to one of the two groups with medicated pessary, prior to 
insertion of the pessary and after its insertion, by means of a transvaginal ultrasound 
technique recently described (25). The transvaginal ultrasonography post-insertion of 
the pessaries may be performed at visit one or at visit two at the latest.
5.4.3. After insertion of the pessary or beginning of the administration with vaginal 
progesterone capsules and until 28 weeks of gestation, participants in the 3 treatment 
groups will be monitored every 4 weeks at the most or more often, if the site has 
established so as a control standard. After 28 weeks, patients should be monitored 
every 2 weeks. At every control visit, procedures applicable to their prenatal control 
and a transvaginal ultrasound by standard technique will be performed (patients 
receiving vaginal capsules), if considered necessary by the physician, or transvaginal 
using the technique recently described (25) (in patients with medicated pessary) to 
measure and record cervical length. The occurrence of possible side effects, 
adherence to treatment, and visits or hospitalizations due to threat or preterm labor 
will also be recorded, as well as the existence of potential causes for ex-post
exclusion from the study. In addition, concomitant medication will be recorded at 
each visit.
5.4.4 Management of participants consulting due to a threat or premature labor will 
be conducted according to the diagnostic and therapeutic guidelines of the Ministry 
of Health (MINSAL) (Clinical Guide for Preventing Preterm Birth -MINSAL 2010) 
and the respective hospital’s Obstetrics and Gynecology Service. In these cases,the 
treating physician will be provided with information about the progesterone treatment 
the patient is receiving in the study, and the decision for her continuation in the 
clinical study will be made jointly as far as possible, since the opinion of the treating 
physician shall predominate.
5.4.5 Every case will be closed at 36 6/7 weeks of gestation, or at the time of preterm 
birth. Data on the birth, condition at birth, and evolution of infants born preterm will 
be analyzed, recording morbidity and mortality through the time of discharge from 
the hospital.
The participant’s attending health team (physicians and midwives) will be informed in 
writing about the participation of these women in the study by means of an identification 


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card that will be given to every woman participating in the study. In the pregnancy card, 
participation of these subjects in the study will be emphasized by means of a self-adhesive 
sticker detailing their participation in one of the treatment groups (pessary or capsule) and 
recorded in the medical history.
5.5. Placement and repositioning of the cerclage pessary containing sustained-release 
progesterone
Once the cervix length and positioning have been examined by transvaginal 
ultrasound, and any vaginal infection has been ruled out or treated, the progesterone pessary 
should be implanted by a professional qualified and trained for that purpose. For placement, 
the participant must be lying in supine position. 
 
 
 
 
 
 The removal of the pessary will be done by vaginal 
examination at week 36 6/7 or earlier, if there is any medical indication for induction of
premature labor or elective cesarean section. The pessary will also be removed from 
participants in preterm birth labor not responding to treatment with tocolytics.
During controls or visits to emergency departments or medical offices, participants 
who report vaginal discharge should be examined by a physician to rule out infection by 
relevant testing (vaginal discharge smears for PCR), and deliver the appropriate treatment 
without the need to remove the pessary. This condition will be considered an adverse event.
In the event that the medicated cerclage pessary is spontaneously expelled it, will be 
repositioned within maximum 72 hours; if this does not occur, the patient will be withdrawn 
from the study but considered in the final statistical analysis under the intention-to-treat 
principle.
5.6. Adherence and resuming the treatment in patients assigned to the group treated with 
vaginal progesterone capsules.
Use of capsules at least during 80% of the exposure time, and resuming the treatment 
not later than72 hours after discontinuation for any cause will be considered an acceptable 
adherence to treatment. If adherence of a patient is below 80% or the treatment is 
interrupted for more than 72 hours, she will be withdrawn from the study but considered in 
thefinal statistical analysis.
5.7. Study participant withdrawal
The progesterone cerclage pessary will be removed if the patient requests so, or if 
there is any adverse event not responding to treatment alternatives such as pathological 
vaginal discharge non-responsive to antibiotic therapy. These participants will not be 
replaced and the information collected from them will be included in the analysis since this 
is based on the intention-to-treat principle.
Follow-up of subjects withdrawn from the investigational product will be the same as 
the standard follow-up.


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5.8. Recording, quality control, and data management
Information about the characteristics of the participants, including demographics 
(race, age, parity, measures for calculation of body mass index [BMI]), and the medical and 
obstetrical records will be obtained directly from the participants and recorded in the study 
file. Information about the outcome of the pregnancy will be obtained from the hospital’s 
medical records file or treating physician. Medical records of participants experiencing 
preterm birth labor before weeks 32 and 34 will be reviewed to determine the cause and 
establish whether the delivery was because of medical indication or spontaneous. 
Spontaneous deliveries will include thosewith prior preterm labor and those with rupture of 
membranes before the onset of labor. Quality control for screening, information 
management, and monitoring of adherence to protocol across the four sites will be 
performed regularly by the clinical study monitor.
6
MATERIALS AND SUPPLIES 
Cerclage pessaries containing sustained-release progesterone will be manufactured by 
Laboratorios AndrómacoS.A. Both the pessaries as well as the 200 mg progesterone soft 
capsules to be administered by vaginal route will be supplied to participants free of charge 
by Laboratorios Andrómaco S.A.

Vaginal formulations of the study:
-
Capsules containing 200 mg of micronized progesterone for vaginal 
administration.
- 
Vaginal device consisting of a cerclage pessary containing 6.3g of sustained-
release progesterone.
-
Vaginal device consisting of a cerclage pessary containing 7.7 g of sustained-
release progesterone.
Laboratorios Andrómaco S.A. will be responsible for printing the applicable codes on 
every container of study formulation.
7
OUTCOMES OF INTEREST
7.1. Primary Outcomes:
Determination of the progesterone effective dose in the cerclage pessary by non-
occurrence of spontaneous delivery before 32 and 34 weeks of gestation.
7.2. Secondary Outcomes:
7.2.1. Occurrence of rupture of membranes:
7.2.1.1. Premature rupture of membranes before 32 and 34 weeks of gestation.
7.2.2. Cervical anatomic changes
7.2.2.1. Cervical length before and after the insertion of the progesterone pessary.
7.2.2.2. Cervix positionrelative to the longitudinal axis of the uterusbefore and after 
insertion of the progesterone pessary considering that this measurement 
may be performed on the same day of the pessary insertion or at Visit 2.


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7.2.2.3. Measurement of the utero-cervical angle formed by the posterior wall of the 
uterus and the longitudinal axis of the cervix before and after insertion of 
the progesterone pessary.
7.2.3 Acceptability
7.2.3.1 Ease of insertion. Measured by means of a questionnaire.
7.2.3.2. Pain of the patient at the time of insertion and during use of the pessary. The 
VAS will be applied from 1 to 10 at Visit 1 (admission, where questions 1 
to 3 will be answered) and at the final study visit (where questions 4 and 
onwards will be answered).
7.2.3.3. Request for early removal of the pessary. Date, gestational age and reason for 
the pessary removal request will be recorded in the data record file.
7.2.3.4. Spontaneous expulsion of the pessary: Date and gestational age at the time of 
expulsion of the pessary without replacement will be recorded in the data 
record file.
7.2.3.5. Changes in vaginal discharge. The participant will be questioned about the 
presence, quantity, and physical characteristics of the discharge at every 
control visit. The clinical signs and symptoms of the patient will also be 
recorded.
7.2.4. Local safety
7.2.4.1. Pain, irritation, pruritus, infection occurring in the patient during treatment.
7.2.4.2. Major maternal complications attributable to the pessary such as 
chorioamnionitis, severe vaginal or cervical trauma.
8
ADVERSE EVENTS
An adverse experience is defined as an unfavorable and unexpected change in the 
structure, function, or chemistry of the body, transiently associated with the use of the study 
product, whether or not related to the use of the drug. Any worsening (i.e., any adverse 
change clinically significant in terms of frequency or severity) of a pre-existing condition 
that is transiently associated with use of the study product is also an adverse experience.
Adverse eventswill be documented from the time of enrollment (i.e., at the time of 
signing the informed consent form) through the last scheduled contact as per the protocol, 
i.e., the date of the last visit/contact (may be a phone call, for example, in case the 
participant withdraws from the study).
Definition of Serious Adverse Event (SAE)
A SAE is any medical incidence that, at any dose:

