By Ahizechukwu C. Eke, MD, MPH
Assistant Professor in Maternal Fetal Medicine, Division of Maternal Fetal Medicine, Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, Baltimore
Dr. Eke reports no financial relationships relevant to this field of study.
SYNOPSIS: In this open-label, equivalence randomized trial of vaginal progestogen compared to intramuscular progestogens for preventing preterm birth in high-risk women, the difference in the risk of preterm birth at < 37 weeks of gestation between both groups was 3.1% (95% confidence interval, -7.6% to 13.8%), which was within the equivalence margin of 15% used in the study.
SOURCE: Choi S-J, Kwak DW, Kil K, et al. Vaginal compared with intramuscular progestogen for preventing preterm birth in high-risk women (VICTORIA Study): A multicentre, open-label randomised trial and meta-analysis. BJOG 2020; June 14. doi: 10.1111/1471-0528.16365. [Online ahead of print].
Preterm birth continues to be a major cause of neonatal morbidity and mortality despite an increase in the use of progestogen supplementation in women at high risk for preterm delivery.1 In this open-label, multicenter, equivalence randomized trial in 21 tertiary centers in South Korea,2 Choi and colleagues described their findings when 200 mg of vaginal progesterone was compared to 250 mg of intramuscular progestogens for the prevention of preterm birth.2 Women were eligible if they were > 20 years of age with a history of prior spontaneous preterm birth or short cervical length (< 25 mm) screened by transvaginal ultrasound between 15 and 22 weeks of pregnancy.2 Exclusion criteria included multiple pregnancies; major congenital anomalies; prophylactic cerclage in current pregnancy; previous history of iatrogenic preterm birth; history of progestogen use within four weeks prior to inclusion in study; history of chronic medical conditions, such as diabetes mellitus, chronic hypertension, epilepsy, heart diseases, asthma, migraine, jaundice, cancer, severe depression, active smoker or alcoholic, hypersensitivity to progestogens, gestational pemphigoid, and porphyria; and a history suspicious of thrombotic disease.2 Eligible women then were randomized to receive either 200 mg vaginal progesterone daily or an intramuscular injection of 250 mg of 17α-hydroxyprogesterone caproate weekly between 16 and 22 weeks of gestation. The primary outcome was preterm birth at
< 37 weeks of gestation. Secondary outcomes included gestational age at delivery, preterm birth at < 34 weeks of gestation, preterm birth at < 28 weeks of gestation, maternal and neonatal morbidities, adverse effects, compliance to medications, and patient satisfaction.
Two hundred sixty-nine women were screened for eligibility between Feb. 12, 2015, and Jan. 1, 2019. Of these, 207 patients were included in the final analysis. The mean age at enrollment was 33 years, with a high proportion of parous women — 93 (78.2%) in the vaginal progesterone arm and 105 (82%) in the intramuscular progesterone arm. The risk of preterm birth at < 37 weeks of gestation in the intention-to-treat analysis was not statistically significant between both groups (vaginal vs. intramuscular group, adjusted relative risk [aRR], 0.845 [0.549-1.301]; P = 0.571). There were no significant differences between women enrolled for a short cervix (n = 103) vs. those enrolled with a history of a prior preterm birth (n = 128).
The risk of the secondary outcomes, including preterm birth at < 34 weeks of gestation (aRR 1.522 [0.741-3.126]; P = 0.222) and preterm birth < 28 weeks of gestation (aRR 2.088 [0.658-6.626]; P = 0.189), was not statistically different between the two groups. The difference in the risk of preterm birth at < 37 weeks of gestation between the two groups was 3.1% (95% confidence interval [CI], -7.6% to 13.8%), which was within the equivalence margin of 15% used in the study.
