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This study compares the effectiveness of cervical cerclage with vaginal progesterone to vaginal progesterone only for the prevention of preterm birth in women with a singleton pregnancy and a short cervical length. Participants will be randomly assigned in a 1:1 ratio to receive cerclage plus progesterone or progesterone only.
This open-label, multi-center, randomized controlled trial aims to compare the effectiveness of cervical cerclage with vaginal progesterone (the combined therapy group) to vaginal progesterone only (the progesterone-only group) for the prevention of preterm birth in women with a singleton pregnancy and a cervical length ≤ 25mm.
After written informed consent, women will be randomly assigned in a 1:1 ratio to receive a cervical cerclage with vaginal progesterone or vaginal progesterone only. Randomization will be carried out by entering participant details into HOPE Epi® (a web portal of HOPE Research Center, My Duc Hospital). Treatment allocation will be assigned according to a computer-generated randomization list stored in the online system, with a permuted random block size of 2, 4, or 6. Blinding will not be possible due to the nature of interventions. However, neonatologists assessing the neonates will be unaware of treatment allocation. Apart from randomization, participants will be monitored and treated according to local protocol.
All women at 16 0/7 to 24 0/7 weeks' gestation with a singleton pregnancy will undergo cervical length measurement and digital examination at screening routinely. Women with a cervical length ≤25 mm will be eligible for the study. Eligible women will further undergo a speculum examination to assess the feasibility of treatment with either cervical cerclage or vaginal progesterone and to exclude premature rupture of the membranes, acute vaginitis, and cervicitis. Only women in whom the clinician assesses both treatments as feasible will be randomized.
Women allocated to a combined therapy group will receive the intervention according to local protocol within a week after randomization. Briefly, cervical cerclage (McDonald technique) will be performed in the operation theatre. From the same day of undergoing cerclage, participants will be receiving 200 mg vaginal progesterone, purchased from the manufacturer (Cyclogest® 200mg, Actavis, United Kingdom), once daily at bedtime. Participants will be asked to record their drug application in a participant diary sheet.
Women allocated to the progesterone-only group will be receiving 200 mg vaginal progesterone, purchased from the manufacturer (Cyclogest® 200mg, Actavis, United Kingdom), once daily at bedtime. Participants will be asked to record their drug application in a participant diary sheet.
In both groups, interventions will be stopped at 37 0/7 weeks of gestation or at delivery.
Primary analysis will be performed on an intention-to-treat basis. The primary outcome, the time from randomization to delivery, will be summarised as median and IQR and compared between the two arms using the Mann-Whitney test. A mean ratio with a 95% confidence interval will be calculated to assess the effect of the treatment. Kaplan-Meier and Cox proportional hazard analysis will be performed in which the gestational week at delivery will be the time scale, continued pregnancy will be the event, and results will be compared with a log-rank test. Hazard ratio (HR) values will be estimated using a Cox proportional hazards model, with a formal test of the proportional hazard assumption.
The secondary outcome will be analysed by reporting continuous variables as mean and standard deviation for normally distributed variables or median and interquartile range (Q1; Q3) for non-normally distributed variables. Categorical variables will be presented as the number of events and proportions. Student T-test or Mann-Whitney U test will be used for continuous outcomes to compare the differences between groups. For categorical outcomes, the Chi-squared or Fisher exact test will be used. In the case of dichotomous endpoints, the relative risk (RR) and 95% confidence interval (CI) values will be calculated using the Wald or Adjusted Wald methods for a small proportion. Per-protocol analysis will also be conducted if needed.
A prespecified subgroup analysis will be performed by quartiles of cervical length, which tested for interaction between cervical length and the treatment effect on the primary outcome, the major secondary outcome and PTB <28, <34, <37 weeks.
The p-values <0.05 will be considered to indicate statistical significance. Statistical analyses will be performed using the R statistical software.
Details of the analysis will be described in a separate statistical analysis plan developed during the study and finalized before the data lock. Cost data will be collected and will be reported on a separated paper.