Results in death; or

Is life-threatening (puts the subject, from the investigator
's perspective, in an 
immediate risk of death due to the experience that took place. This includes direct 
life-threatening experiences but not those that could potentially put life at risk), or

Requires or prolongs hospitalization of the patient (hospitalization is defined as an 
admission, regardless of length of stay, even if hospitalization is a precautionary 
measure in order to continuously monitor the patient). If this hospitalization is due 
to a non-worsening pre-existing condition, it is not to be considered as a serious 
adverse experience.


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
Results inpersistent or significant inability/disability (major impairment to the 
ability to perform daily life functions); or

Is an abnormal congenital defect or birth defect

Is considered a clinically significant medical event
A scheduled hospital admission, for example, for elective surgery, is not considered a 
SAE if documented at the time of enrollment.
All patients randomized in the study are pregnant women, therefore, hospitalizations 
related to scheduled parturitions/full term deliveries will not be considered as adverse 
events nor as serious or relevant adverse events.
Definition of Adverse Event of Special Interest
Adverse events of special interest are adverse events considered important for 
assessment of the safety profile regardless of seriousness, expectancy, and severity 
classification.
Preterm birth is the birth of a fetus before 37 weeks of pregnancy. Preterm birth will be 
considered an event of special interest and should consequently be reported within 24 hours.
Expected Adverse Events
Expected Adverse Events will be evaluated by the Sponsor.
An unexpected adverse event is one where the nature or severity is not consistent with the 
information contained in the relevant source document, i.e. the Investigator Brochure.
In addition, reports that add significant information about the specificity or seriousness 
of a known, already documented adverse reactionare unexpected adverse events. For 
example, an adverse event more specific or more serious than expected would be 
considered "unexpected."
Definition of Adverse Drug Reactions
An Adverse Drug Reaction is any harmful and undesirable response to an 
Investigational Medicinal Product (IMP) or drug, regardless of the dose administered.
All adverse events reported by subjects spontaneously at any time point should also be 
documented.
All adverse events should be documented in the CRF with the following information 
according to the case:
•Description (adverse events reported within the term)
•Start date
•End date or continuation
•Whether the adverse event was serious
•Severity


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•Outcome
•Mitigation actions
•Causal relationship with the IMP
•Definition of severity
The clinical severity of an adverse event will be classified as:
Mild:
The signs and symptoms can be easily tolerated. Symptoms may be ignored and 
disappear when the subject is distracted.
Moderate
Symptoms cause discomfort but are tolerable, not ignorable, impairing concentration 
ability
Severe
Symptoms affecting daily life activities.
For adverse events where intensity changes over time, the maximum intensity observed 
throughout the adverse event will be documented.
Adverse events that occur during the enrollment period, but prior to the first 
administration of the IMP and worsen during or after administration of the IMP will be 
documented as new adverse events.
Definition of outcomes at the time of the last observation of the adverse event
The outcome at the time of the last observation will be classified as:

Recovered/Resolved

Recovering/Resolving

Not recovered/Not resolved

Recovered/Resolved with sequelae

Fatal

Unknown (unknown should only be used if, at the time of the subject’s last visit in 
a trial, the outcome of the adverse event is unknown to the investigator, for 
example, because the subject was a lost to follow-up)
Definition of the mitigation actions:
None:
No mitigation actions have been provided
Start of new 
medication:
Start of new medication or change in the dosage or route of 
administration of a drug due to an adverse event (which will be 
listed before/concomitantly with the medication sheet) that is used 
as a mitigation action.
Interruption of 
the study:
Discontinuation of the subject participation in the study was 
required due to an adverse event.
Other:
Allother mitigation actions, e.g., physical therapy, surgery.


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With the exception of “none”, multiple mitigation actions can be taken for an adverse 
event.
Classification of causality:
The causal relationship of an adverse event to the investigational product will be 
classified according to terminology as follows. The proposed criteria for each term are to be 
considered and not exhaustive and neither are required to be entirely fulfilled for choosing 
the respective term:
Terms for 
classification of 
causality 
Criteria for choosing causality classification terms
Conditional/Unclassifi
ed
Additional data for proper evaluation are under examination.
Not Evaluable/Not
Assessment of available data may not be performed because the 
information is insufficient or contradictory, and may not be 
Classifiable:
supplemented or verified.
Unrelated:
Data with sufficient evidence to accept that there is no causal 
relationship with the administration of the IMP (i.e., there is no 
time relationship with the administration of the investigational 
product or another cause has been proved).
Not possible:
Data without sufficient evidence to accept that there is no causal 
relationshipto the administration of the IMP, though neither with 
evidence or argument to suggest a causal relationship (e.g., the 
temporal relationship with the administration of the investigational 
product makes a causal relationship unlikely and other drugs, 
chemicals, or underlying disease[s] provide plausible explanations).
Possible:
Data or a foundation with limited evidence suggesting a causal 
relationship (e.g. existence of a reasonable time sequence with the 
administration of the drug, but the adverse event could also be 
explained by concurrent disease[s] or other drugs or chemicals. 
Information regarding drug abstinence may not exist or be unclear).
Probable/Possible
Data or a foundation of enough evidence to suggest a causal 
relationship (e.g. existence ofa reasonable time sequence with 
administration of the drug, the adverse event is unlikely to be 
attributed to concurrent disease[s] or other drugs or chemicals, and 
the response regarding dechallenge is clinically reasonable).
Certain
Data with evidence of a causal relationship (i.e., a clinical event, 
including alterations in laboratory tests, occurs under a plausible 
relationship with the time of administration of the drug, and 
simultaneous disease or other drugs or chemical substances may not 
explain it. Response to drug dechallenge should be well-defined 
and clinically plausible, using a successful rechallenge procedure 
where appropriate).
Follow-up of subjects with an adverse event


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Follow-up on any clinically relevant, laboratory abnormality, or vital signs result adverse 
event will be performed until a satisfactory solution or stabilization is reached, or the 
clinical evaluation indicates that an additional evaluation is not warranted.
Reporting serious adverse events
Any serious adverse event (SAE) regardless of cause, occurring to any woman admitted 
into the study, must be notified by the Principal Investigator within 24 hours to 
DrugSafetyCOE@grunenthal.com,and to the respective Institutional Review Boards. 
These reports should include all supporting documentation available (with the name of the 
subject crossed out) for each event, the summary of the hospital discharge.
The Technical Director of Laboratorios Andrómaco S.A., Rodrigo Jara 
will communicate the SAE to the local health regulatory authorities. Every SAE 
must be followed until it is completely characterized. This report must be sent earlier than 2 
days after the study staff were notified of the event.
The Principal Investigator must submit a report called a Security Report Form (SRF), 
which includes a description of the event, the therapy initiated, and the testing procedures. The 
following information must be reported with the first report of a SAE:

Study identification

Subject identification

Subject’s dateof birth (if available) or age (at the onset of the adverse event)

Gender of the subject

Indicate whether the condition was pre-existing or not, and if so, if it worsened

First administration of the IMP (date and time, if available)

Last administration ofthe IMP (date and time, if available)

Brief description of the event, and mitigation arrangements taken, actions undertaken 
(does the adverse experience cause the study drug to be discontinued or interrupted?)

