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Low study recruitment
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The purpose of this study is to determine if a repeat course of betamethasone given to pregnant women with preterm premature rupture of membranes (PPROM) will decrease the infant's length of stay in the neonatal intensive care unit (NICU) and the overall neonatal morbidity associated with this condition.
While the fetal benefits of a repeat course of antenatal corticosteroids have been demonstrated in several randomized controlled studies, to the investigators' knowledge they have not been adequately demonstrated in women with PPROM. Given the potential benefit of a repeat course of antenatal corticosteroids in women with PPROM on decreasing neonatal morbidity and the reassuring data from various cohorts on its safety, the investigators sought to propose a randomized controlled trial (RCT) with the hypothesis that a repeat course of antenatal corticosteroids in women with PPROM decreases neonatal morbidity.
Objectives
Hypotheses The investigators hypothesize that treatment of women with PPROM between 24 and 34 weeks of gestation with a repeat course of antenatal corticosteroids decreases infant length of stay in the NICU and neonatal morbidity.
Aim To describe and compare the neonatal outcomes of PPROM infants exposed to a repeat course of antenatal corticosteroids compared to infants in the same antenatal conditions who are exposed to only one betamethasone course.
Subject Safety and Data Monitoring This study does not place subjects at risk of their safety. This medication is well studied and known to be safe in pregnancy.
Data monitoring will be performed and viewed by study personnel only. The data will be de-identified and a study number will be assigned to each patient. The patient's identity will be secured on a UTMB encrypted laptop device and a hard copy stored in the locked file cabinet in the locked office of the principal investigator.
Procedures to Maintain Confidentiality:
Data will be viewed by study personnel only. The data will then be de-identified and a study number will be assigned to each patient. The patient's identity will then be secured on a UTMB encrypted laptop device and a hard copy stored in the locked file cabinet in the locked office of the principal investigator.
Potential Benefits The potential benefits to subjects participating in the study include possible decreased neonatal morbidity and length of stay in the NICU.
Biostatistics Using data from the University of Texas Medical Branch (UTMB) on women with PPROM between 24 and 34 weeks, who fit the inclusion criteria, and who received the standard one course of betamethasone, the average length of stay in the NICU was 59.3 ± 36.3 days. The gestational age at delivery in this cohort was 26.5 ± 3.2 weeks.
Assuming that a second course of betamethasone reduces the length of stay needed in the NICU by 35%, and for a power of 80% and alpha 0.05, it is anticipated that enrollment of 49 women in each group will be needed, or 98 women total.
At UTMB, there are approximately 400 women per year hospitalized with PPROM. Assuming 50% of eligible women consent, the investigators estimate to finish recruitment for this study in 1-2 years.
Sample Size and Assumptions
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Betamethasone | Experimental | Women admitted with PPROM who will receive a second course of two betamethasone 12mg intramuscular (IM) injections given 24 hours apart. |
|
| Saline Placebo | Placebo Comparator | Women admitted with PPROM who will receive intramuscular saline placebo, given as two injections 24 hours apart. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Betamethasone | Drug | Betamethasone 12mg IM given every 24 hours for two doses |
|
| Measure | Description | Time Frame |
|---|---|---|
| Average Number of Days in the Neonatal Intensive Care Unit (NICU) | Mean number of days participants remained admitted to the Neonatal Intensive Care Unit (NICU) during hospitalization following birth. | daily from birth of infant up to one year or discharge from the NICU, whichever occurred first |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Composite Neonatal Morbidity | defined as ≥ 1 of the following: RDS (oxygen requirement, clinical diagnosis, and consistent chest radiograph), bronchopulmonary dysplasia (requirement for oxygen support at 30 days of life), severe IVH (grades III or IV), periventricular leukomalacia, blood culture-proven sepsis, necrotizing enterocolitis, or perinatal death (stillbirth or death before neonatal hospital discharge) |
| Measure | Description | Time Frame |
|---|---|---|
| Labor Latency | time from diagnosis of PPROM from admission until delivery of neonate or until completion of the study | time from admission to delivery up to one year, or through study completion |
| Infectious Morbidities |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Benjamin Bush, MD | University of Texas Medical Branch in Galveston | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Texas Medical Branch in Galveston | Galveston | Texas | 77555 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 25422655 | Background | Atarod Z, Taghipour M, Roohanizadeh H, Fadavi S, Taghavipour M. Effects of single course and multicourse betamethasone prior to birth in the prognosis of the preterm neonates: A randomized, double-blind placebo-control clinical trial study. J Res Med Sci. 2014 Aug;19(8):715-9. | |
