Follitropin Alfa Research Articles

Patient and nurse evaluation of the improved follitropin alfa pen injector for infertility treatment

Patient and nurse evaluation of the improved follitropin alfa pen injector for infertility treatment

XM17 Follitropin Alfa (Ovaleap(®)): A Review in Reproductive Endocrine Disorders.

The subcutaneous recombinant human follicle-stimulating hormone XM17 follitropin alfa (Ovaleap(®)) is approved in the EU as a biosimilar of follitropin alfa (Gonal-f(®)) for use in all indications for which the reference product is approved, including as a multifollicular stimulant in women undergoing superovulation for assisted reproductive technology (ART) treatment. In a nonblind, phase I study in healthy female volunteers, the pharmacokinetic profile of XM17 follitropin alfa was bioequivalent to that of reference follitropin alfa following single dosing. Moreover, in a multinational, phase III study, the efficacy of XM17 follitropin alfa as a multifollicular stimulant was equivalent to that of reference follitropin alfa in terms of the number of retrieved oocytes (primary endpoint) in women undergoing controlled ovarian stimulation for ART treatment. There were no clinically relevant differences in oocyte quality between XM17 follitropin alfa and reference follitropin alfa, with biochemical, clinical and ongoing pregnancy rates and take-home baby rates not significantly differing between the treatment groups. XM17 follitropin alfa was generally well tolerated in this patient population, with its tolerability profile generally similar to that of reference follitropin alfa and with no new unexpected tolerability concerns identified. Thus, XM17 follitropin alfa is an effective treatment option in patients requiring follitropin alfa therapy for various reproductive endocrine disorders, providing a useful alternative to reference follitropin alfa.

Usability engineering study in the European Union of a redesigned follitropin alfa pen injector for infertility treatment

ABSTRACTObjectives: The prefilled, multidose, GONAL-f ® (follitropin alfa) pen injector was redesigned to improve ease of use and pen functionality. This usability engineering evaluation aimed to demonstrate that the redesigned pen injector could be used by the intended users to safely and effectively deliver follitropin alfa.Methods: Formative and summative usability engineering evaluations of the pen injector, training and instructions for use (IFU) were conducted. This included an expert review, and formative and summative evaluations involving patients with infertility and fertility nurses. For the summative evaluation, participants received training and subsequently performed tasks based on three selected hazard-related use scenarios to evaluate real-world use, including simulated injections.Results: The formative evaluations confirmed that the pen injector was ready for summative evaluation. Task performance was high in the summative evaluation for both patients and nurses; the tasks that were observed to be most difficult to complete were priming the pen, completing an incomplete injection and completing the treatment diary. Participants rated the device as having above average usability. Most patients ranked the overall system (pen injector, device training and IFU) and its individual components to be either ‘extremely easy’ or ‘somewhat easy’ to use.Conclusions: These usability engineering evaluations demonstrated that patients and nurses could safely and effectively use the redesigned GONAL-f pen injector, and that they also found the IFU and device training to be easy to use.

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

BackgroundOvaleap® (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.MethodsPatients 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.ResultsOne 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.ConclusionsThese 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 registrationEudraCT number: 2009-017674-20. Current controlled trials register number: ISRCTN74772901.

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).

BackgroundPharmacokinetic 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.MethodsThis 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.ResultsSimilar 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.ConclusionsOvaleap® 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 RegistrationEudraCT: 2009-017674-20. Current controlled trials: ISRCTN74772901. Date of trial registration: 19 March 2010.

PIH24 - The Comparative Pharmacoeconomic Analysis of Using Korifollitropin Alfa with Ganirelix and Follitropin Alfa with Cetrorelix for Ovarian Stimulation

PIH24 - The Comparative Pharmacoeconomic Analysis of Using Korifollitropin Alfa with Ganirelix and Follitropin Alfa with Cetrorelix for Ovarian Stimulation

Uso de la hormona folículo estimulante humana recombinante en la infertilidad anovulatoria