Maximum intensity

SAE severity criteria

Outcome

Concomitant medication at the onset of the event and if one of the concomitant 
medications is also suspected of having caused the event

Relevant history/pre-existing medical condition

The relationship with the study drug evaluated by the Investigator (determination of 
causality: Is the study drug the cause of the adverse experience?)
Any additional information relating to the adverse event until the termination of the 
trial or the final result shall be reported in the follow-up report without delay.
9
STATISTICS
This project aims to conduct a randomized, open-label, controlled, clinical-exploratory 
phase II study evaluating the efficacy of a cerclage pessary containing one of 2 doses of 
sustained-release micronized progesterone for prevention of preterm birth, compared to the 
treatment method currently used by obstetrics-gynecology specialists, which comprises the 
administration of one daily capsule by vaginal route of 200 mg of progesterone. A total of 


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270 pregnant participants at risk of preterm birth will be enrolled, screened, and randomized 
to the 3 groups of treatment previously described. The number of patients listed (n = 270) 
refers to the number of patients who effectively are enrolled and successfully complete the 
study. Therefore, an enrollment of at least 10% over that number (27 patients or more) 
should be considered due to the eventual withdrawal or early loss to follow-up of patients 
initially recruited.
As primary results, the proportions of spontaneous preterm delivery before gestation
weeks 32 and 34 will be compared between the control group and the 2 groups with the 
pessaries containing different doses of progesterone. The risk of spontaneous preterm birth 
from the time of inclusion in the study through the gestation weeks 32 and 34 will be 
determined by a Kaplan-Meier analysis
21, where gestational age will be the time scale and 
spontaneous delivery will be the event; elective parturitions will be censored. For the 
purpose of this analysis, pregnancies will no longer be considered as high risk for the event 
if delivery occurs at the week of gestation 34 (34 0/7) or beyond.
As secondary outcomes, those qualitative variables in pregnant participants at risk of 
preterm birth will be evaluated, and the percentage distribution of acceptability responses or 
side effects recorded will be determined. For the quantitative variables (measurements of 
length and cervical angulation), the averages and standard deviations of the values found 
will be compared. Accordingly, each participant will work as her own control.
9.1. Sample Size
The calculation of the sample size is based on the power to detect differences in the 
proportion of spontaneous delivery before 32 and 34 weeks of gestation between the 
cerclage pessary formulations with respect to the control group (vaginal capsules containing 
200 mg progesterone). Collecting data from at least 90 women in each group will provide a 
power of at least 80% to detect differences at a rate of 40% or more using a two-tailed test 
with α=0.05 for a non-correctedChi square.
We estimate that up to 10% of enrolled women may not complete the study, so it is 
planned to enroll at least 99 pregnant women per group to reach at least 198 treated with the 
cerclage pessaries, and 99 treated with soft progesterone capsules as control group (i.e., 99 
per vaginal formulation).
9.2. Statistical analysis
For quantitative variables, descriptive statistics will be used (mean, standard deviation, 
minimum, median, maximum, 95% CI, and number of observations), whereas for 
categoricalvariables, frequencies and percentages analyses will be carried out. Results will 
be tabulated by treatment arm and pooled. The different vaginal formulations and 
progesterone will be formally compared. Results on efficacy and safety will be studied for 
each group separately and pooled, if relevant.
The proportion of women reporting adverse events during treatment will be cross-
compared between the different doses using the Fisher
's exact test or the Chi-square test.
All statistical analyses will be performed using the statistical software SPSS (Version 
12) or Epistat 4.0.


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10
STUDY OVERSIGHT
A Study’s Steering Committee will be established and constituted by the medical 
advisor, clinical monitor, CORFO project Director, 
The Study’s Steering Committee is responsible for overseeing the 
progress of the study, adherence to the protocol, safety of the participants and discussion of 
new information relevant to the study.
Study Coordinators/CORFO project Director, code 
 
Medical advisor
 
Principal Investigator
At each participating site, a physician specialized in Obstetrics and Gynecology will be 
fully responsible for conducting the study at his/her site. The Principal Investigator will also 
be responsible for recruiting patients and ensuring that the study is conducted in accordance 
with the protocol and the Good Clinical Practice guidelines.
Dr. Ariel Fuentes García at the Instituto de Investigación Materno Infantil (IDIMI) 
–Maternidad, Hospital Clínico San Borja Arriarán (HCSBA).
Dr. Pablo Lavín Acevedo at the UNICERH, South Department of Obstetrics & 
Gynecology 
–
School 
of 
Medicine
UCHHospital Barros Luco
Dr. Christian Figueroa Lassalle at the CIMAF-CASR
Dr. Angélica Díaz at the Department of Obstetrics & Gynecology located at the 
Hospital Luis Tisné Brousse
11
ETHICAL CONSIDERATIONS
The sponsor of the study is Laboratorios Andrómaco S.A.
According to the established in Chile, recruitment of patients for this type of studies is 
governed by Act 20120. Before any procedure or intervention takes place, the informed 
consent form must be signed.
According to scientific evidence currently available, this study is classified as a 
“minimum risk” study for the patients and their unborn children.
12
PROTOCOL AMENDMENTS
Any substantial amendment to this protocol requires approval from the Independent 
Ethics Committee prior to its implementation.
13
ACCESS TO THE DATABASE/DOCUMENTS
Participating investigators and institutions will have access to controls, audits, 
reviews, and regulatory inspections by the entities governing the study, and will provide 
required data and documents safeguarding the identity of the participating patients.


