Randomized, active-controlled, comparative phase 3 efficacy and safety equivalence trial of Ovaleap® (recombinant human follicle-stimulating hormone) in infertile women using assisted reproduction technology (ART)

Background: Pharmacokinetic studies with XM17 (Ovaleap®), a recombinant human follicle-stimulating hormone (r-hFSH, follitropin alfa), have demonstrated good safety and tolerability in healthy women whose endogenous FSH levels were down-regulated with a long agonist protocol. In these studies, Ovaleap® pharmacokinetics were dose-proportional and bioequivalent to the reference follitropin alfa product (Gonal-f®). The objective of the present study is to determine whether Ovaleap® is equivalent to Gonal-f® with respect to the number of oocytes retrieved in infertile but ovulatory women undergoing assisted reproductive technology (ART) therapy. Methods: This multinational, multicenter, randomized (1:1), active-controlled, assessor-blind, comparative study included infertile normally gonadotrophic women 18 to 37 years old with a body mass index of 18 to 29 kg/m2 and regular menstrual cycles of 21 to 35 days undergoing ART therapy. During a 5-day fixed-dose phase, women received 150 IU/day of Ovaleap® (n = 153) or Gonal-f® (n = 146), followed by an up to 15-day dose-adaptation phase during which doses could be adjusted every 3 to 5 days, up to a maximum of 450 IU/day. Ovaleap® was to be deemed equivalent to Gonal-f® if the two-sided 0.95 confidence interval (CI) for the difference in the number of oocytes retrieved fell within the equivalence range of ±3 oocytes. Results: Similar numbers of oocytes were retrieved in the 2 treatment groups. The mean ± SD number of oocytes retrieved was 12.2 ± 6.7 in the Ovaleap® group and 12.1 ± 6.7 in the Gonal-f® group (intent-to-treat [ITT] population). Regression analysis estimated a mean difference of 0.03 oocytes between the treatment groups (95 % CI: −0.76-0.82), which was well within the prespecified equivalence range of ±3 oocytes. Ovaleap® and Gonal-f® showed favorable and comparable safety profiles, with no unexpected safety findings. Conclusions: Ovaleap® has shown the same efficacy and safety as Gonal-f® for stimulation of follicular development in infertile women (up to 37 years of age) who are undergoing ART therapy. Trial Registration EudraCT: 2009-017674-20. Current controlled trials: ISRCTN74772901. Date of trial registration: 19 March 2010

Safety and efficacy of Ovaleap® (recombinant human follicle-stimulating hormone) for up to 3 cycles in infertile women using assisted reproductive technology: a phase 3 open-label follow-up to Main Study

Background: Ovaleap® (follitropin alfa), a recombinant human follicle-stimulating hormone intended for use in controlled ovarian stimulation in women undergoing assisted reproductive technologies (ART), showed therapeutic equivalence to Gonal-f® in a multinational, multicenter, randomized, controlled, assessor-blind phase 3 Main Study. The current study examined safety, including immunogenicity, and efficacy of Ovaleap® in an open-label, uncontrolled, follow-up treatment period of up to 2 additional treatment cycles in patients who did not become pregnant in the phase 3 Main Study. Methods: Patients with negative biochemical or clinical pregnancy in the phase 3 Main Study, regardless of treatment group (ie, Ovaleap® or Gonal-f®), were eligible to participate. Patients received Ovaleap® (Merckle Biotec GmbH, Ulm, Germany) for up to 2 additional cycles, administered using a reusable semi-automated pen device. The primary objective was the assessment of safety, including adverse events (AEs), ovarian hyperstimulation syndrome (OHSS), and anti-drug antibodies. Tolerability, patient satisfaction with the Ovaleap® pen device, and efficacy outcomes (as evaluated in the Main Study) were also assessed. Results: One hundred forty-seven patients were included in cycle 2, and 61 patients were included in cycle 3. In cycles 2 and 3, 10.9% (16/147) and 6.6% (4/61) of patients experienced treatment-emergent AEs (TEAEs), respectively. Three serious TEAEs (ie, appendicitis, OHSS, and borderline ovarian tumor) were reported and successfully resolved. The OHSS TEAE was the only OHSS reported in the study (0.7% [1/147]). Positive findings on anti-drug antibody assays in 6 serum samples did not show neutralizing activity or clinical relevance in biochemical pregnancy rate. No hypersensitivity reaction occurred. Most patients reported “very good”/“good” local tolerability. All patients were “very confident”/“confident” about dose accuracy and correctness of the injection. They all found use of the pen “very convenient”/“convenient” and were all “very satisfied”/“satisfied” with the pen device. Efficacy outcomes were consistent with the phase 3 Main Study. Conclusions: These findings further support the safety, including immunogenicity, and efficacy of Ovaleap® for stimulation of follicular development in infertile women undergoing ART. The findings support continued use of Ovaleap® for multiple cycles or a switch to Ovaleap® if pregnancy is initially not achieved with Gonal-f®. Trial registration: EudraCT number: 2009-017674-20. Current controlled trials register number: ISRCTN74772901

