Barbara Cometti

A randomized, controlled trial comparing the efficacy and safety of aqueous subcutaneous progesterone with vaginal progesterone for luteal phase support of in vitro fertilization

STUDY QUESTION Is the ongoing pregnancy rate with a new aqueous formulation of subcutaneous progesterone (Prolutex®) non-inferior to vaginal progesterone (Endometrin®) when used for luteal phase support of in vitro fertilization? SUMMARY ANSWER In the per-protocol (PP) population, the ongoing pregnancy rates per oocyte retrieval at 12 weeks of gestation were comparable between Prolutex and Endometrin (41.6 versus 44.4%), with a difference between groups of −2.8% (95% confidence interval (CI) −9.7, 4.2), consistent with the non-inferiority of subcutaneous progesterone for luteal phase support. WHAT IS KNOWN ALREADY Luteal phase support has been clearly demonstrated to improve pregnancy rates in women undergoing in vitro fertilization (IVF). Because of the increased risk of ovarian hyperstimulation syndrome associated with the use of hCG, progesterone has become the treatment of choice for luteal phase support. STUDY DESIGN, SIZE, DURATION This prospective, open-label, randomized, controlled, parallel-group, multicentre, two-arm, non-inferiority study was performed at eight fertility clinics. A total of 800 women, aged 18–42 years, with a BMI of ≤30 kg/m2, with <3 prior completed assisted reproductive technology (ART) cycles, exhibiting baseline (Days 2–3) FSH of ≤15 IU/L and undergoing IVF at 8 centres (seven private, one academic) in the USA, were enrolled from January 2009 through June 2011. PARTICIPANTS/MATERIALS, SETTING, METHODS In total, 800 women undergoing IVF were randomized after retrieval of at least three oocytes to an aqueous preparation of progesterone administered subcutaneously (25 mg daily) or vaginal progesterone (100 mg bid daily). Randomization was performed to enrol 100 patients at each site using a randomization list that was generated with Statistical Analysis Software (SAS®). If a viable pregnancy occurred, progesterone treatment was continued up to 12 weeks of gestation. MAIN RESULTS AND THE ROLE OF CHANCE Using a PP analysis, which included all patients who received an embryo transfer (Prolutex = 392; Endometrin = 390), the ongoing pregnancy rate per retrieval for subcutaneous versus vaginal progesterone was 41.6 versus 44.4%, with a difference between groups of −2.8% (95% CI −9.7, 4.2), consistent with the non-inferiority of subcutaneous progesterone for luteal phase support. In addition, rates of initial positive β-hCG (56.4% subcutaneous versus 59.0% vaginal; 95% CI −9.5, 4.3), clinical intrauterine pregnancy with fetal cardiac activity (42.6 versus 46.4%; 95% CI −10.8, 3.2), implantation defined as number of gestational sacs divided by number of embryos transferred (33.2 versus 35.1%; 95% CI −7.6, 4.0), live birth (41.1 versus 43.1%; 95% CI −8.9, 4.9) and take-home baby (41.1 versus 42.6%; 95% CI −8.4, 5.4) were comparable. Both formulations were well-tolerated, with no difference in serious adverse events. Analysis with the intention-to-treat population also demonstrated no difference for any outcomes between the treatment groups. LIMITATIONS, REASONS FOR CAUTION The conclusions are limited to the progesterone dosing regimen studied and duration of treatment for the patient population examined in this study. WIDER IMPLICATIONS OF THE FINDINGS Subcutaneous progesterone represents a novel option for luteal phase support in women undergoing IVF who for personal reasons prefer not to use a vaginal preparation or who wish to avoid the side effects of vaginal or i.m. routes of administration. STUDY FUNDING/COMPETING INTERESTS The study was funded by Institut Biochimique SA (IBSA). CAJ, BC, ST and CJ are employees of IBSA. FH currently consults for IBSA. TRIAL REGISTRATION NUMBER NCT00828191.

Factors affecting success rates in two concurrent clinical IVF trials: an examination of potential explanations for the difference in pregnancy rates between the United States and Europe

OBJECTIVE To compare a US clinical trial of gonadotropin therapy for IVF with a similar European trial to determine what factors may explain the higher clinical pregnancy rate in the US trial. DESIGN Comparison of baseline, treatment, and outcome variables in the United States (US) and European trials. SETTING IVF practices in the US (n=4) and Europe (n=6). PATIENT(S) 297 women undergoing IVF. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Clinical pregnancy rate. RESULT(S) Clinical pregnancy rates were 43.4% in the US compared with 29.7% in Europe (p=0.016), with a live birth rate of 38.2% versus 27.6% (p=0.064). This difference in clinical pregnancy rate could not be explained by differences in the US versus Europe for number of embryos transferred (2.3 vs. 2.6) or female age (34.6 vs. 30.4). Although the starting dose of gonadotropin was higher in the US trial compared with the European trial (300 versus 225 IU), the total dose of gonadotropin was only slightly higher in the US. In multiple logistic regression analysis of 81 pretransfer variables on clinical pregnancy, the only two found to be significant predictors of outcome were baseline endometrial thickness following down-regulation and number of days of gonadotropin treatment. CONCLUSION(S) This study suggests the possibility that US pregnancy rates may be higher in part because of differences in down-regulation or gonadotropin dosing. Other factors not assessed in these studies or in national datasets likely also contribute to the difference in pregnancy rates.