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References
1.Guía 
Clínica 
Prevención 
Parto 
Prematuro 
MINSAL 
2010: 
http://www.minsal.gob.cl/portal/url/item/721fc45c972f9016e04001011f0113bf.pdf
2.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 J Obstet 
Gynecol. 2006; 194:1360-5.
3.To MS, Skentou CA, Royston P, Yu CK, Nicolaides KH. Prediction of patient-specific 
risk of early preterm delivery using maternal history and sonographic measurement of 
cervical length: a population-based prospective study. Ultrasound Obstet Gynecol 2006; 27: 
362-7
4.Vaisbuch E, Romero R, Erez O, Kusanovic JP, Masaki-Tovi S, Gotsch F, Romero V, 
Ward C, Chaiworapongsa T, Mittal P, Sorokin Y and Hassan S. Clinical significance of early 
(<20 weeks) vs. late (20–24 weeks) detection of sonographic short cervix in asymptomatic 
women in the midtrimester. Ultrasound Obstet Gynecol 2010; 36: 471-481
5.Maria Teresa Mella, MD, and Vincenzo Berghella, MD. Prediction of Preterm Birth: 
Cervical Sonography. Sem Perinatol 2009; 33: 317-324
6.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 J Obstet 
Gynecol. 2006; 194:1360-5.
7.A.P. Kenyon, D. Peebles. Myth: Tocolysis for prevention of preterm birth has a major 
role in modern obstetrics. Seminars in Fetal & Neonatal Medicine 2011; 16: 242-246
8.Dodd JM, Crowther CA, Cincotta R, Flenady V and Robinson JS. Progesterone 
supplementation for preventing preterm birth: a systematic review and meta-analysis. Acta 
Obstet Gynecol Scand 2005; 84: 526-533
9.Berghella V. Novel developments on cervical length tamizaje and progesterone for 
preventing preterm birth. BJOG 2009;116:182–187.
10.S. S. Hassan, R. Romero, D. Vidyadhari, S. Fusey, J. K. Baxter et al. Vaginal 
progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a 
multicenter,
randomized, double-blind, placebo-controlled trial. Ultrasound in Obstetrics & Gynecology, 
2011; 38, (1):18–31.
11.Suneet P. Chauhan, MD; James A. Scardo, MD; Edward Hayes, MD; Alfred Z. 
Abuhamad, MD; Vincenzo Berghella, MD. Twins: prevalence, problems, and preterm births. 
American Journal of Obstetrics & Gynecology, 2010 Oct; 203(4): 305-15
12.Rouse DJ, Caritis SN, Peaceman AM, Sciscione A, Thom EA, Spong CY, Varner M, 
Malone F, Iam JD, Mercer BM, Thorp J, Sorokin Y, Carpenter M, Lo J, Ramin S, Harper M, 
Anderson G; National Institute of Child Health and Human Development Maternal-Fetal 
Medicine Units Network. A Trial of 17 Alpha-Hydroxyprogesterone Caproate to prevent 
prematurity in twins. N Engl J Med 2007; 357:454-61.
13.Jayasooriya, GS and Lamont, RF . The use of progesterone and other progestational 
agents to prevent spontaneous preterm labour and preterm birth. Expert Opin. Pharmacother. 
2009; 10(6): 1007-1016
14.Simcox R, Seed PT, Bennett P, et al. A randomized controlled trial of cervical scanning 
vs history to determine cerclage in women at high risk of preterm birth (CIRCLE trial). Am J 
Obstet Gynecol. 2009; 200(6):623.e1-6.
15.Newcomer J. Pessaries for the treatment of incompetent cérvix and premature delivery. 
Obstet Gynecol Surv 2000; 55: 443-48
16.Arabin B, Halbesma JR, Vork F, Hübener M, van Eyck J. Is treatment with vaginal 
pessaries an option in patients a sonographically detected short cervix? J Perinat Med 2003; 
31: 122-33
17.Maria Goya, Laia Pratcorona, Carme Merced, Carlota Rodó, Leonor Valle, Azahar 
Romero, Miquel Juan, Alberto Rodríguez, Begoña Muñoz, Belén Santacruz, Juan Carlos 
Bello-Muñoz, Elisa Llurba, Teresa Higueras, Luis Cabero, Elena Carreras, on behalf of the 
Cervical Pessary to Avoid Prematurity (PECEP) Trial Group. Cervical pessary in pregnant 


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Protocol PCP 002
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women with a short cérvix (PECEP): an open-label randomised controlled trial. Lancet 2012; 
379, (9828): 1800-6
18.Berghella V, Bega G, Tolosa JE, Berghella M. Ultrasound assessment of the cervix. Clin 
Obstet Gynecol. 2003 Dec;46(4):947-62.
19.Induction of Labor. ACOG Practice Bulletin. Obstetrics&Gynecology August 2009; Vol. 
114, No. 2, Part 1.
20.Caritis, SN. Cervical pessary use and preterm birth: how little we know. Lancet 2012; 
379, (9828): 1769-70
21.Sivin, I., Mishell, DR Jr., et al. A multicenter study of levonorgestrel-estradiol 
contraceptive vaginal rings. I. Use effectiveness". Contraception 1981; 24:341-348.
22.Díaz, S., Jackanicz, T.M. et al. Fertility regulation in nursing women.VIII. Progesterone 
plasma levels and contraceptive efficacy of a progesterone-releasing vaginal ring. 
Contraception 1985; 32:603-622.
23.Cross RG. Treatment of habitual abortion due to cervical incompetence. Lancet 1959; 2: 
127.
24.Lachelin G, McGarrigle H, Seed P, Briley A, Shennan A, Poston L. Low saliva 
progesterone concentrations are associated with spontaneous early preterm labour (before 34 
weeks of gestation) in women at increased risk of preterm delivery. BJOG 
2009;116(11):1515-9
25.Goya M, Pratcorona L, Higueras T, Perez-Hoyos S, Carreras E, Cabero L. Sonographic 
cervical length measurement in pregnantwomen with a cervical pessary. Ultrasound Obstet 
Gynecol 2011; 38: 205–9.

SAP_001.pdf: 
A Randomized, Open-Label, Controlled, Multi-Center Study on the 
Efficacy of a Sustained Release Progesterone Cerclage Cervical 
Pessary at Doses of 6.3 g or 7.7 g for the Prevention of Preterm Birth 
and a Maximum Duration of 20 Weeks. 
NCT Number: 02225353 
Protocol ID: EC12012/10IEI-9339 
Date of Document:  12 May 2017 


 
Confidential 
Page 1 of 16 
 
 
STATISTICAL ANALYSIS PLAN 
 
Protocol PCP 002 / PHASE II 
 
Multicenter, controlled, open label and randomized study, about the efficacy of a vaginal 
cerclage pessary with sustained release of progesterone, in doses of 6.3 g or 7.7 g, for the 
prevention of Premature Birth, with a maximum duration of 20 weeks 
 
Research Product  
Cerclage Pessaries containing 6,3 g or 7,7 g of  
sustained release of micronized progesterone in each 
 
Prepared for 
Grünenthal México 
Prepared by: 
 
 
Colonia del Valle 
México DF 03100 
 
May 12, 2017 / Version 3 
 
 
APPROVED BY: 
 
 
SIGNATURE  
 
 
DATE 
 
  
 
 
    
 
Head of Clinical Products Development for Latin America 
 
 


PCP 002 / FASE II 
 
Versión: 3.0 
Date: 12May2017 
Statistical Analysis Plan 
Confidential 
Page 2 of 16 
 
CONTENTS 
 
1. 
INTRODUCTION ........................................................................................................................................... 3 
2. 
OBJECTIVES ................................................................................................................................................. 3 
PRIMARY ....................................................................................................................................................................... 3 
SPECIFICS .................................................................................................................................................................... 3 
3. 
STUDY DESIGN ............................................................................................................................................ 3 
EVALUATION VISITS ................................................................................................................................................... 4 
SAMPLE SIZE ................................................................................................................................................................ 4 
RANDOMIZATION ........................................................................................................................................................ 4 
4. 
DOCUMENTS AND CHANGE OF VERSIONS ........................................................................................ 5 
CHANGES IN THE PLAN .............................................................................................................................................. 5 
5. 
ANALYSIS CONVENTIONS ........................................................................................................................ 5 
GENERAL PRINCIPLES ................................................................................................................................................ 5 
DATABASE MANAGEMENT ......................................................................................................................................... 7 
6. 
POPULATION DEFINITIONS ...................................................................................................................... 7 
7. 
SUBJECT DISPOSITION ............................................................................................................................. 7 
PROTOCOL DISCONTINUATIONS ............................................................................................................................. 7 
8. 
DEMOGRAPHY AND POPULATION CHARACTERISTICS .................................................................. 7 
MEDICAL HISTORY...................................................................................................................................................... 8 
PHYSICAL EXAM .......................................................................................................................................................... 8 
VITAL SIGNS ................................................................................................................................................................ 8 
GYNECOLOGICAL EXAM ............................................................................................................................................. 8 
OBSTETRIC HISTORY ................................................................................................................................................. 9 
PREBIRTH CONTROL .................................................................................................................................................. 9 
LABORATORIES ........................................................................................................................................................... 9 
INCLUSION AND EXCLUSION CRITERIA .................................................................................................................. 9 
9. 
TREATMENT COMPLIANCE ...................................................................................................................... 9 
10. 
EFFICACY ANALYSIS .................................................................................................................................. 9 
STATISTICAL HYPOTHESIS ....................................................................................................................................... 9 
PRIMARY ANALYSIS .................................................................................................................................................. 10 
SECONDARY ANALYSIS ............................................................................................................................................ 11 
11. 
SAFETY ANALYSIS .................................................................................................................................... 13 
11.1 ADVERSE EVENTS ............................................................................................................................................. 13 
11.2 INCIDENCE RATES AND NUMBER OF EVENTS .............................................................................................. 14 
11.3 PREVIOUS AND CONCOMITANT MEDICATIONS .......................................................................................... 15 
12. 
TABLES, LISTINGS AND FIGURES ........................................................................................................ 15 
13. 
REFERENCES ............................................................................................................................................. 16 