| 25545441 | Background | Brookfield KF, El-Sayed YY, Chao L, Berger V, Naqvi M, Butwick AJ. Antenatal corticosteroids for preterm premature rupture of membranes: single or repeat course? Am J Perinatol. 2015 May;32(6):537-44. doi: 10.1055/s-0034-1396690. Epub 2014 Dec 29. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Betamethasone | Women admitted with PPROM who will receive a second course of two betamethasone 12mg intramuscular (IM) injections given 24 hours apart. Betamethasone: Betamethasone 12mg IM given every 24 hours for two doses |
| FG001 | Saline Placebo | Women admitted with PPROM who will receive intramuscular saline placebo, given as two injections 24 hours apart. Placebo: Sterile 0.9% normal saline solution given IM every 24 hours for two doses |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Betamethasone | Women admitted with PPROM who will receive a second course of two betamethasone 12mg intramuscular (IM) injections given 24 hours apart. Betamethasone: Betamethasone 12mg IM given every 24 hours for two doses |
| BG001 | Saline Placebo |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Average Number of Days in the Neonatal Intensive Care Unit (NICU) | Mean number of days participants remained admitted to the Neonatal Intensive Care Unit (NICU) during hospitalization following birth. | Neonates were assessed for this Outcome Measure. | Posted | Mean | Full Range | days | daily from birth of infant up to one year or discharge from the NICU, whichever occurred first |
|
1 year
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Betamethasone | Women admitted with PPROM who will receive a second course of two betamethasone 12mg intramuscular (IM) injections given 24 hours apart. Betamethasone: Betamethasone 12mg IM given every 24 hours for two doses |
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The study began in 2015 and underwent multiple Principal Investigator (PI) transitions. The data provided represents the information currently available to the study team.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Gayle Olson Koutrouvelis MD, MPH | UTMB | 409-747-4905 | golson@utmb.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | May 16, 2023 | Mar 21, 2025 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| C563032 | Preterm Premature Rupture of the Membranes |
| C566881 | Respiratory Distress Syndrome In Premature Infants |
| D012128 | Respiratory Distress Syndrome |
| ID | Term |
|---|---|
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D012120 | Respiration Disorders |
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| ID | Term |
|---|---|
| D001623 | Betamethasone |
| ID | Term |
|---|---|
| D011246 | Pregnadienetriols |
| D011245 | Pregnadienes |
| D011278 | Pregnanes |
| D013256 | Steroids |
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| Placebo | Drug | Sterile 0.9% normal saline solution given IM every 24 hours for two doses |
|
|
| assessed daily up to 120 days after birth or discharge from hospital, whichever occured first |
| Average Number of Days Requiring Supplemental Oxygen or Ventilatory Support | Amount of time, expressed in days from birth, that the infant required supplemental oxygen of any form, including nasal cannula, positive airway pressure, or ventilatory support. Reported as the mean number of days participants required supplemental oxygen therapy or ventilatory support. | daily from birth until discharge from the NICU or up to 1 year of age, whichever occurred first. |
| Number of Participants Who Developed Respiratory Distress Syndrome (RDS) | Will be quantified as either present or absent. RDS defined as: compatible symptoms with radiographic evidence of hyaline membrane disease or respiratory insufficiency of prematurity requiring ventilatory support for ≥ 24 hrs | assessed daily up to 120 days after birth or discharge from hospital, whichever occurred first |
| Grade III or IV Intraventricular Hemorrhage (IVH) | Will be quantified as either present or absent. Grade III IVH defined as ventricles enlarged by accumulating blood. Grade IV IVH defined as bleeding extending into brain matter around the ventricles. | assessed daily up to 120 days after birth or discharge from hospital, whichever occurred first |
| Number of Participants With Neonatal Sepsis | confirmed by culture in the first 72 hours of life | daily up to 72 hours of life |
| Number of Participants With Necrotizing Enterocolitis (NEC) Stage 2 or 3 | Will be quantified as either present or absent. Stage 2 NEC will be defined as mild to moderate systemic illness, absent bowel sounds, abdominal tenderness, pneumatosis intestinalis or portal venous gas, metabolic acidosis, decreased platelets. Stage 3 NEC will be defined as severely ill, marked distention, signs of peritonitis, hypotension, metabolic & respiratory acidosis, disseminated intravascular coagulopathy, pneumoperitoneum if bowel perforation present. | assessed daily up to 120 days after birth or discharge from hospital, whichever occurred first |
| Number of Perinatal Death(s) | defined as stillbirth or death before neonatal discharge | assessed daily up to 120 days after birth or discharge from hospital, whichever occurred first |
Chorioamnionitis will be defined as at least one temperature elevation above 38°C combined with at least two of the following signs: maternal or fetal tachycardia, uterine tenderness, foul smelling vaginal discharge, white blood count > 18,000. Postpartum endometritis will be defined as postpartum temperature elevation above 38°C without other localizing sources of infection and with either uterine tenderness or foul-smelling lochia.
