Search

Study Question: Are progesterone vaginal pessaries 400 mg twice a day (bid) non-inferior to progesterone vaginal gel (90 mg) once a day (od) in the primary endpoint of clinical pregnancy rate after 38 days of luteal phase support in women undergoing in vitro fertilisation (IVF)?Summary Answer: Non-inferiority of progesterone vaginal pessaries 400 mg bid to progesterone 8% vaginal gel (90 mg od) was shown for clinical pregnancy rate after 38 days of luteal phase support.What Is Known Already: To maximise successful embryo transfer after IVF, additionally administered progesterone is used for proper endometrium transformation in the luteal phase. Vaginally administered progesterone results in adequate secretory transformation of the endometrium.Study Design, Size, Duration: This multicentre, multinational, open, randomised, two-parallel group, non-inferiority Phase 3 clinical trial was carried out at 17 study sites in five European countries (Belgium, Bulgaria, Czech Republic, Hungary and Serbia) between October 2013 and August 2014. An interactive web response system (IWRS) was implemented for treatment allocation at the sites. Power analysis, based on the assumptions of a non-inferiority margin of -9%, a significance level of α 2.5% (one-sided), power 90%, at a reference pregnancy rate for the progesterone vaginal gel group of 30%, as well as applying a dropout rate of 10%, yielded a total number of 766 patients to be randomised.Participants/materials, Setting, Methods: Women aged between 18 and 40 years with a clinical indication for IVF/intracytoplasmic sperm injection (ICSI) and embryo transfer were eligible to participate. The clinical pregnancy rate was assessed by fetal heart movement measured by transvaginal ultrasound at day 38 (D38) (primary endpoint) and D70. Also assessed were biochemical pregnancy rate (assessed by serum β-hCG ≥25 IU/L), clinical implantation rates at D38, patient evaluation of vaginal bleeding and discharge (assessed by diary) and adverse event (AE) incidence, severity and relationship to study medication.Main Results and the Role Of Chance: A total of 769 female patients were randomised to progesterone 400 mg vaginal pessaries bid (n = 385, 50.1%) or progesterone 90 mg vaginal gel od (n = 384, 49.9%). Patients receiving progesterone vaginal pessaries and progesterone vaginal gel were comparable in demographics, baseline characteristics and number of retrieved oocytes. In the full analysis set (FAS; n = 369 progesterone vaginal pessaries and n = 368 progesterone vaginal gel), clinical pregnancy rates on D38 were 38.3% for progesterone vaginal pessaries and 39.9% for progesterone vaginal gel. In the per protocol analysis set (PP; n = 357 progesterone vaginal pessaries and n = 356 progesterone vaginal gel), clinical pregnancy rates on D38 were 38.1% for progesterone vaginal pessaries and 40.4% for progesterone vaginal gel. For the differences in pregnancy rates between the progesterone vaginal pessaries group and the progesterone vaginal gel, the lower limit of the 97.5% CI was -8.6 and -9.5% for the FAS and PP datasets, respectively. The original prespecified non-inferiority margin of -9% was thus met in the FAS dataset but was marginally below this in the PP dataset. However, the pregnancy rate of the comparator was higher than the anticipated rate of 30%, and a predetermined logistic regression model including treatment group, country and age group effects without interaction terms showed non-inferiority of progesterone vaginal pessaries to progesterone vaginal gel for both the FAS and PP populations, in that the lower limits of the 95% CIs were above 0.7 for both analyses. As a result of this, the relevant authorities accepted to widen the acceptable non-inferiority margin to -10%, and as such both the FAS and PP populations succeeded in showing non-inferiority. Biochemical pregnancy and clinical implantation rates were comparable for both treatments. Both treatment groups showed similar high compliance throughout the study, and the safety profiles were also comparable between the groups. Drug-related AEs occurred with frequencies of 15.1% with progesterone vaginal pessaries and 14.4% with progesterone vaginal gel.Limitations, Reasons For Caution: Clinical pregnancy rate is a surrogate for the outcome of live birth rate.Wider Implications Of the Findings: Progesterone 400 mg pessaries bid for luteal phase support is an effective, safe and tolerable treatment option for women undergoing IVF during ART.Study Funding/competing Interest(s): This work was funded by Actavis Group PTC ehf., Iceland, part of Teva Pharmaceuticals, and by L.D. Collins & Co. Ltd. Gedeon Richter plc has recently entered into a license and distribution agreement to commercialise the vaginal pessaries in the European Union (except Ireland/UK). The progesterone vaginal pessaries studied are now marketed as Cyclogest®, Amelgen®, Cyclovita®, Luteum and Cygest® throughout the EU, Asia and Middle East & North Africa. The competing interests are as follows. H.S.: employee of Gedeon Richter plc/PregLem S.A. C.K.: consultant to L.D. Collins & Co. Ltd and received consulting fees for work performed. T.D.H.: at the initiation and completion of this study, full professor at KU Leuven and Head of Leuven University Fertility Center at the University Hospital Gasthuisberg, Leuven, Belgium. In October 2015, T.D.H. became vice president of Global Medical Affairs Fertility at the pharmaceutical company Merck-marketing authorisation holder of the Progesterone vaginal gel (Crinone®)-and has remained a part-time professor at KU Leuven (Belgium) and adjunct professor at Yale University (New Haven, CT, USA). T.B.M.: at the initiation and completion of this study, employee of Actavis Group PTC ehf. I.K.: consultant to Actavis, later TEVA and received consulting fees for work performed. S.H.: at the initiation and completion of this study, employee of Actavis Group PTC ehf.Trial Registration Number: EudraCT number 2013-001105-81.Trial Registration Date: 2 July 2013.Date Of First Patient’s Enrolment: 9 October 2013. [ABSTRACT FROM AUTHOR]