Interim analysis will be done after completion of data recruitment of the first 162 participants, by an independent Data Safety Monitoring Committee. The Data Safety Monitoring Committee will be asked to assess the primary endpoint for effectiveness. Also, the Data Safety Monitoring Committee will be provided insight into the serious adverse events (SAEs) that have occurred. The interim analysis will be conducted using a two-sided significant test with the Haybittle-Peto spending function and a type I error rate of 5 percent with p <0.001 (Z alpha = 3.29) being a reason to stop the trial. The continuation of the study will depend on the advice of Data Safety Monitoring Committee.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Combined therapy group (cervical cerclage plus vaginal progesterone) | Experimental | Women will be receiving the cervical cerclage according to local protocol within a week after randomization, using the McDonald technique. Within one day after the procedure, they will be receiving 200 mg vaginal progesterone, purchased from the manufacturer (Cyclogest® 200mg, Actavis, United Kingdom), once daily at bedtime. Participants will be asked to record their drug application in a patient diary sheet. |
|
| Progesterone only group | Active Comparator | Women allocated to the progesterone only group will be receiving 200 mg vaginal progesterone, purchased from the manufacturer (Cyclogest® 200mg, Actavis, United Kingdom), once daily at bedtime. Participants will be asked to record their drug application in a patient diary sheet. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Cervical cerclage | Procedure | Cervical cerclage using the McDonald technique under anaesthesia. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Time from randomization to delivery | Number of days between randomization and delivery | From date of randomization until the date of delivery |
| Measure | Description | Time Frame |
|---|---|---|
| Composite poor neonatal outcomes (major sencondary endpoint) | Stillbirth or neonatal death, intraventricular haemorrhage, respiratory distress syndrome, necrotizing enterocolitis or neonatal sepsis. | From 20 weeks of gestation to 28 days after estimated due date |
| Miscarriage <22 weeks (late miscarriage) |
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Inclusion Criteria:
Exclusion Criteria:
(*Women with acute cervicitis, vaginitis or severe vaginal discharge are eligible once they have been treated and if they have a CL ≤25 mm between 16 0/7 - 24 0/7 weeks of gestation.)
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Thanh V Le, MD | Contact | +84934124733 | bsthanh.lv@myduchospital.vn | |
| Lan N Vuong, MD, PhD | Contact | +84903008889 | drlan@yahoo.com.vn |
| Name | Affiliation | Role |
|---|---|---|
| Lan N Vuong, MD, PhD | University of Medicine and Pharmacy at Ho Chi Minh City | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| My Duc Hospital | Recruiting | Ho Chi Minh City | Ho Chi Minh City | 70000 | Vietnam |
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| ID | Term |
|---|---|
| D047928 | Premature Birth |
| ID | Term |
|---|---|
| D007752 | Obstetric Labor, Premature |
| D007744 | Obstetric Labor Complications |
| D011248 | Pregnancy Complications |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
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| ID | Term |
|---|---|
| D023802 | Cerclage, Cervical |
| D011374 | Progesterone |
| ID | Term |
|---|---|
| D013513 | Obstetric Surgical Procedures |
| D013514 | Surgical Procedures, Operative |
| D011282 | Pregnenediones |
| D011283 | Pregnenes |
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| Vaginal progesterone | Drug | Cyclogest® 200mg, Actavis, United Kingdom, applied once daily at bedtime. |
|
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spontaneous loss of pregnancy between 12 to 22 weeks is termed as late miscarriage |
| From date of randomization to 22 weeks of gestation |
| Gestational age at delivery | Gestational age at delivery | At delivery |
| Preterm birth <24 weeks, <28 weeks, <32 weeks, <34 weeks and <37 weeks of gestation | Preterm birth is defined as any birth ≥ 22 and < 37 completed weeks of gestation. Any birth < 22 weeks is defined as late miscarriage | At delivery |
| Spontaneous preterm birth <24 weeks, <28 weeks, <32 weeks, <34 weeks and <37 weeks of gestation | Spontaneous preterm birth, including preterm labour, preterm spontaneous rupture of membranes, preterm premature rupture of membranes, and cervical weakness before 24 weeks, 28 weeks, 32 weeks, 34 weeks, and 37 weeks of gestation, respectively, does not include indicated preterm delivery for maternal or fetal conditions. | At delivery |
| Iatrogenic preterm birth <24 weeks, <28 weeks, <32 weeks, <34 weeks and <37 weeks of gestation | Iatrogenic preterm birth, including planned delivery that occurs before 24 weeks, 28 weeks, 32 weeks, 34 weeks, and 37 weeks of gestation, respectively, due to maternal and/or fetal causes. | At delivery |
| Onset of labor | Classified as spontaneous, labor induction, or elective C-section. | At birth |
| Mode of delivery | Classified as vaginal delivery or C-section (elective, suspected fetal distress, non-progressive labor). | At birth |
| Live birth | Defined as the complete expulsion or extraction from a woman of a product of fertilization after 22 completed weeks of gestational age; which, after such separation, breathes or shows any other evidence of life, such as heartbeat, umbilical cord pulsation or definite movement of voluntary muscles, irrespective of whether the umbilical cord has been cut or the placenta is attached. A birth weight of 500 grams or more can be used if gestational age is unknown | At birth |