A regressive model for dynamic instabilities during the condensation of R404A and R507 refrigerants

This paper presents the results of experimental research and mathematical modelling on the influence of dynamic instabilities on the condensation phase change of R507 refrigerant in tubular mini-channels. This agent is currently being utilised as a temporary substitute for R404A, with R448A intended as the target substitute. In addition to the results, this paper contains a dimensional analysis procedure based on the Π-Buckingham theorem that has allowed for the development of a regressive model for the velocities of the dynamic instabilities. The experimental part of this paper was conducted using tubular mini-channels with internal diameters of 1.44, 2.3, and 3.3 mm.http://www.elsevier.com/locate/ijhmt2020-10-01hj2019Mechanical and Aeronautical Engineerin

GnRH-Agonist Cycles versus Combined Pretreatment with Oral Contraceptive Pills in Long Protocol GnRH-Agonist Cycles: A Randomised Controlled Trial

The strategy of in vitro fertilization (IVF) procedures relies on the increasing pregnancy rate and decreasing the risk of premature ovulation and ovarian hyperstimulation syndrome. They are also designed to avoid weekend oocyte retrievals. Combined oral contraceptive (OC) pills are among the medicines used to accomplish these objectives. Alternatively, estradiol can be used instead of OC to obtain similar results. The aim of our study was to compare the differences in pregnancy rates (PRs), implantation rates, and miscarriage rates between a short agonist protocol with estradiol priming and a long protocol with combined OC. Of the 298 women who participated in this study, 134 achieved clinical pregnancies (45.0%). A higher PR (58.4%, = 80, compared to 40.3%, = 54) was achieved in the long protocol after OC pretreatment group. The implantation rate was also higher for this group (37.8% versus 28.0%; = 0.03). The miscarriage rate was 15.0% ( = 12) for the long protocol after OC pretreatment group and 20.4% ( = 11) for the short agonist group ( = 0.81). The short agonist protocol required a 5.7% lower human menopausal gonadotropin (hMG) dosage than the long protocol but surprisingly the number of oocytes retrieved was also smaller

Individualized versus conventional ovarian stimulation for in vitro fertilization: a multicenter, randomized, controlled, assessor-blinded, phase 3 noninferiority trial

Objective To compare the efficacy and safety of follitropin delta, a new human recombinant FSH with individualized dosing based on serum antimüllerian hormone (AMH) and body weight, with conventional follitropin alfa dosing for ovarian stimulation in women undergoing IVF. Design Randomized, multicenter, assessor-blinded, noninferiority trial (ESTHER-1). Setting Reproductive medicine clinics. Patient(s) A total of 1,329 women (aged 18â40 years). Intervention(s) Follitropin delta (AMH <15 pmol/L: 12 μg/d; AMH â¥15 pmol/L: 0.10â0.19 μg/kg/d; maximum 12 μg/d), or follitropin alfa (150 IU/d for 5 days, potential subsequent dose adjustments; maximum 450 IU/d). Main Outcomes Measure(s) Ongoing pregnancy and ongoing implantation rates; noninferiority margins â8.0%. Result(s) Ongoing pregnancy (30.7% vs. 31.6%; difference â0.9% [95% confidence interval (CI) â5.9% to 4.1%]), ongoing implantation (35.2% vs. 35.8%; â0.6% [95% CI â6.1% to 4.8%]), and live birth (29.8% vs. 30.7%; â0.9% [95% CI â5.8% to 4.0%]) rates were similar for individualized follitropin delta and conventional follitropin alfa. Individualized follitropin delta resulted in more women with target response (8â14 oocytes) (43.3% vs. 38.4%), fewer poor responses (fewer than four oocytes in patients with AMH <15 pmol/L) (11.8% vs. 17.9%), fewer excessive responses (â¥15 or â¥20 oocytes in patients with AMH â¥15 pmol/L) (27.9% vs. 35.1% and 10.1% vs. 15.6%, respectively), and fewer measures taken to prevent ovarian hyperstimulation syndrome (2.3% vs. 4.5%), despite similar oocyte yield (10.0 ± 5.6 vs. 10.4 ± 6.5) and similar blastocyst numbers (3.3 ± 2.8 vs. 3.5 ± 3.2), and less gonadotropin use (90.0 ± 25.3 vs. 103.7 ± 33.6 μg). Conclusion(s) Optimizing ovarian response in IVF by individualized dosing according to pretreatment patient characteristics results in similar efficacy and improved safety compared with conventional ovarian stimulation. Clinical Trial Registration Number NCT01956110

