A multicenter, randomized, open-label, investigator initiated trial of vaginal compared with intramuscular progesterone for prevention of preterm birth in high risk pregnant wome

Not Applicable

Completed

• Conditions: Pregnancy, childbirth and the puerperium

• Registration Number: KCT0004006
• Lead Sponsor: Ewha Womans University

Brief Summary

Objectives: The aim of this study is to compare the efficacy of two different regimens of progesterone therapy in preventing preterm birth (PTB) less than 37 weeks of gestation. Methods: This is a multi-center, randomized, open-label, equivalence trial including pregnant women with a history of prior spontaneous PTB or short cervical length (CL) (<25 mm). Eligible subjects were screened at 15-22 weeks of gestation and randomized to either use of daily 200 mg vaginal micronized natural progesterone (vaginal group) or weekly intramuscular injection of 250 mg 17a-hydroxyprogesterone caproate (IM group). Stratified randomization was carried out according to participitating centers and indications of progesterone therapy as follow: (A) history of prior spontaneous PTB and CL =25 mm, (B) CL <25 mm without history of prior spontaneous PTB, (C) history of prior spontaneous PTB and CL <25 mm. Progesterone treatment was continued until either 36 completed weeks of gestation or occurrence of premature rupture of membranes or PTB. The primary outcome variable was PTB <37 weeks of gestation, and the secondary outcome were PTB <34, <28 weeks of gestation, maternal and neonatal morbidities, adverse events, compliance of medication, and patient preference. Both intention-to-treat and per protocol analysis were performed. This trial is registered at ClinicalTrials.gov (NCT02304237). Results: Between Feb 11, 2015, and Aug 22, 2018, 266 women were randomly assigned into the vaginal group (n=131) and the IM group (n=135). Thirty-six women were dopped out after randomization (20 and 16 women in the vaginal and IM group, respectively), and a total of 230 (111 and 119 women in the vaginal and IM group, respectively) were available for intention-to-treat analysis. The two groups were comparable regarding the maternal characteristics, obstetric history, CL at randomization, and follow up CL measurements, however, the compliance of medication was significantly lower in the vaginal group compared to the IM group (93.4±13.3% vs. 97.5±8.5%, P=0.011). The rates of PTB <37 weeks of gestation were not significantly different between the two groups (24.3% vs. 25.2%, p=0.876). The difference in the rates of PTB <37 weeks of gestation between two groups was 0.9%, and the 95% confidence intervals was -12.1% and 10.3%, which were within the pre-set equivalence margin of 15%. The secondary outcomes including PTB <34, <28 weeks of gestation, maternal and neonatal morbidities, adverse events, and patient preference were similar in the two groups. The results were similar in the per protocol analysis. Conclusion: Daily vaginal progesterone administration and weekly intramuscular progesterone injection were equivalent regarding the efficacy of prevention of PTB <37 weeks of gestation in women with a history of prior spontaneous PTB or short CL.

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Last Update Posted: 17 June 2019

Recruitment & Eligibility

• Status: Completed
• Sex: Female
• Target Recruitment: 266

Inclusion Criteria

1. Pregnant women at age >20 years
2. Women with a history of prior spontaneous preterm birth (PTB) or short cervical length (CL)
- Spontaneous PTB: PTB <37 weeks of gestation due to spontaneous preterm labor or preterm premature rupture of membranes
- Short cervical length(CL): CL <25 mm as measured by transvaginal ultrasound at 15-22 weeks of gestation
3. Women who are at 16-22 weeks of gestation at the point of the first administration of investigational drugs
4. Pregnant women who give informed consent to the study

Exclusion Criteria

1.Multifetal pregnancy
2.Major congenital anomalies diagnosed during antenatal examination
3.Elective prophylactic cervical cerclage <16 weeks of gestation during current pregnancy
4.Dilated cervix
5.Previous intentional preterm birth due to maternal or fetal indications, such as preeclampsia and fetal growth restriction
6.Type I or II diabetes mellitus
7.Epilepsy
8.Chronic medical diseases including uncontrolled hypertension (systolic blood pressure = 160 mmHg or diastolic blood pressure 110 mmHg at screening), chronic renal disease (serum creatinine level of more than two-folds than upper normal range), and renal failure who needs dialysis
9.History of progesterone therapy within 4 weeks before screening
10.Severe heart diseases, asthma, migraine liver diseases, hepatic tumor, cholestatic jaundice (serum aspartate transaminase, alanine transaminase, bilirubin level of more than more than two-folds than upper normal range)
11.Unknown abnormal uterine bleeding
12.History or suspicious of breast cancer, uterine cancer or other reproductive organ cancer, and history of other cancer during the past 5 years
13.History or suspicious of thrombotic diseases (thrombotic phlebitis, cerebrovascular diseases, pulmonary embolism, retinal thrombosis)
14.History of gestational herpes
15.Porphyria
16.Severe depression
17.Women who need other vaginal treatment
18.Heavy smoker or alcohol abuse
19.Participants of other clinical trial during the past 3 months of screening (non-interventional observational studies are not excluded)
20.Hypersensitivity to progesterone
21.Any other patients who are judged by investigators to be inappropriate for participation in the trial

Study & Design

• Study Type: Interventional Study
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Preterm birth <37 weeks of gestation

Secondary Outcome Measures

Name	Time	Method
Preterm birth <34 weeks of gestation;Preterm birth <28 weeks of gestation;Neonatal outcome;Neonatal complication;Maternal complication;Compliance;Patient's preference;Adverse effects