Pharmacokinetics and safety profile of a novel progesterone aqueous formulation administered by the s.c. route

A novel aqueous progesterone formulation was developed. Study I: Three-way cross-over, open-label study in 24 post-menopausal women. Comparison of the pharmacokinetic profiles of a single 100 mg dose of test product administered by subcutaneous (s.c.) and intramuscular (i.m.) injection and an i.m. reference oily product. Study II: Three-way cross-over open-label study of 25, 50 and 100 mg s.c. single doses of the aqueous formulation in 12 post-menopausal women. Study III: Parallel-group, observer-blinded study in 25 fertile women administered multiple s.c. 25 and 50 mg doses of the aqueous formulation once daily for 11 days. Baseline-corrected pharmacokinetic parameters were evaluated. Aqueous formulation (100 mg) was promptly absorbed, achieving progesterone peak serum levels at an earlier time than the reference (1 h vs. 7 h; p < 0.0001). Test and reference were bioequivalent in the extent of exposure: confidence intervals for AUC0-t geometric means ratios were within the pre-specified 80–125% limits. Pharmacokinetics was linear over the range of doses studied. Steady state was reached within 4 days of multiple dose treatment. All treatments were well tolerated. Considering the advantages given by the possibility of self-medication, the s.c. aqueous formulation could offer a convenient alternative for patients on assisted reproductive technology treatments.

A randomized trial comparing the endometrial effects of daily subcutaneous administration of 25 mg and 50 mg progesterone in aqueous preparation.

OBJECTIVE To study the efficacy of a new P preparation in aqueous solution for subcutaneous injection for inducing the predecidual transformation of the endometrium. DESIGN Prospective, single-blinded, randomized, parallel pilot trial. SETTING University-affiliated clinical research center. PATIENT(S) Twenty-five regularly cycling female volunteers. INTERVENTION(S) Volunteers, aged 18-45 years, body mass index 19-25 kg/m(2), whose ovaries were suppressed with a GnRH agonist were estrogenized for 14 or 21 days with the use of transdermal systems delivering 0.1 mg/d E₂. After confirming that the endometrial thickness was >7 mm, the women were randomized to 25 mg or 50 mg of subcutaneous P injections daily for 11 days, after which the endometrium was sampled with the use of a Pipelle device. The endometrial biopsies were evaluated by two independent pathologists. Adverse events and subjective tolerance were checked every day by the study investigator. MAIN OUTCOME MEASURE(S) Predecidual changes in endometrial biopsies obtained after 11 days of subcutaneous administration of P. RESULT(S) Of 24 biopsies performed (one dropout), 22 provided tissue for histologic analysis. Evidence of predecidual changes in the endometrial stroma was found in 100% of the cases, with no differences between the two studied doses. CONCLUSION(S) Both doses of the new aqueous P preparation available for subcutaneous administration demonstrated predecidual changes in 100% of the interpretable endometrial biopsies in total absence of endogenous P. This offers good prospect of efficacy in luteal phase support for the lowest dose tested, 25 mg/d, the physiologic amount produced daily by the ovary during the midluteal phase. CLINICAL TRIAL REGISTRATION NUMBER NCT00377923.

Subcutaneous Progesterone Is Effective and Safe for Luteal Phase Support in IVF: An Individual Patient Data Meta-Analysis of the Phase III Trials.