PCP 002 / PHASE II 
 
Version: 3.0 
Date: 12May2017 
Statistical Analysis Plan 
Confidential 
Page 3 of 16 
 
1. 
INTRODUCTION  
 
This statistical analysis plan is for Andromaco Laboratory S.A., Protocol PCP 002, 
multicenter, randomized, controlled, open label study to evaluate the efficacy of a vaginal 
cerclage pessary with a sustained progesterone release, in doses of 6.3 g and 7.7 g for the 
prevention of premature birth. 
 
The reference materials for this plan include the Clinical Protocol (Version 3, 16 May 2016) 
and the documents with data specific for the study. 
 
As a background of statistical methods that will be mentioned herein, this sections offers a 
general vision of the study’s objectives and design.  It is understood that this is only a 
summary and that the protocol is the final reference for all the matters discussed as follows. 
2. 
OBJECTIVES 
PRIMARY 
To evaluate the efficacy of two cerclage pessaries containing 6,3 g and 7,7 g of micronized 
progesterone of sustained release, in the prevention of premature birth, established through 
spontaneous delivery after 32 weeks but before 34 weeks of gestation, when the pessary is 
inserted between week 16 and 24, and removed at 36 6/7 weeks of gestation in pregnant 
women at risk of premature birth. 
 
SPECIFICS 
 
Record the occurrence of premature rupture of membranes before weeks 32 and 34 
weeks of gestation. 
 
Evaluation of anatomical characteristics of the cervix in pregnant women: position and 
length. 
 
Establish the acceptability and tolerance in pregnant women, with the use of the 
cerclage pessary. 
 
Evaluation of local and systemic safety in pregnant women, with the use of the 
cerclage pessary. 
3. 
STUDY DESIGN 
 
A phase II, efficacy, multicenter, controlled, open label, parallel and randomized 
exploratory clinical study. It will include singleton pregnant subjects, with history of 
premature birth and/or short neck and an increased risk of premature birth, who, after 
reading the informed consent, voluntarily accepted to participate in the study. 
 
For the secondary outcomes, subjects will be their own controls on the following variables 
to assess: anatomical characteristics of the cervix – position and length; development of 
surveys in pregnant women to establish the acceptability and tolerance of the intervention; 
and aspects of local and systemic safety. 
 
 


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Two hundred and seventy +10% pregnant women with risk of premature birth will be 
enrolled at the participating sites. This population will be divided into 3 groups of treatment 
with 90 participants each, where control group (A) is with intravaginal capsule of 
micronized progesterone 200 mg, groups B and C are pessaries with 6.3 g and 7.7 g of 
sustained release progesterone respectively. 
 
In the prenatal and/or ultrasound control between 16 and 24 weeks of gestation, they will 
be informed and invited to participate in the study. The inclusion of the volunteers will be 
in all cases until weeks 24 (0/0) of gestation. The volunteers will be selected on the basis 
of their clinical history and by trans-vaginal ultrasound performed between 16 and 24 
weeks. All volunteers with unique pregnancy and cervical length ≤25 mm but ≥10 mm, will 
be invited to participate in the study. Prior to inclusion in the study, it is confirmed the 
vitality of the fetus or other exclusion criteria detailed later. Subjects who refuse to 
participate in the study will receive the current standard of care in each participating site, 
according to their condition. 
 
EVALUATION VISITS 
The study includes 8 visits to the site.  The programmed schedule of assessments for its 
conduction and the activities to take place in each and one of them are specified in Table 
1. 
 
SAMPLE SIZE 
The sample size calculation is based on the power to detect differences in the proportion 
of spontaneous birth between 32 and 34 weeks of gestation, between the formulations of 
cerclage pessaries with respect to the control group (vaginal progesterone 200 mg 
capsules). Data collected of at least 90 women in each group will provide at least 80% of 
the power to detect differences with a rate of 40% or more, using a test of Chi-square of 
two tails with α = 0.05 without correction. 
 
We estimate that up to 10% of the enrolled women may not complete the study, so it must 
be planned to enroll at least 99 pregnant women in each group to reach at least 198 
treated subjects with cerclage pessary and 99 subjects treated with soft capsules of 
progesterone as a control group (i.e. 99 per each vaginal formulation). 
 
RANDOMIZATION 
The randomization will be generated by an independent statistician. The program will be 
linked in sequential numbers with the code of randomized treatment. A qualified staff 
member of ANDROMACO laboratory will keep randomization codification, until the 
database is clean and ready for analysis. The treatment will be dispensed according to the 
randomization code, the women with unique pregnancy enrolled, will be randomized to 
receive one of the vaginal formulations of the study. 
 
For the next volunteer, the site will have the next randomization number available. Each 
woman will receive only the formulation corresponding to the randomization number. The 
Investigator will record on the log the randomization number and the printed code on each 
formulation container. Each sites coordinator will assign the randomization code to the 
volunteers. 
 


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Subjects will be randomized to the following three study groups: 
 
- Control Group (A): Intravaginal capsule of micronized progesterone 200 mg on a daily basis. 
- Pessary Group (B): Pessary with 6.3 g of sustained release progesterone for a period of 
around 4 to 5 months. 
- Pessary Group (C): Pessary with 7.7 g of sustained release progesterone for a period of 
around 4 to 5 months. 
4. 
DOCUMENTS AND CHANGE OF VERSIONS 
 
Versión # 
Date of Review 
Date of Approval 
Reason for Change 
1.0 
05Apr2017 
 
N/A 
2.0 
21Apr2017 
 
Additions to different sections 
3.0 
12May2017 
 
English Version and 
clarification of some issues 
CHANGES IN THE PLAN 
At the moment there are no changes to the protocol or in the conduction of the study. 
5. 
ANALYSIS CONVENTIONS  
The statistical analysis will be made by ILS Clinical Research under the authorization of 
Laboratorio Andrómaco S.A. 
GENERAL PRINCIPLES 
The statistical analysis will be provided to give a general summary of the study subjects 
and a vision of the efficacy and safety of the results. The data provided by the sites will be 
summarized for this purpose. Tables of absolute and relative frequencies will be 
constructed for the quality variables.  All the percentages will be presented with a decimal. 
The quantitative variables will be summarized with the number of subjects participating 
(n), mean, standard deviation (SD), and median, maximal and minimal. 
 
Two tailed test will be carried out for all the analysis and the type I error is 0.05 for 
continuous variables and the discrete variables. All p values shall be rounded to three 
decimal and the values under 0.001 will be presented as <0.001 and values greater than 
0.999 will be presented as 1.000. A comparison of the treatment groups will be done with 
respect to the demographic and baseline characteristics using inferential statistical 
techniques to detect if any of these variables may condition the results in the dependent 
variables. Comparisons in qualitative variables will be carried out using the Cochran-
Mantel-Haenszel (CMH) test of general association, while the comparisons in quantitative 
variables will be made with a test of comparison of means (ANOVA analysis of variance) 
for independent samples with normal distribution. In the cases of no normality on the 
continuous variables, or in case of not belonging to the exponential family for discrete 
data, the parametric tests will be replaced for nonparametric tests such as Kruskal-Wallis 
or Friedman. These tests will be presented in each table as deemed necessary. All 
confidence 
intervals 
will 
be 
two-tailed 
and 
at 
95%.


