Clinical trial NCT00163020: 17OHP for Reduction of Neonatal Morbidity Due to Preterm Birth (PTB) in Twin and Triplet Pregnancies
Official title: 17-Alpha-Hydroxyprogesterone Caproate for Reduction of Neonatal Morbidity Due to Preterm Birth in Twin and Triplet Pregnancies - A Concurrent Randomized Double-blinded Clinical Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Preterm Birth
Keywords: Preterm Birth
Preterm Delivery
Multiple gestation
17-alpha-hydroxyprogesterone caproate
Progesterone
Lead sponsor: Pediatrix
Sponsor class: OTHER
First posted: 2005-09-13
Enrollment: 321
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Hypothesis: Among women with twin or triplet pregnancies, weekly injections of 17-alpha-hydroxyprogesterone caproate (17OHP), started before 24 weeks of gestation, will reduce neonatal morbidity by reducing the rate of preterm delivery.

This study involves two concurrent double-blinded randomized clinical trials of 17OHP versus placebo. Each trial will test the efficacy and safety of 17OHP in women with a specific risk factor for preterm birth. The two risk factors to be studied are:

1. Twin pregnancy
2. Triplet pregnancy

Detailed description: Prematurity is a leading cause of neonatal morbidity and mortality in the USA. Nationally, 12% of all babies deliver before term and 3% deliver before 32 wks gestational age (GA). Recent studies suggest that 17OHP and other progesterone derivatives may reduce the rate of preterm birth among women with a history of prior preterm birth. However, it has not been demonstrated that this reduction in preterm birth is accompanied by a clinically significant reduction in neonatal complications. Further, most women who deliver preterm have no history of a prior preterm birth. Little is known about whether progesterone treatment is effective in women with other risk factors for preterm birth such as multiple gestation. The proposed study will assess the role of 17OHP in women with twin or triplet pregnancies and will assess the impact on neonatal health, not merely the impact on gestational age at delivery. Prior studies were not designed to be large enough to have statistical power to assess effects on neonatal morbidity.

In the 6 trials combined in the Goldstein meta-analysis, only 279 women were treated with 17OHP and only 73 women had a preterm delivery. The NICHD study presented by Meis approximately doubles the world-wide experience, with 306 women under treatment, of whom 73 delivered prior to 35 wks. Yet, this study was not designed to have power to show a reduction in neonatal complications but only a reduction in preterm birth rates.

The present study is the first to be specifically designed to have adequate power to test whether 17OHP reduces neonatal morbidity among women with one of two specific risk factors for preterm birth.

Eligibility criteria: Inclusion Criteria:

1. Gestational age (GA) 15-23w0d gestational age at the time of recruitment
2. GA 16w0dk to 23w6d at the time of randomization and initiation of injections
3. Maternal age 18 years or older
4. One of these risk factors for spontaneous preterm birth:

   1. Twins in current pregnancy, dichorionic placentation
   2. Triplets in current pregnancy, trichorionic placentation
5. Intact membranes
6. Patient has had at least one detailed 2nd-trimester ultrasound examination documenting placentation, chorionicity, fetal number, fetal size, amniotic fluid volumes, and fetal anatomy. (This examination must comply with minimum standards such as those published by the American Institute of Ultrasound in Medicine, American College of Radiology, or American College of Obstetricians \& Gynecologists It is NOT mandatory that this examination be performed at the research-study center.)
7. Investigator believes patient will be reliable with follow-up visits and believes that delivery data and neonatal data are likely to be available.

Exclusion Criteria:

1. Symptomatic uterine contractions in current pregnancy
2. Contraindication to interventions intended to prolong the pregnancy (including lethal fetal anomalies, amnionitis, preeclampsia, severe oligohydramnios, severe growth delay, fetal death appears imminent or inevitable)
3. Risk factors for major neonatal morbidity unrelated to preterm delivery (such as monochorionic placentation in multiple gestation, major malformations, certain medication exposures)
4. Preexisting maternal medical condition that might be worsened by progesterone therapy, including: asthma requiring medications, renal insufficiency, seizure disorder, ischemic heart disease, active cholecystitis, impaired liver function, history of thromboembolic disorder, history of breast cancer, history of major depression requiring hospitalization.
5. Preexisting maternal medical condition associated with a high risk of preterm delivery including: refractory hypertension, diabetes with nephropathy or retinopathy, renal insufficiency, active systemic lupus erythematosus. Note that a history of prior preterm birth is NOT an exclusion.
6. Use of progesterone or progesterone-derivative medication after 15 weeks gestation in current pregnancy.
7. Allergy to 17OHP or oil vehicle.
8. Placement of emergent cerclage (defined as one placed after the occurrence of cervical change such as dilation, funneling, or effacement) with this pregnancy. Prophylactic cerclage is NOT an exclusion (defined as one placed before any cervical change, for example, because of a history of cervical incompetence, or because of a prior cervical procedure such as LEEP or cone biopsy).