Les entreprises communes au sein du CAEM (l'exemple des relations polono-soviétiques, 1984-1988)

Joint venture enterprises within Comecon (the example of Soviet-Polish relations 1984-1988) The idea of setting up joint venture enterprises within Comecon, especially between the USSR and individual member countries, is one of the elements in the programme for transformation of the economic mechanisms of that organization. The author outlines the problem of joint ventures within Comecon taking Poland as his example. Occasion- naly, he has to put forward theories of his own, to make up for the absence of reliable data, since economic relations between the USSR and Poland are still the subject of considerable reticence. After outlining the origins of the problem, he turns to the history of joint Soviet- Polish enterprises, which have had their difficulties. But co-operation between the two countries has none the less made progress as is shown by the list of enterprises already functioning, and the number of projects at present in operation. The author considers that Soviet-Polish economic relations have recently entered a new phase, but no one can predict their development with any certainty, on account of the upheavals at present taking place in Eastern Europe as a whole.L'idée de créer des sociétés mixtes dans le cadre du Comecon, surtout entre l'U.R.S.S. et d'autres pays membres, est l'un des éléments du programme de transformation des mécanismes économiques de cette organisation. L'auteur esquisse le problème des sociétés mixtes intra-Comecon en prenant la Pologne pour exemple, il avance parfois des hypothèses personnelles pour pallier le manque de données fiables, les relations économiques entre l'U.R.S.S. et la Pologne restant toujours entourées d'une grande discrétion. Après avoir retracé les origines du problème, il entreprend l'histoire des entreprises mixtes polono-soviétiques qui n'est pas allée sans heurts. Mais la coopération entre les deux pays a néanmoins progressé comme le démontrent la liste d'entreprises déjà en activité et les projets qui sont actuellement négociés. L'auteur estime qu'une nouvelle étape s'est récemment ouverte dans les relations économiques polono-soviétiques, mais nul ne peut prévoir avec certitude leurévolution compte tenu des bouleversements en cours dans l'ensemble de l'Europe de l'Est.Kuczynski Waldemar. Les entreprises communes au sein du CAEM (l'exemple des relations polono-soviétiques, 1984-1988). In: Revue d'études comparatives Est-Ouest, vol. 21, 1990, n°1. pp. 27-39

Le chemin de retour. (L'évolution des opinions sur le marché et la propriété en Pologne, 1956-1982)

The way back. (The evolution of opinions about the market and property in Poland, 1956-1982) The economic aspects of the changes which have taken place in Poland since 1956 may be analysed in the light of the successive revisions of ideology. This goes from the reform of marxism during the first years of Gomulka's accession to power, to the general liberalization of 1986, by way of the return to orthodoxy at the end of the 1960's, and the renewal of reforming ideas after 1975 and particularly after 1980. To-day the debate has moved on, and the question is one of speculation on whether the socialist economy should be abandoned. The two opposing camps are divided on this point, as is shown by the author, after his account of the evolution of Polish thinking on the subject of the market and property during the period under discussion, and his description of the policies adopted.L'aspect économique des changements intervenus en Pologne depuis 1956 peut être analysé au travers des révisions idéologiques qui se sont succédé. Cela va de la réforme du marxisme pendant les premières années au pouvoir de Gomulka à la libéralisation générale amorcée en 1986 en passant par le retour à l'orthodoxie de la fin des années 60 et le renouveau des idées réformatrices après 1975 et surtout après 1980. Aujourd'hui le débat s'est déplacé et la question consiste à se demander s'il faut abandonner l'économie socialiste ? Les deux camps en présence sont divisés sur ce point comme le montre l'auteur après avoir retracé toute l'évolution de la réflexion polonaise sur le marché et la propriété au cours de la période considérée et rappelé les stratégies adoptées.Kuczynski Waldemar. Le chemin de retour. (L'évolution des opinions sur le marché et la propriété en Pologne, 1956-1982). In: Revue d'études comparatives Est-Ouest, vol. 21, 1990, n°2. pp. 29-39