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Table 1: Study Schedule of Assessments 
Activities 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Final Visit 
Demography 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Physical Exam 
X 
X 
X 
X 
X 
X 
X 
X 
Gynecological Exam 
X 
 
 
 
 
 
 
 
Vital Signs 
X 
X1 
X1 
X1 
X1 
X1 
X1 
X1 
Transvaginal Ultrasound 
X 
X2 
X 
X 
X 
X 
X 
X 
Pre-birth Control 
X 
 
 
 
 
 
 
 
Obstetric Background 
X 
 
 
 
 
 
 
 
Lab Tests (Blood and Urine) 
X 
 
 
 
 
 
 
 
Eligibility 
X 
 
 
 
 
 
 
 
Vaginal Discharge 
X 
X3 
X3 
X3 
X3 
X3 
X3 
X3 
Randomization 
X 
 
 
 
 
 
 
 
Pessary Insertion 
X 
 
 
 
 
 
 
 
Acceptability and tolerance to the insertion 
X 
 
 
 
 
 
 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
Evaluation of the Pessary’s Adhesion 
(Groups B and C) 
 
X 
X 
X 
X 
X 
X 
X 
Treatment Compliance (Group A) 
 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
Subject’s Evaluation 
 
X 
X 
X 
X 
X 
X 
X 
Birth4 
 
 
 
 
 
 
 
X 
1. 
Pulse and Temperature are added 
2. 
Confirmatory 
3. 
Smear 
4. Birth Characteristics: Medication (corticosteroids, antibiotics, tocolysis), hospital admissions; Delivery (Home, Via, interruption); Newborn baby (gender, 
weight, size, gestational age, head circumference, weight EG, Apgar score); Neonatal complications (infection, respiratory distress syndrome, 
Intraventricular hemorrhage, Necrotizing Enterocolitis, retinopathy, Blood Transfusion, other); Interventions; Conditions at discharge. 
 


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The statistical analysis will be made with SAS software, version 9.2 or greater.  
DATABASE MANAGEMENT 
The data will be attached to the statistical report.  The subjects that will not participate in the 
analysis (subjects that only completed baseline) will not be included in the tables and 
figures but they will be included in the listings of data.  
  
6. 
POPULATION DEFINITIONS 
In order to meet the needs of the sub-groups of the Protocol, the following population sub-
groups are defined: 
 
Per Protocol (PP): It is defined as the subset of participants who meet the criteria of 
selection, who expressed their desire to participate in the study, who signed the informed 
consent form, that the drug has been administered to them and have completed all the visits 
required or till the termination of the pregnancy as per Protocol. 
 
Intention to treat (ITT): It is defined as the subset of participants who meet the selection 
criteria, showing their desire to participate in the study, who signed the informed consent 
form, that the drug has been administered to them, who have at least completed the initial 
visit and at least one of the subsequent visits to the pessary referred to in the Protocol. 
 
The main efficacy analysis will be carried out with a focus Per Protocol (PP), however it will 
also be carried out per Intention to Treat (ITT) all the analysis. Otherwise, the main safety 
analysis will be completed as ITT. 
 
7. 
SUBJECT DISPOSITION 
The subjects that were randomized, completed the study PP and the ITT will be 
summarized in a table indicating the frequency number and percentage.  A CONSORT 
diagram will be included to observe the availability of subjects in the study. 
PROTOCOL DISCONTINUATIONS 
The number of subjects and their percentage will be included in the table that includes 
those subjects that were excluded due to lack of compliance to the requested criteria in the 
protocol.  It is important to identify the subjects that did not conclude the study before the 
definition of populations to study. Discontinuations to the protocol include:  Adverse Events 
leading to discontinuation, failure to meet inclusión/exclusión criteria, failure to comply with 
the treatment, failure to comply with the visits, concomitant medication, medical 
contraindication, voluntary withdrawal of the subjects, death, or others.   
 
8. 
DEMOGRAPHY AND POPULATION CHARACTERISTICS 
 
Baseline characteristics and demographics will be summarized for PP and ITT population 
defined in section 2.3.1 
 
 


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Categorical variables will be summarized in tables of frequencies and percentages. 
Continuous variables will be described by mean, standard deviation, median, max and min. 
 
They will be compared by treatment. For continuous variables a variance analysis (ANOVA) 
will be used for means comparison for independent samples. Categorical variables will be 
compared through the test of      Cochran-Mantel-Haenszel. 
 
Demographic characteristics included age (years), race, weight, height and Body Mass 
Index (BMI). 
 
MEDICAL HISTORY 
 
The medical history refers to whether the subject presents or presented any relevant 
conditions (Yes/No), a summary of conditions, diseases or surgical procedures and if these 
are still active or not. The data will be summarized in tables of frequencies and percentages 
based on the total number of subjects included in each treatment group and will only be 
handled for informatory purposes. 
 
PHYSICAL EXAM 
 
The physical exam includes examining body parts such as the abdomen, gallbladder, 
cardiovascular, 
endocrine, 
gastrointestinal 
and 
immune 
system, 
muscle-skeletal, 
neurological, psychiatric, respiratory, limbs, head, nose, eyes, ears, lymph nodes and 
allergies, nutritional facts, scars, skin, thyroid, etc. This will be evaluated in detail at baseline 
and documented in each visit just if there exist clinical relevance. The information will be 
summarized in tables of frequencies and percentages based on the total number of subjects 
in each treatment group and will only be handled for informatory purposes. 
VITAL SIGNS 
Vital signs consider values of systolic and diastolic blood pressure, heart rate, pulse and 
temperature. These shall be reviewed as part of the physical examination and the 
information will be presented in every visit. The information will be summarized in tables 
with number of participating subjects (n), mean, standard deviation (SD), median, max and 
min and will only be handled for informatory purposes. 
 
GYNECOLOGICAL EXAM 
 
The gynecological exam includes examination of breasts, external genitalia, vagina, cervix, 
uterus, other abnormalities, etc. The information will be summarized in tables of frequencies 
and percentages based on the total number of subjects in each treatment group and will 
only be handled for informatory purposes. 
 
 


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OBSTETRIC HISTORY 
 
This item considers the history of childbirth in pregnancy, such as premature labor or 
rupture of membrane, before 35 weeks in preceding pregnancy, with viable fetus. The 
information will be summarized in tables of frequencies and percentages based on the total 
number of subjects in each treatment group and will only be handled for informatory 
purposes. 
PREBIRTH CONTROL  
This control considers the obstetric formula (GPA), the date of the last normal menstruation 
and gestational age in accordance with the Date of Last Normal Menstruation (DLNM) and 
gestational age though Transvaginal Ultrasound in weeks. The obstetric formula will be 
summarized in tables of frequencies and percentages determined within each group and 
the gestational ages in the tables with the number of participating subjects (n), mean, 
standard deviation (SD), median, max and min, and will only be handled for informatory 
purposes. 
LABORATORIES 
To be done only at baseline and blood and urine samples will be taken. 
INCLUSION AND EXCLUSION CRITERIA 
These will be summarized according to the compliance of them.  The information will be 
summarized in tables with frequencies and percentages according to the total number of 
subjects included in each treatment group and will only be handled for informatory 
purposes.  
9. 
TREATMENT COMPLIANCE 
For Group A, at the start of each visit, it will be recorded the number of capsules dispensed 
at the previous visit and the number of capsules used, the treatment compliance will be 
estimated in percentage. The compliance should be between 80 and 120% for each patient. 
For groups B and C, it will only be recorded if removal of the pessary was necessary. In this 
case the subject will be early terminated from the study and the reason for discontinuation 
will be recorded. 
10. 
EFFICACY ANALYSIS 
STATISTICAL HYPOTHESIS 
Null Hypothesis: 
 
There is no difference between the methods of cerclage pessaries with a sustained release of 
6.3 and 7.7 g of progesterone (Treatments B and C, respectively) with respect to the control 
method (Treatment A) for at least 20 weeks. 
 