OBJETIVO: Estudiar los efectos usando dosis múltiples de la FSH humana recombinante en nueve mujeres con hipogonadismo hipogonadotrófico, analizando su capacidad de inducir el crecimiento folicular y síntesis de esteroides ováricos. DISEÑO: Trabajo clínico abierto. MATERIAL Y MÉTODOS: De nueve casos de hipogonadismo gonadotrófico, una tenía diagnóstico de síndrome de Kallman, una deficiencia aislada de gonadotropinas y siete panhipopituitarismo secundario a hipofisectomía. Se administró inyecciones 1M de hFSHr (Folitropina alfa Instituto Ares-Serono, Ginebra) en dosis crecientes (semana 1: 75 UI/dia, semana 2: 150 UI/dia, semana 3: 225 UI/día) durante un promedio de 17 dias (rango: 15-19). Se efectuó toma de muestras de sangre regularmente y estudios ultra sonográficos frecuentes para monitorizar el desarrollo folicular. Para las mediciones hormonales se recurrió al radioinmunoanálisis. RESULTADOS: Las concentraciones séricas iniciales de FSH y de hormona luteinizante (LH) fueron 0.48 (0.9-1.22) UI/L y 0.26(˂0.15, 0.41) UI/L, respectivamente. Los valores máximos de FSH durante la prueba llegaron a 10.3 (7.9-13.6) UI/L, en tanto que las concentraciones séricas de LH significativamente permanecieron estables 0.33 (0.19-0,52) UI/L. Los niveles séricos de androstenediona y testosterona no mostraron cambios significativos durante la administración de hFSHr y el estradiol sérico reveló sólo un aumento leve: 131.7 (51-239) pmol/L. Se desarrollaron folículos múltiples que llegaron a dimensiones preovulatorias (˃ 14 mm), con un índice de desarrollo folicular de 1.92 ± 0.7 mm/día. CONCLUSIONES: Del presente trabajo se deduce que la hFSHr resultó efectiva en mujeres con deficiencia de gonadotropinas para estimular el crecimiento folicular normal hasta la etapa preovulatoria e inducción de ovulación, sin impedirlo el aumento leve observado del estradiol. Asimismo, los niveles séricos de LH endógeno extremadamente bajos cursaron con secreción androgénica deficitaria, indicando la necesidad de contar con dicha gonadotropina para inducir una apropiada síntesis de esteroides.

Phase 1 safety, tolerability, and pharmacokinetic study of single ascending doses of XM17 (recombinant human follicle-stimulating hormone) in downregulated healthy women.

BackgroundXM17 is a recombinant human follicle-stimulating hormone (follitropin alfa) for stimulation of multifollicular development in women undergoing controlled ovarian hyper-stimulation during assisted reproductive therapy and for treatment of anovulation. Manufactured using Chinese hamster ovary cells transfected with the human follicle-stimulating hormone gene, XM17 has an identical amino acid sequence to that of the human protein as well as to those of the other approved recombinant human follicle-stimulating hormone products. Glycosylation patterns may differ slightly between products. The objectives of this first-in-human study were to assess the safety, tolerability, pharmacokinetics, and dose-proportionality of single ascending subcutaneous doses of XM17 in healthy young female volunteers.MethodsEndogenous follicle-stimulating hormone was downregulated by implanting a 1-month depot of goserelin acetate 3.6 mg on day 0 in eligible subjects. On day 14 of the experimental period, subjects received one of four ascending doses of XM17. Blood sampling to obtain the pharmacokinetic profile of XM17 was done at frequent intervals until 168 hours post-dose.ResultsFollowing downregulation of endogenous follicle-stimulating hormone to <4 IU/L, 40 subjects (of mean age 29±5.4 years) received single subcutaneous doses of 37.5 (n=4, pilot group), 75, 150, or 300 IU (n=12 each) of XM17. The mean serum concentration-time profiles of XM17 revealed dose-related increases in maximum concentration (Cmax) within 24 hours followed by monoexponential decay for the three higher dose levels. Slopes estimated by linear regression for Cmax and AUC0–168h were ~1.0 (0.9052 IU/L and 1.0964 IU·h/L, respectively). For each IU of XM17 administered, Cmax and AUC0–168h rose by 0.032 IU/L and 2.60 IU·h/L, respectively. Geometric mean elimination half-life ranged from 54 to 90 hours. No antibodies to XM17 were detected. The most common treatment-emergent adverse events were headache (12 events in eleven [27.5%] subjects) and dizziness (four events in four [10%] subjects); two subjects (5%) reported mild pain on touch at the injection site.ConclusionSingle subcutaneous doses of XM17 up to 300 IU in healthy young women exhibited dose-proportional pharmacokinetics with good safety and tolerability.

Managing infertility with the follitropin alfa prefilled pen injector - patient considerations.

Gonadotropin treatment has been used in fertility treatment since the 1930s. First, preparations coming from animals were injected, then, gonadotropins prepared from the pituitary glands of human cadavers. A great step was achieved with the introduction of human menopausal gonadotropin extracted from the urine of postmenopausal women. When cases of Creutzfeld-Jacob disease were recognized after the use of human pituitary-derived hormone injections, urinary gonadotropins were increasingly purified and then produced by the use of recombinant DNA technology. Recombinant gonadotropins were characterized by the extreme high specificity and the nearly 100% purity. This allows for follitropin alfa, the first recombinant-human follicle stimulating hormone (r-hFSH) approved, to be quantified and filled by mass, with a small variance of only ±2% and no more with a bioassay with a variance of 45%. With recombinant preparations, it is also possible to cover the tremendous growing demand for gonadotropins. Ovarian stimulation has become a self-injecting procedure for the patients. Accurate and easy-to-use injection devices which minimize pain, difficulty, and stress are essential for patient compliance. So, two pen injectors adapted from the well-known insulin pen were introduced in fertility treatment, one as a multiple-use device rechargeable with premixed, prefilled cartridges with r-hFSH (follitropin β) and the other a disposable, prefilled drug delivery system with a liquid formulation of follitropin alfa filled by mass. The efficacy in comparison to the quite more cumbersome handling with ampoules and syringes has been proven very quickly. In several studies, it has been shown that patients had a preference to the prefilled follitropin alfa pen due to the faster preparation and were more confident of accurate dosing. The follitropin alfa (filled by mass [FbM]) prefilled pen is a move toward better quality of treatment and also better quality of life for the women within the stressful period of fertility treatment.