| time from admission until maternal discharge from the hospital and up until 6 weeks postpartum, or through study completion |
| 9932550 | Background | Elimian A, Verma U, Canterino J, Shah J, Visintainer P, Tejani N. Effectiveness of antenatal steroids in obstetric subgroups. Obstet Gynecol. 1999 Feb;93(2):174-9. doi: 10.1016/s0029-7844(98)00400-1. |
| 10636498 | Background | Elimian A, Verma U, Visintainer P, Tejani N. Effectiveness of multidose antenatal steroids. Obstet Gynecol. 2000 Jan;95(1):34-6. doi: 10.1016/s0029-7844(99)00471-8. |
| 25437730 | Background | Gyamfi-Bannerman C, Son M. Preterm premature rupture of membranes and the rate of neonatal sepsis after two courses of antenatal corticosteroids. Obstet Gynecol. 2014 Nov;124(5):999-1003. doi: 10.1097/AOG.0000000000000460. |
| 18723909 | Background | Mazumder P, Dutta S, Kaur J, Narang A. Single versus multiple courses of antenatal betamethasone and neonatal outcome: a randomized controlled trial. Indian Pediatr. 2008 Aug;45(8):661-7. |
| 11430973 | Background | National Institutes of Health Consensus Development Panel. Antenatal corticosteroids revisited: repeat courses - National Institutes of Health Consensus Development Conference Statement, August 17-18, 2000. Obstet Gynecol. 2001 Jul;98(1):144-50. doi: 10.1016/s0029-7844(01)01410-7. |
| 24084566 | Background | Practice bulletins No. 139: premature rupture of membranes. Obstet Gynecol. 2013 Oct;122(4):918-930. doi: 10.1097/01.AOG.0000435415.21944.8f. |
| 11893433 | Background | Wijnberger LD, Mostert JM, van Dam KI, Mol BW, Brouwers H, Visser GH. Comparison of single and repeated antenatal corticosteroid therapy to prevent neonatal death and morbidity in the preterm infant. Early Hum Dev. 2002 Apr;67(1-2):29-36. doi: 10.1016/s0378-3782(01)00248-1. |
| 15008385 | Background | Yang SH, Choi SJ, Roh CR, Kim JH. Multiple courses of antenatal corticosteroid therapy in patients with preterm premature rupture of membranes. J Perinat Med. 2004;32(1):42-8. doi: 10.1515/JPM.2004.007. |
Women admitted with PPROM who will receive intramuscular saline placebo, given as two injections 24 hours apart. Placebo: Sterile 0.9% normal saline solution given IM every 24 hours for two doses |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
Women admitted with PPROM who will receive intramuscular saline placebo, given as two injections 24 hours apart.