Objective To summarize efficacy and safety data on a new progesterone compound which is available for subcutaneous administration as compared to vaginally administered progesterone for luteal phase support in patients undergoing IVF treatment. Design Data from two randomized phase III trials (07EU/Prg06 and 07USA/Prg05) performed according to GCP standards with a total sample size of 1435 per-protocol patients were meta-analyzed on an individual patient data level. Setting University affiliated reproductive medicine unit. Patients Subcutaneous progesterone was administered to a total of 714 subjects and vaginal progesterone was administered to a total of 721 subjects who underwent fresh embryo transfer after ovarian stimulation followed by IVF or ICSI. The subjects were between 18 and 42 years old and had a BMI <30kg/m2. Interventions Subcutaneous progesterone 25 mg daily vs. either progesterone vaginal gel 90 mg daily (07EU/Prg06) or 100 mg intravaginal twice a day (07USA/Prg05) for luteal phase support in IVF patients. Main outcome measures Ongoing pregnancy rate beyond 10 gestational weeks, live birth rate and OHSS risk. Results The administration of subcutaneous progesterone versus intra-vaginal progesterone had no impact on ongoing pregnancy likelihood (OR = 0.865, 95% CI 0.694 to 1.077; P = n.s.), live birth likelihood (OR = 0.889, 95% CI 0.714 to 1.106; P = n.s.) or OHSS risk (OR = 0.995, 95% CI 0.565 to 1.754; P = n.s.) in regression analyses accounting for clustering of patients within trials, while adjusting for important confounders. Only female age and number of oocytes retrieved were significant predictors of live birth likelihood and OHSS risk. Conclusion No statistical significant or clinical significant differences exist between subcutaneous and vaginal progesterone for luteal phase support.

A prospective, randomised, investigator-blind, controlled, clinical study on the clinical efficacy and tolerability of two highly purified hMG preparations administered subcutaneously in women undergoing IVF

Abstract The aim of this multicentre, prospective, randomised, investigator blind, controlled clinical trial was to evaluate the clinical efficacy and tolerability of a highly purified human menopausal gonadotrophin (hMG) preparation (Merional-HG) when administered to patients undergoing controlled ovarian stimulation (COS) for in-vitro fertilisation (IVF) procedure enrolled in hospital departments. One hundred fifty-seven patients were randomised in two parallel groups: 78 started COS with Merional-HG and 79 with Menopur. Results of the study showed that both highly purified hMG preparations were equivalent in terms of number of oocytes retrieved (primary endpoint: 8.8 ± 3.9 versus 8.4 ± 3.8, p = 0.54). In the patients treated with Merional-HG, we observed a higher occurrence of mature oocytes (78.3% versus 71.4%, p = 0.005) and a reduced quantity of gonadotrophins administered per cycle (2.556 ± 636 IU versus 2.969 ± 855 IU, p < 0.001). Fertilisation, cleavage, implantation rates and the number of positive β-human chorionic gonadotrophin (hCG; pregnancy) tests and the clinical pregnancy rate were comparable in the two groups. Both treatments were well tolerated. In conclusion, the results of this study support the efficacy and safety of Merional-HG administered subcutaneously for assisted reproduction techniques. Efficiency of Merional-HG appears to be higher due to reduced quantity of drug used and the higher yield of mature oocytes retrieved.

Randomized controlled trial comparing highly purified (HP-hCG) and recombinant hCG (r-hCG) for triggering ovulation in ART

Background: A randomized controlled trial (RCT) comparing highly purified human Choriogonadotrophin (HP-hCG) and recombinant hCG (r-hCG) both administered subcutaneously for triggering ovulation in controlled ovarian stimulation (COS) for Assisted Reproductive Technology (ART). Methods: Multi-centre (n = 4), prospective, controlled, randomized, non-inferiority, parallel group, investigator blind design, including 147 patients. The trial was registered with www.clinicaltrials.gov, using the identifier: NCT00335569. The primary endpoint is the number of oocytes retrieved, while the secondary endpoints include embryo implantation, pregnancy and delivery rates as well as safety parameters. Results: The number of retrieved oocytes was not inferior when HP-hCG was used as compared to r-hCG: the mean number was 13.3 (6.8) in HP-hCG and 12.5 (5.8) in the r-hCG group (p = 0.49) with a 95% CI (−1.34, 2.77). Regarding the secondary outcomes, there were also no differences in fertilization rate at 57.3% (467/815) vs. 61.3% (482/787) (p = 0.11), the number of embryos available for transfer and cryopreservation (2PN stage) and implantation, pregnancy and delivery rates. Furthermore, there were no differences in the number and type of adverse events reported. HP-hCG was therefore not inferior to r-hCG. Conclusions: HP-hCG and r-hCG are equally efficient and safe for triggering ovulation in ART and, both being administered subcutaneously, equally practical and well tolerated by patients.