 


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Alternative Hypothesis: 
There is a difference between the Control Method (Treatment A) with respect to the one of 
cerclage pessaries with a sustained release of 6.3 and 7.3 of progesterone for a period of 4 
to 5 months.  
 
“There is a difference between the methods of cerclage pessaries with a sustained release of 
6.3 and 7.3 g of progesterone (Treatments B and C respectively) with respect to the Control 
Method (Treatment A) for a period of 4 to 5 months”. 
PRIMARY ANALYSIS 
The primary objective is to evaluate the efficacy of two cerclage pessaries with doses of 6.3 
and 7.7 g of sustained release micronized progesterone with respect to the standard 
treatment of 200 mg of progesterone in capsules administered daily. The primary efficacy 
analysis will be assessed by comparing the proportions of spontaneous premature delivery 
after 32 weeks but before 34 weeks of gestation, as primary results, among treatments 
through the CMH test. Also, the odds ratio and 95% confidence interval will be estimated, 
considering Group A as the control to be compared with groups B and C. Secondly, the 
comparison of proportions between the groups C and A will be done with the intention to 
confirm the significant difference between the highest dose and the standard treatment. 
Afterwards, the same comparison of proportions will be done with treatment B in order to 
establish the difference between the group of a minor dose and the standard. Finally the 
comparison between treatment B and C will be done hoping to demonstrate there is a 
difference of superiority between B and C where C must be minor than B regarding the 
number of low-risk pregnancies. The transitivity between treatments will be established 
according to the results. This is expected to be as follows: 
 
                                    
 
this is in terms of decrease of the proportion of pregnancies with premature risk. In this way 
it will determined the effective response to progesterone in the cerclage pessary through the 
occurrence of spontaneous delivery after 32 weeks but before 34 weeks  of gestation. The 
evaluation of the error type 1 will be with a value of 0.05 for the type of variable being used. 
 
As part of the exploratory analysis for the efficacy of treatments, the risk of spontaneous 
premature birth from the moment of inclusion in the study until the weeks 32 and 34 of 
gestation, will be determined with the Kaplan-Meier analysis, where the gestational age is 
the timeline, spontaneous delivery will be the event and elective deliveries will be censored. 
A singleton pregnant subject between 16 and 24 weeks of gestation will be eligible to 
participate in the study when she meets one of the following two conditions: 
 
Cervical length between 10 to 25 mm and without risk factors 
 
Cervical length greater or equal to 10 mm and with pre-existing risk factors in the 
immediate preceding pregnancy characterized by: 
o premature delivery before the week 35 (with a viable fetus) 
o premature rupture of membrane prior to week 35 (with a viable fetus) 
 
There are two ways to measure the gestational age which are the following: 
 
 
Gestational Age according to DLNM (weeks) 
 
Gestational Age according to Transvaginal Ultrasound (weeks) 


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The time of gestational age will be evaluated through log-rank tests among treatments. The 
null hypothesis is stated as the no treatment differences in the gestational ages. 
 
Kaplan-Meier (product limit) estimates of the gestational age distribution will be calculated 
and their corresponding 95% confidence interval (CI) will be presented: 25th percentile, 
mean, median, and 75th percentile. 
 
The analysis will be performed for the two measurements of gestational time, considering 
the Transvaginal ultrasound the one most accurate. 
 
For the purposes of this analysis, pregnancies will no longer be considered of high risk in 
the event birth takes place in week 34 (34 0/7) of gestation or more. 
 
SECONDARY ANALYSIS 
For some of the secondary variables, subjects will be their own controls in the following 
variables to evaluate and the following analysis are proposed: 
 
Occurrence of membranes’ ruptures: Premature rupture of membranes after 32 weeks but 
before 34 weeks of gestation. The Cochran-Mantel-Haenszel (CMH) test will be used, 
where the incidence of rupture of membranes in each group will be compared and will be 
identified through the registration of adverse events. 
 
Anatomical cervical changes (Only groups B and C): The length of the cervix and cervical 
angle variables, will be described as continuous and measured variables through time, 
using the test of comparison of means through the Analysis of Variance (ANOVA) for 
repeated measures, considering the baseline result as a covariate in the comparison and 
shall be based on the sum of squares type III. The difference between groups regarding the 
change from baseline will be assessed through t tests paired within ANOVA, utilizing the 
difference in means estimated by least squares. These comparisons will be made amongst 
all treatment groups with pessary. 
 
Acceptability and tolerability of insertion (only groups B and C): 
Acceptability and tolerability will be assessed through a questionnaire which must be 
completed at the beginning and end of the study. Questions (i) and (ii) are answered at visit 
1, question iii (VAS) is answered at visit 1 and final visit, and questions (iv) to (ix) are 
answered at the final visit.  
 
It is composed of several items 
(i)  
Ease of insertion (visit 1). This question has the following categories: 1 = very 
good, 2 = good, 3 = regular, 4 = bad and 5 = very bad; and only one of them will 
be selected. 
(ii)  
Subjects pain at the time of insertion (visit 1). This question has the following 
categories: 1 = without pain, 2 = with little pain, 3 = with moderate pain, 4 = with 
intense pain and 5 = with unbearable pain; and only one of them will be selected. 


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(iii)         Visual Analog Scale of pain (VAS) (visit 1 and final visit): this scale is evaluated in 
10 points where 10 represents the worst pain suffered during her lifetime and 1 
the absence of pain. 
 
Analysis for the VAS will be described as continuous and measured variables through time 
using the test of comparison of means through the Analysis of Variance (ANOVA) and must 
be based on the sum of squares type III. The treatment differences regarding the change 
from baseline, will be assessed through t tests paired within ANOVA, utilizing the difference 
in means estimated by least squares. These comparisons will be made amongst all 
treatment groups. 
 
(iv) 
Expulsion of the Pessary (Yes/No, Final Visit). The date, gestational age of 
expulsion of the pessary without replacement will be recorded in the log. 
(v) 
Sensation upon the release of the pessary (Final visit). This question has the 
following categories: 1 = never, 2 = almost never, 3 = occasionally, 4 = frequently, 
5 = always; and only one of them will be selected. 
(vi) 
Release of vaginal fluid (Final visit). This question has the following categories: 1 
= never occurred, 2 = No changes, 3 = little increase, 4 = big increased 5 = 
change in color; and only one of them will be selected. 
(vii) 
Sexual intercourse with pessary (Final Visit). This question has the following 
categories: 1 = better, 2 = as always, 3 = with discomfort, 4 = with pain, 5 = no 
intercourse; and only one of them will be selected. 
(viii) 
Request for early withdrawal of the pessary (Yes/No, Final visit). The date, 
gestational age and reason of withdrawal from the pessary will be recorded in the 
log.  
(ix) 
Recommendation (Yes/No, Final Visit). 
 
For all the above items except number (iii), the information will be summarized in the 
frequency and percentage tables according to the total number of subjects included in each 
treatment group and will be handled only for informatory purposes.  
 