Placebo: Sterile 0.9% normal saline solution given IM every 24 hours for two doses
|
|
| Secondary | Number of Participants With Composite Neonatal Morbidity | defined as ≥ 1 of the following: RDS (oxygen requirement, clinical diagnosis, and consistent chest radiograph), bronchopulmonary dysplasia (requirement for oxygen support at 30 days of life), severe IVH (grades III or IV), periventricular leukomalacia, blood culture-proven sepsis, necrotizing enterocolitis, or perinatal death (stillbirth or death before neonatal hospital discharge) | Neonates were assessed for this Outcome Measure. | Posted | Count of Participants | Participants | assessed daily up to 120 days after birth or discharge from hospital, whichever occured first |
|
|
|
| Secondary | Average Number of Days Requiring Supplemental Oxygen or Ventilatory Support | Amount of time, expressed in days from birth, that the infant required supplemental oxygen of any form, including nasal cannula, positive airway pressure, or ventilatory support. Reported as the mean number of days participants required supplemental oxygen therapy or ventilatory support. | Neonates were assessed for this Outcome Measure. | Posted | Mean | Full Range | days | daily from birth until discharge from the NICU or up to 1 year of age, whichever occurred first. |
|
|
|
| Secondary | Number of Participants Who Developed Respiratory Distress Syndrome (RDS) | Will be quantified as either present or absent. RDS defined as: compatible symptoms with radiographic evidence of hyaline membrane disease or respiratory insufficiency of prematurity requiring ventilatory support for ≥ 24 hrs | Neonates were assessed for this Outcome Measure | Posted | Count of Participants | Participants | assessed daily up to 120 days after birth or discharge from hospital, whichever occurred first |
|
|
|
| Secondary | Grade III or IV Intraventricular Hemorrhage (IVH) | Will be quantified as either present or absent. Grade III IVH defined as ventricles enlarged by accumulating blood. Grade IV IVH defined as bleeding extending into brain matter around the ventricles. | Neonates were assessed for this Outcome Measure. | Posted | Count of Participants | Participants | assessed daily up to 120 days after birth or discharge from hospital, whichever occurred first |
|
|
|
| Secondary | Number of Participants With Neonatal Sepsis | confirmed by culture in the first 72 hours of life | Neonates were assessed for this Outcome Measure. | Posted | Count of Participants | Participants | daily up to 72 hours of life |
|
|
|
| Secondary | Number of Participants With Necrotizing Enterocolitis (NEC) Stage 2 or 3 | Will be quantified as either present or absent. Stage 2 NEC will be defined as mild to moderate systemic illness, absent bowel sounds, abdominal tenderness, pneumatosis intestinalis or portal venous gas, metabolic acidosis, decreased platelets. Stage 3 NEC will be defined as severely ill, marked distention, signs of peritonitis, hypotension, metabolic & respiratory acidosis, disseminated intravascular coagulopathy, pneumoperitoneum if bowel perforation present. | Neonates were assessed for this Outcome Measure. | Posted | Count of Participants | Participants | assessed daily up to 120 days after birth or discharge from hospital, whichever occurred first |
|
|
|
| Secondary | Number of Perinatal Death(s) | defined as stillbirth or death before neonatal discharge | Neonates were assessed for this Outcome Measure. | Posted | Count of Participants | Participants | assessed daily up to 120 days after birth or discharge from hospital, whichever occurred first |
|
|
|
| Other Pre-specified | Labor Latency | time from diagnosis of PPROM from admission until delivery of neonate or until completion of the study | Not Posted | time from admission to delivery up to one year, or through study completion | Participants |
| Other Pre-specified | Infectious Morbidities | Chorioamnionitis will be defined as at least one temperature elevation above 38°C combined with at least two of the following signs: maternal or fetal tachycardia, uterine tenderness, foul smelling vaginal discharge, white blood count > 18,000. Postpartum endometritis will be defined as postpartum temperature elevation above 38°C without other localizing sources of infection and with either uterine tenderness or foul-smelling lochia. | Not Posted | time from admission until maternal discharge from the hospital and up until 6 weeks postpartum, or through study completion | Participants |
| 1 |
| 17 |
| 0 |
| 17 |
| 0 |
| 17 |
| EG001 | Saline Placebo | Women admitted with PPROM who will receive intramuscular saline placebo, given as two injections 24 hours apart. Placebo: Sterile 0.9% normal saline solution given IM every 24 hours for two doses | 1 | 16 | 0 | 16 | 0 | 16 |
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| D000072473 |
| Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D013259 | Steroids, Fluorinated |
| Severe IVH |
|
| Periventricular Leukomalacia |
|
| Blood Culture-Proven Sepsis |
|
| Necrotizing Enterocolitis |
|
| Perinatal Death |
|