Primary outcomes:
measure: Newborn Respiratory Distress Syndrome (RDS)
timeFrame: Measured from delivery until 30 days after baby was discharged from the hospital
measure: Use of Oxygen Therapy at 28 Days of Newborn Life
timeFrame: Measured at 28 days after birth.
measure: Newborn Sepsis
timeFrame: measured during the first week following birth
measure: Newborn Pneumonia
timeFrame: measure during the first 28 days after birth.
measure: Newborn Intraventricular Hemorrhage Grade 3 or 4
timeFrame: measured during the first 28 days after birth
measure: Newborn Periventricular Leukomalacia (PVL)
timeFrame: measured in the first 28 days after birth.
measure: Newborn Necrotizing Enterocolitis (NEC)Requiring Surgery
timeFrame: measured in the first 28 days after birth
measure: Newborn Retinopathy of Prematurity (ROP)
timeFrame: measured during the first 28 day after birth
measure: Newborn Asphyxia With Ischemic Injury of Brain, Heart, Kidneys, or Liver
timeFrame: measured during the first 28 days after delivery
measure: Perinatal Death
timeFrame: measured from randomization to 28 days after birth.
Secondary outcomes:
measure: Individual Components of Neonatal Morbidity (RDS, IVH-III/IV, Bronchopulmonary Dysplasia(BPD), PVL, Sepsis, NEC, ROP-Stage 3/4, Perinatal Death)
timeFrame: measured as any event noted in the first 28 day following birth.
measure: Twins: Delivery Prior to 28 Weeks (Wks), 32 Wks, 34wks, and 37 Wks
timeFrame: Gestational age noted at time of birth
measure: Triplets: Delivery Prior to 28 Wks, 32 Wks, 35 Wks
timeFrame: noted at delivery
measure: Newborn Gestational Age (GA) at Delivery
timeFrame: determined at the time of birth
measure: Newborn Birthweight
timeFrame: measure following delivery
measure: Participant Drop-out Rates
timeFrame: any time from randomization to completion of final dose of study medication
measure: Participant Side Effects Requiring Cessation of Therapy
timeFrame: anytime from initial injection to final injection at 34 weeks.
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Banner Good Samaritan Hospital
state: Arizona
city: Tucson
country: United States
facility: Tucson Medical Center
state: Arizona
city: Laguna Hills
country: United States
facility: Saddleback Memorial Medical Center
state: California
city: Long Beach
country: United States
facility: Long Beach Memorial Medical Center
state: California
city: Orange
country: United States
facility: University of Southern California-Irvine Medical Center
state: California
city: San Jose
country: United States
facility: Good Samaritan Hospital
state: California
city: Denver
country: United States
facility: Swedish Medical Center
state: Colorado
city: Denver
country: United States
facility: Presbyterian/St Luke's Hospital
state: Colorado
city: Denver
country: United States
facility: Rose Medical Center
state: Colorado
city: Lonetree
country: United States
facility: Skyridge Medical Center
state: Colorado
city: Des Moines
country: United States
facility: Mercy Medical Center
state: Iowa
city: Kansas City
country: United States
facility: Saint Luke's Hospital, Kansas City
state: Missouri
city: Chattanooga
country: United States
facility: Erlanger Medical Center
state: Tennessee
city: Dallas
country: United States
facility: Baylor University Medical Center
state: Texas
city: Fort Worth
country: United States
facility: Harris Methodist Fort Worth Hospital
state: Texas
city: Kirkland
country: United States
facility: Evergreen Hospital
state: Washington
city: Seattle
country: United States
facility: Swedish Medical Center
state: Washington
city: Tacoma
country: United States
facility: Tacoma General Hospital
state: Washington
Study officials:
affiliation: Obstetrix Medical Group, Inc.
name: Kimberly Maurel, RN, MSN, CNS
role: STUDY_DIRECTOR
affiliation: Obstetrix Medical Group, Inc.
name: Andrew Combs, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Goldstein P, Berrier J, Rosen S, Sacks HS, Chalmers TC. A meta-analysis of randomized control trials of progestational agents in pregnancy. Br J Obstet Gynaecol. 1989 Mar;96(3):265-74. doi: 10.1111/j.1471-0528.1989.tb02385.x.
citation: da Fonseca EB, Bittar RE, Carvalho MH, Zugaib M. Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: a randomized placebo-controlled double-blind study. Am J Obstet Gynecol. 2003 Feb;188(2):419-24. doi: 10.1067/mob.2003.41.
citation: Meis PJ, Klebanoff M, Thom E, Dombrowski MP, Sibai B, Moawad AH, Spong CY, Hauth JC, Miodovnik M, Varner MW, Leveno KJ, Caritis SN, Iams JD, Wapner RJ, Conway D, O'Sullivan MJ, Carpenter M, Mercer B, Ramin SM, Thorp JM, Peaceman AM, Gabbe S; National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med. 2003 Jun 12;348(24):2379-85. doi: 10.1056/NEJMoa035140.
citation: American College of Obstetricians & Gynecologists. Special problems of multiple gestation. Educational Bulletin 253, 1998.