           
 
Changes in vaginal discharge  
 
Clinical evaluation and/or bacteriological research will take place, infections will be treated 
with the appropriate antibiotic in case it is confirmed. For these cases, the insertion of a 
cerclage pessary with sustained-release of progesterone, will take place later at the end of 
the treatment, but before 24 (0/1) weeks of gestation. It will be monitored in each visit. 
In each control, the participant will be asked about the presence, quantity and physical 
characteristics of the vaginal discharge. To discard presence or absence of infections, the 
subject will be asked about the need to do a smear of the vaginal discharge for PCR and the 
need for treatment. The information will be summarized in tables of frequencies and 
percentages based on the total number of subjects included in each treatment group per 
visit. A generalized CMH test will be used to assess whether changes in vaginal discharge 
were different in any of the groups through time. 
 
 


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Children Evaluation 
 
New born will be described in the aspects of demography, physical exam (gestational age), 
cephalic perimeter, APGAR score, neonatal complications, medical interventions and 
discharge status. Summary tables of descriptive statistics, absolute and relative frequencies 
will be included in the analysis only as a descriptive purposes. 
11. 
SAFETY ANALYSIS 
11.1 ADVERSE EVENTS 
 
The evaluation of adverse events (AE) will be monitored throughout the study, by direct 
observation at each visit. 
 
All AE will be recorded (according to the definition), and not only those where the 
investigator suspects a causal relationship with the treatment. Adverse events of interest; 
i.e., those in which the investigator at each site must pay particular attention are those that 
have been defined as local safety (pain, irritation, itching and infection) and major maternal 
complications attributable to the pessary as chorioamnionitis, severe vaginal or cervical 
trauma. 
 
All the AE will be encoded in MedDRA version 19.1 or higher to be summarized by System 
Organ Class (SOC) / Preferred Term (PT). 
 
The following 3 overview tables will be generated by treatment group and overall: 
 
1) Summary of the number and percentage of subjects with at least 1: 
• AE 
• Serious AE 
• Non-serious AE 
• Unexpected AE 
• Severe AE 
• Related AE 
• Related serious AE 
• AE leading to discontinuation from IMP 
The percentage denominator will be the number of subjects in the safety analysis. 
  
2) Summary presenting the number of AEs per subject categorized as 0, 1, 2, 3, 4, 5, 
and >5; 
 
3) Summary of the number and percentage of AEs for: 
• AEs 
• Serious AEs 
• Non-serious AEs 
• Unexpected AEs 
• Related AEs 
• Related serious AEs 
• AEs leading to discontinuation from IMP 
The percentage denominator will be the total number of AEs. 
 


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11.2 INCIDENCE RATES AND NUMBER OF EVENTS 
The incidence of an AE is defined as the number of subjects with occurrence of this AE 
during the period of interest. The incidence rate (CIR for crude incidence rate) of an AE is 
defined as the number of subjects with occurrence of this AE during the period of interest 
divided by the total number of subjects in the respective group (e.g., dose group). 
 
The incidence, incidence rate, the number of events and the percentage of events (related 
to the total number of events) will be summarized by PT (sorted by decreasing incidence 
rate in the overall column) for 
• AEs 
• related AEs 
• AEs leading to treatment discontinuation 
 
A separate table per type of AE will be prepared. Only AEs occurring in at least 5% of 
subjects overall will be included in the text. Tables will be sorted by decreasing incidence 
overall. 
 
The incidence, incidence rate, the number of events and the percentage of events (related 
to the total number of events) will be summarized by SOC and PT (sorted alphabetically) for 
each 
• AEs 
• serious AEs 
• non-serious AEs 
• related AEs 
• serious treatment related AEs 
• AEs leading to treatment discontinuation 
 
For serious AEs, the incidence, incidence rate, the number of events, and the percentage of 
events will also be presented for serious treatment related AEs, serious fatal AEs and 
serious fatal related AEs. 
 
For all enrolled subjects, the incidence, incidence rate, the number of events, and the 
percentage of events (related to the total number of events) will be summarized by SOC 
and PT(sorted alphabetically) for each. 
 
The number and percentage of events will be summarized by SOC and PT(sorted 
alphabetically) for the following AE descriptors. Presentation will be for AEs only. 
• intensity: mild, moderate, severe 
• causal relationship to the imp: related (with subcategories: possible, probable/likely, 
certain), not related (with subcategories: not related, unlikely), unknown (with 
subcategories: conditional/unclassified, unassessable/unclassifiable, causal relationship 
missing) 
• outcome: recovered/resolved, recovering/resolving, not recovered/not resolved, 
recovered/resolved with sequelae, fatal, unknown 
• non-IMP related countermeasures: none, newly started medication, others 
• action taken with imp: dose not changed, dose reduced, drug interrupted, trial 
discontinuation, unknown. 
 
 


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Denominator for percentage calculation will be the number of all AEs for the presentation 
overall SOCs, and the number of AEs per SOC or PT respectively, for the presentation per 
SOC or PT, respectively. 
 
The following tables will be presented as part of this analysis: 
 
 
Table of AE that ended in discontinuation, presented by SOC and PT 
 
Table of AE presented PT 
 
Table of serious AE presented PT 
 
Table of non-serious AE presented PT 
 
Table of related AE presented PT 
 
Table of AE related and serious, presented PT 
 
Table of AE presented SOC and PT 
 
Table of serious AE presented SOC and PT 
 
Table of non-serious AE presented SOC and PT 
 
Table of related AE related, presented SOC and PT 
 
Table of related and serious AE presented PT 
 
Table of AE presented SOC and PT and intensity 
 
Table of AE presented SOC and PT and action taken 
 
Table of Unexpected AE (non-serious and serious) presented PT 
 
AEs by primary SOC, PT, and outcome 
 
AEs by primary SOC, PT and non-IMP related countermeasure 
 
AES by primary SOC, PT, and causal relationship to IMP 
 
11.3 PREVIOUS AND CONCOMITANT MEDICATIONS 
Incidence rates for previous and concomitant medications will be summarized by number of 
subjects with at least one medication, the naming convention will be codified by Anatomical 
Therapeutic Classification (ATC) / Therapeutic Chemical Level II. 
12. 
TABLES, LISTINGS AND FIGURES 
All the tables, listings and figures will have a complete description of the content, including 
the name of the company, protocol, population studied and date of elaboration. On the 
footnote will be indicated the database, program name and output name. All figures will 
make reference to the tables and listings utilized for their elaboration. All the lists will be 
ordered by subject number. 
Data listings for all data sets will be displayed as an annex to the CSR. Also the following version of the 
listings will be included: 
 
Subject completion/discontinuation – all enrolled subjects 
 
Adverse events leading to trial discontinuation – all enrolled subjects 
 
Other reasons for discontinuation – all allocated subjects 
 
Serious adverse events other than death– all enrolled subjects 
 
Adverse events leading to IMP dose decrease or interruption of IMP – all enrolled 
subjects 
 
Adverse events – all enrolled subjects 
 
Laboratory and vital signs parameters 
 


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Statistical Analysis Plan 
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13. 
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CRC. 
Medical Dictionary for Regulatory Activities (MedDRA), Version 18.1. IFPMA, International 
Committee on Harmonization. Geneva, Switzerland. 2001. 
Stokes, Maura E., Davis, Charles S., Koch, Gary G., Categorical Data Analysis Using the 
SAS® System, Cary, NC: SAS Institute Inc., 1997 (3rd Printing). 
WHO drug dictionary. WHO Collaborating Centre for International Drug Monitoring. 
Uppsala, Sweden, (Box 26, S-751 03), 2013.