Endometrial thickness on the day of embryo transfer is a poor predictor of IVF treatment outcome

Abstract STUDY QUESTION What is the independent contribution of endometrial thickness (EMT) on day of embryo transfer to achieving an ongoing pregnancy and live birth after IVF treatment? SUMMARY ANSWER EMT is a poor predictor of IVF success and has only little independent prognostic value. WHAT IS KNOWN ALREADY In a number of previous studies, pregnancy rates have been found to be lower in patients with thin endometrium. STUDY DESIGN, SIZE, DUARATION This is a retrospective analysis of data from two large, randomized phase III studies (conducted in Europe and the USA) comparing s.c. progesterone with vaginal progesterone for luteal phase support. The studies were very similar in design, patient population and outcome, and the study data were combined and analysed on an individual patient level. PARTICIPANTS/MATERIALS, SETTING, METHOD Subjects were infertile patients with an indication for IVF/ICSI, aged between 18 and 42 years, BMI <30 kg/m2, <3 prior ART cycles and ≥ 3 oocytes after controlled ovarian stimulation with GnRH-agonist or GnRH-antagonist. EMT was assessed on day of embryo transfer (n = 1401). The association of EMT and ongoing pregnancy rate was determined by comparison of outcomes by quantiles of EMT. The predictive capacity of EMT for ongoing pregnancy achievement was assessed at each millimeter cut-off. Finally, a regression model was built to determine the contribution of EMT among other confounders, such as age and oocyte numbers, on the likelihood of ongoing pregnancy and live birth. MAIN RESULTS AND THE ROLE OF CHANCE In univariate analysis, ongoing pregnancy rates correlate to EMT. In patients above a cut-off of ≥9 mm EMT, the chance of pregnancy was higher as compared to patients with an EMT of 3–8 mm (odds ratio (OR) = 1.69, 95% CI: 1.23–2.35, P = 0.001; sensitivity 88.89%, specificity 17.52%, positive predictive value 39.02%, negative predictive value 72.64% and likelihood ratio 1.08). In multivariate regression analysis, after controlling for trial, female age and oocyte numbers, EMT was a statistically significant predictor of live birth (OR = 1.05, 95% CI: 1.00–1.10; P = 0.0351). If EMT indeed is an independent factor affecting outcome, this finding implies that at a baseline live birth rate of 20% an increase of 2 mm in EMT should result in an increase of the live birth rate of ~1.6%. LIMITATIONS REASONS FOR CAUTION The independent contribution of EMT to live birth likelihood is small and may result from (undetermined) confounding. The EMT on day of embryo transfer is usually higher as compared to the EMT on day of triggering final oocyte maturation when it is conventionally assessed during routine cycle monitoring. Furthermore, endometrial lining pattern and/or subendometrial Doppler flow have not been assessed and, accordingly, the conclusions of this work are limited to only the thickness of the endometrium. WIDER IMPLICATIONS OF THE FINDINGS EMT can be ignored during cycle monitoring of the majority of IVF patients and only the extremes of EMT deserve further diagnostic work-up. STUDY FUNDING/COMPETING INTERESTS The study was supported by IBSA. G.G. has received personal fees and non-financial support from MSD, Ferring, Merck-Serono, Finox, TEVA, IBSA, Glycotope, Abbott, Gedeon-Richter as well as personal fees from VitroLife, NMC Healthcare, ReprodWissen, BioSilu and ZIVA. S.T. and B.C. are employees of IBSA. TRIAL REGISTRATION NUMBER NCT00827983 and NCT00828191 (clinicaltrials.gov). Trial registration date 23 January 2009 (NCT00827983 and NCT00828191). DATE OF FIRST PATIENT’S ENROLMENT January 2009 (NCT00827983 and NCT00828191).

A randomized controlled trial comparing the efficacy and safety of two HMG preparations gaining their LH bioactivity from different HCG sources

In this prospective, controlled, randomized, multicentre, non-inferiority study, efficacy and safety of two HMG preparations (Menopur®- Ferring and Meriofert®- IBSA Institut Biochimique SA) for ovarian stimulation were compared (270 women undergoing IVF aged between 18 and 39 years; BMI 30 kg/m2 or less; less than three prior completed assisted reproduction technique cycles). A standard long down-regulation with gonadotrophin-releasing hormone agonist protocol, with HCG triggering was used; primary end-point was total number of oocytes retrieved; attention was paid toovarian hyperstimulation syndrome (OHSS). No statistically significant differences between the treatment groups were reported for most of the clinically significant end-points, including embryo quality, fertilization rate, implantation rate, ongoing pregnancy rate and live birth rate. Total number of oocytes retrieved was higher in the new HMG group compared with the reference (11.6 ± 6.6 and 9.7 ± 5.9, respectively, with a 95% CI of the difference equal +0.43 to +3.43). Increased number of oocytes was obtained through a shorter stimulation, but HMG units per oocyte retrieved were equivalent. The safety profile of the products for frequency of ovarian hyperstimulation syndrome was the same. This study showed that the new HMG preparation is a viable alternative for conducting ovarian stimulation in IVF cycles.

Assessment of the immunogenicity of gonadotrophins during controlled ovarian stimulation

Gonadotrophin hormones are used for the controlled ovarian stimulation (COS) as part of the in vitro fertilization techniques. Therapeutic proteins have the potential to induce an unwanted immune response.