Introduction: The present study aimed to assess the costs and consequences of using an innovative medical technology, misoprostol vaginal insert (MVI), for the induction of labor (IOL), in place of alternative technologies used as a standard of care.Methods: This was a retrospective study on cost and resource utilization connected with economic model development. Target population were women with an unfavorable cervix, from 36 weeks of gestation, for whom IOL is clinically indicated. Data on costs and resources was gathered via a dedicated questionnaire, delivered to clinical experts in five EU countries. The five countries participating in the project and providing completed questionnaires were Austria, Poland, Romania, Russia and Slovakia. A targeted literature review in Medline and Cochrane was conducted to identify randomized clinical trials meeting inclusion criteria and to obtain relative effectiveness data on MVI and the alternative technologies. A hospital perspective was considered as most relevant for the study. The economic model was developed to connect data on clinical effectiveness and safety from randomized clinical trials with real life data from local clinical practice.Results: The use of MVI in most scenarios was related to a reduced consumption of hospital staff time and reduced length of patients' stay in hospital wards, leading to lower total costs with MVI when compared to local comparators.Conclusions: IOL with the use of MVI generated savings from a hospital perspective in most countries and scenarios, in comparison to alternative technologies.Funding: Sponsorship, article processing charges, and the open access charge for this study were funded by Ferring Pharmaceuticals Poland. [ABSTRACT FROM AUTHOR]

Background: In women with a singleton pregnancy and sonographic short cervix in midgestation, vaginal administration of progesterone reduces the risk of early preterm birth and improves neonatal outcomes without any demonstrable deleterious effects on childhood neurodevelopment. In women with twin pregnancies, the rate of spontaneous early preterm birth is 10 times higher than that in singletons, and in this respect, all twins are at an increased risk of preterm birth. However, 6 trials in unselected twin pregnancies reported that vaginal administration of progesterone from midgestation had no significant effect on the incidence of early preterm birth. Such apparent lack of effectiveness of progesterone in twins may be due to inadequate dosage or treatment that is started too late in pregnancy.Objective: The early vaginal progesterone for the prevention of spontaneous preterm birth in twins, a randomized, placebo-controlled, double-blind trial, was designed to test the hypothesis that among women with twin pregnancies, vaginal progesterone at a dose of 600 mg per day from 11 to 14 until 34 weeks' gestation, as compared with placebo, would result in a significant reduction in the incidence of spontaneous preterm birth between 24+0 and 33+6 weeks.Study Design: The trial was conducted at 22 hospitals in England, Spain, Bulgaria, Italy, Belgium, and France. Women were randomly assigned in a 1:1 ratio to receive either progesterone or placebo, and in the random-sequence generation, there was stratification according to the participating center. The primary outcome was spontaneous birth between 24+0 and 33+6 weeks' gestation. Statistical analyses were performed on an intention-to-treat basis. Logistic regression analysis was used to determine the significance of difference in the incidence of spontaneous birth between 24+0 and 33+6 weeks' gestation between the progesterone and placebo groups, adjusting for the effect of participating center, chorionicity, parity, and method of conception. Prespecified tests of treatment interaction effects with chorionicity, parity, method of conception, compliance, and cervical length at recruitment were performed. A post hoc analysis using mixed-effects Cox regression was used for further exploration of the effect of progesterone on preterm birth.Results: We recruited 1194 women between May 2017 and April 2019; 21 withdrew consent and 4 were lost to follow-up, which left 582 in the progesterone group and 587 in the placebo group. Adherence was good, with reported intake of ≥80% of the required number of capsules in 81.4% of the participants. After excluding births before 24 weeks and indicated deliveries before 34 weeks, spontaneous birth between 24+0 and 33+6 weeks occurred in 10.4% (56/541) of participants in the progesterone group and in 8.2% (44/538) in the placebo group (odds ratio in the progesterone group, adjusting for the effect of participating center, chorionicity, parity, and method of conception, 1.35; 95% confidence interval, 0.88-2.05; P=.17). There was no evidence of interaction between the effects of treatment and chorionicity (P=.28), parity (P=.35), method of conception (P=.56), and adherence (P=.34); however, there was weak evidence of an interaction with cervical length (P=.08) suggestive of harm to those with a cervical length of ≥30 mm (odds ratio, 1.61; 95% confidence interval, 1.01-2.59) and potential benefit for those with a cervical length of <30 mm (odds ratio, 0.56; 95% confidence interval, 0.20-1.60). There was no evidence of difference between the 2 treatment groups for stillbirth or neonatal death, neonatal complications, neonatal therapy, and poor fetal growth. In the progesterone group, 1.4% (8/582) of women and 1.9% (22/1164) of fetuses experienced at least 1 serious adverse event; the respective numbers for the placebo group were 1.2% (7/587) and 3.2% (37/1174) (P=.80 and P=.06, respectively). In the post hoc time-to-event analysis, miscarriage or spontaneous preterm birth between randomization and 31+6 weeks' gestation was reduced in the progesterone group relative to the placebo group (hazard ratio, 0.23; 95% confidence interval, 0.08-0.69).Conclusion: In women with twin pregnancies, universal treatment with vaginal progesterone did not reduce the incidence of spontaneous birth between 24+0 and 33+6 weeks' gestation. Post hoc time-to-event analysis led to the suggestion that progesterone may reduce the risk of spontaneous birth before 32 weeks' gestation in women with a cervical length of <30 mm, and it may increase the risk for those with a cervical length of ≥30 mm. [ABSTRACT FROM AUTHOR]