The primary outcome of this equivalence randomized trial by Choi et al was preterm birth at < 37 weeks of gestation (a surrogate endpoint). The use of surrogate endpoints, defined by the Food and Drug Administration (FDA) as “a marker, such as a laboratory measurement, radiographic image, physical sign, or other measure, that is not itself a direct measurement a clinical benefit”3 as primary efficacy clinical trial endpoints in preterm birth research has been an issue of debate.4 Following the publication of the post-approval confirmatory randomized clinical trial for 17α-hydroxyprogesterone caproate (PROLONG randomized trial)5 in 2019, the FDA held an advisory committee meeting to discuss its findings. The debate included whether gestational age can be used as a surrogate endpoint for how neonates feel, function, and survive. Although gestational age may be a good surrogate endpoint for some clinical outcomes, in preterm birth clinical trials, gestational age, especially in early pregnancy, fails to reliably capture the effect of many interventions in clinical practice.6 Instead, clinical outcomes, such as neonatal morbidity and mortality, serve as better clinical endpoints of how neonates would function and survive.
The authors used an equivalence randomized trial design to study the association between vaginal progesterone and 17α-hydroxyprogesterone caproate and the risk of preterm birth. They noted that the difference in the risk of preterm birth at < 37 weeks of gestation between the two groups was -7.6% to 13.8% (95% CI), which was within the equivalence margin of 15% used in the study. The primary objective of equivalence trials is to show that two medications are not different from each other (are equivalent) within a pre-specified delta margin (interval of clinical equivalence), usually < 20% for most trials. Preterm birth equivalence trials are critically important, especially given the current dilemma in the management of pregnant women with a history of prior spontaneous preterm birth, following the publication of the results of the PROLONG trial. Using equivalence trials, current therapies used for preventing preterm birth (17α-hydroxyprogesterone caproate, cervical pessary, and vaginal progesterone) can be compared in head-to-head randomized trials to determine if these therapies are equivalent. Although Choi et al demonstrated equivalence between 17α-hydroxyprogesterone caproate and vaginal progesterone in this study, it should be noted that equivalence trials often are difficult to understand and interpret in clinical practice. As a result, equivalence trial designs are seldom used in assessing drug effectiveness because the study objective of equivalence trials is to show that a new therapy (vaginal progesterone in this case) is equivalent to standard therapy (17α-hydroxyprogesterone caproate).
Since this is an equivalence trial, a reasonable conclusion for clinicians in practice would be that vaginal progesterone is equivalent to 17α-hydroxyprogesterone caproate (within the pre-specified margin of effect of ±15%) for the management of women with a history of prior spontaneous preterm birth and/or short cervical length. As such, interpreting this study as “vaginal progesterone is as ‘effective’ as 17α-hydroxyprogesterone caproate” would be incorrect, since the primary aim of equivalence trials is to evaluate equivalence, not effectiveness.
- Eke AC, Sheffield J, Graham EM. 17α-hydroxyprogesterone caproate and the risk of glucose intolerance in pregnancy: A systematic review and meta-analysis. Obstet Gynecol 2019;133:468-475.
- Choi S-J, Kwak DW, Kil K, et al. Vaginal compared with intramuscular progestogen for preventing preterm birth in high-risk pregnant women (VICTORIA study): A multicentre, open-label randomised trial and meta-analysis. BJOG 2020; June 14. doi: 10.1111/1471-0528.16365. [Online ahead of print].
- Food and Drug Administration. FDA facilitates the use of surrogate endpoints in drug development. Nov. 5, 2018. https://www.fda.gov/drugs/fda-facilitates-use-surrogate-endpoints-drug-development-november-5-2018-issue
- Meher S, Alfirevic Z. Choice of primary outcomes in randomised trials and systematic reviews evaluating interventions for preterm birth prevention: A systematic review. BJOG 2014;121:1188-1194; discussion 1195-1196.
- Blackwell SC, Gyamfi-Bannerman C, Biggio JR Jr, et al. 17-OHPC to prevent recurrent preterm birth in singleton gestations (PROLONG Study): A multicenter, international, randomized double-blind trial. Am J Perinatol 2020;37:127-136.
- Temple RJ. A regulatory authority's opinion about surrogate endpoints. In: Nimmo WS, Tucker GT, eds. Clinical Measurement in Drug Evaluation. Wiley;1995:3-22.