| Use of tocolytic drugs | Use of any tocolytic drug to treat preterm labour | From 24 0/7 to 33 6/7 weeks' gestation |
| Use of Post cerclage antibiotics | Use of any treatment antibiotics after the cerclage procedure | Within one week after the cerclage procedure |
| Use of antenatal corticosteroids | Use of antenatal corticosteroids to prevent respiratory distressed syndrome | From 24 0/7 to 33 6/7 weeks' gestation |
| Use of MgSO4 for neuroprotection | Use of MgSO4 for neuroprotection | From 24 0/7 to 31 6/7 weeks' gestation |
| Fetal growth restriction | It is defined as the failure of the fetus to meet its growth potential due to a pathological factor, most commonly placental dysfunction. | From randomization to delivery |
| Preterm premature rupture of membranes | When membrane rupture occurs before labor and before 37 weeks of gestation | From randomization to before 37 weeks of gestation |
| Length of maternal admission for labour | Number of maternal admission days for labour | Up to 2 weeks after birth |
| Total length of admission for threatened preterm labor | Number of admission days for treatment of preterm labour | From 22 0/7 to 36 6/7 weeks of gestation |
| Chorioamnionitis | Intraamniotic infection (diagnosed according to The American College of Obstetricians and Gynecologists Committee on Obstetric Practice No 712, 2017 (reaffirmed 2022)) | From randomization to delivery |
| Maternal mortality | female deaths from any cause related to or aggravated by pregnancy or its management (excluding accidental or incidental causes) during pregnancy and childbirth or within 42 days of termination of pregnancy, irrespective of the duration and site of the pregnancy | From randomization to during pregnancy and childbirth or within 42 days of termination of pregnancy |
| Maternal side effects | Vaginal discharge, vaginal bleeding, vaginal infection (confirmed by vaginal discharge culture), preterm premature rupture of membranes, chorioamnionitis, necrosis or rupture of the cervix, cervical laceration, vaginal or bladder injury. | From date of randomization until delivery |
| Birthweight | Weight of the newborn measured right after delivery | At birth |
| Birthweight <1500 g | Weight of the newborn <1500g | At birth |
| Birthweight <2500 g | Weight of the newborn <2500g | At birth |
| Congenital anomalies | Structural or functional disorders that occur during intra-uterine life and can be identified prenatally and at birth. Congenital anomalies can be caused by single gene defects, chromosomal disorders, multifactorial inheritance, environmental teratogens, and micronutrient deficiencies. The time of identification will be reported. | After randomization to at birth |
| 1-min Apgar score | Apgar score at 1 minute after birth | 1 min after birth |
| 5-min Apgar score | Apgar score at 5 minute after birth | 5 min after birth |
| Admission to neonatal intensive care unit | Admission to neonatal intensive care unit of baby | At birth and up to 28 days after birth |
| Length of stay in the neonatal intensive care unit | Number of admission days to neonatal intensive care unit | Up to 28 days after estimated due date |
| Neonatal death | Death of a live-born baby within 28 days of birth | Within the first 28 days of life after delivery |
| All stillbirth | Defined as the death of a fetus prior to the complete expulsion or extraction from its mother after 20 completed weeks of gestational age. The death is determined by the fact that, after such separation, the fetus does not breathe or show any other evidence of life, such as heartbeat, umbilical cord pulsation, or definite movement of voluntary muscles. It includes deaths occurring during labor. All stillbirth will be defined as a baby born with no signs of life at ≥ 20 weeks of gestation | After 20 weeks of gestation |
| Early stillbirth | A baby born with no signs of life at ≥ 20 weeks and < 28 weeks of gestation | ≥ 20 weeks and < 28 weeks of gestation |
| Late stillbirth | A baby born with no signs of life at ≥ 28 weeks of gestation | After 28 weeks of gestation |
| Perinatal death | Either stillbirth or neonatal death | From 20 weeks of gestation to the first 28 days of life after delivery |
| Respiratory distress syndrome | Diagnosed as the presence of tachypnoea >60/minute, sternal recession and expiratory grunting, need for supplemental oxygen, and a radiological picture of diffuse reticulogranular shadowing with an air bronchogram | Up to 28 days after estimated due date |
| Intraventricular haemorrhage II B or worse | Diagnosed by repeated neonatal cranial ultrasound by the neonatologist according to the guidelines on neuro-imaging described by de Vries et al | Up to 28 days after estimated due date |
| Necrotizing enterocolitis | An acquired gastrointestinal disease associated with significant morbidity and mortality in prematurely born neonates. Necrotizing enterocolitis will be diagnosed according to Bell et al., 1978 | Up to 28 days after estimated due date |
| Neonatal sepsis | Diagnosed on the combination of clinical signs and positive blood cultures of the newborn | Up to 28 days after estimated due date |
| D000091642 | Urogenital Diseases |
| D011278 |
| Pregnanes |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D003339 | Corpus Luteum Hormones |
| D042341 | Gonadal Hormones |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| D045167 | Progesterone Congeners |
| D012739 | Gonadal Steroid Hormones |