Human factors engineering and design validation for the redesigned follitropin alfa pen injection device

Objectives: To demonstrate, using human factors engineering (HFE), that a redesigned, pre-filled, ready-to-use, pre-asembled follitropin alfa pen can be used to administer prescribed follitropin alfa doses safely and accurately.Methods: A failure modes and effects analysis identified hazards and harms potentially caused by use errors; risk-control measures were implemented to ensure acceptable device use risk management. Participants were women with infertility, their significant others, and fertility nurse (FN) professionals. Preliminary testing included ‘Instructions for Use’ (IFU) and pre-validation studies. Validation studies used simulated injections in a representative use environment; participants received prior training on pen use.Results: User performance in preliminary testing led to IFU revisions and a change to outer needle cap design to mitigate needle stick potential. In the first validation study (49 users, 343 simulated injections), in the FN group, one observed critical use error resulted in a device design modification and another in an IFU change. A second validation study tested the mitigation strategies; previously reported use errors were not repeated.Conclusions: Through an iterative process involving a series of studies, modifications were made to the pen design and IFU. Simulated-use testing demonstrated that the redesigned pen can be used to administer follitropin alfa effectively and safely.

Multicenter, noninterventional, post-marketing surveillance study to evaluate dosing of recombinant human follicle-stimulating hormone using the redesigned follitropin alfa pen in women undergoing ovulation induction.

This prospective, noninterventional, post-marketing surveillance study evaluated doses of recombinant human follicle-stimulating hormone (r-hFSH) using the redesigned follitropin alfa pen in women who were anovulatory or oligomenorrheic and undergoing ovulation induction (OI) alone or OI with intrauterine insemination. The primary endpoint was the proportion of patients who achieved monofollicular or bifollicular development (defined as one or two follicles ≥15 mm). Secondary endpoints included characteristics of ovulation stimulation treatment, such as mean total and mean daily r-hFSH doses. Data were analyzed for 3,193 patients from 30 German fertility centers. The proportion of patients with monofollicular or bifollicular development was 71.1% (n=2,270 of a total of 3,193 patients; intent-to-treat population). The mean±standard deviation total and daily doses of r-hFSH were 696.9±542.5 IU and 61.7±29.4 IU, respectively. The three doses prescribed most frequently were: 37.5 IU (n=703 from N=3,189; 22.0%), 50.0 IU (n=1,056 from N=3,189; 33.1%), and 75.0 IU (n=738 from N=3,189; 23.1%) on the first day of stimulation; and 37.5 IU (n=465 from N=3,189; 14.6%), 50.0 IU (n=922 from N=3,189; 28.9%), and 75.0 IU (n=895 from N=3,189; 28.1%) on the last day of stimulation. This noninterventional, post-marketing surveillance study found that monofollicular or bifollicular development was achieved in 71% of patients studied and the small dose increment (12.5 IU) of the redesigned follitropin alfa pen allowed individualized treatment of women undergoing OI.

A multi-centre phase 3 study comparing efficacy and safety of Bemfola® versus Gonal-f® in women undergoing ovarian stimulation for IVF

Bemfola (follitropin alfa) (Finox AG, Switzerland), a new recombinant FSH, has a comparable pharmacological profile to that of Gonal-f (Merck Serono, Germany), the current standard for ovarian stimulation. A randomized, multi-centre, Phase 3 study in women undergoing IVF or intracytoplasmic sperm injection (n = 372) showed Bemfola yielding similar efficacy and safety profiles to Gonal-f. Women aged 20–38 years of age were randomized 2:1 to receive a single, daily, subcutaneous 150 IU dose of either Bemfola or Gonal-f. This study tested equivalence in the number of retrieved oocytes using a pre-determined clinical equivalence margin of ±2.9 oocytes. Compared with Gonal-f, Bemfola treatment resulted in a statistically equivalent number of retrieved oocytes (Bemfola 10.8 ± 5.11 versus Gonal-f 10.6 ± 6.06, mean difference: 0.27 oocytes, 95% confidence interval: −1.34, 1.32) as well as a similar clinical pregnancy rate per embryo transfer in first and second cycles (Bemfola: 40.2% and 38.5%, respectively; Gonal-f: 48.2% and 27.8%, respectively). No difference in severe ovarian hyperstimulation syndrome was observed between treatment groups (Bemfola: 0.8%; Gonal-f: 0.8%). This study demonstrates similar clinical efficacy and safety profiles between Bemfola and Gonal-f, and suggests that Bemfola can be an appropriate alternative in ovarian stimulation protocols.

Cabozantinib and follitropin alfa recommended in Wales

Cabozantinib and follitropin alfa recommended in Wales

Randomized, controlled, open-label, non-inferiority study of the CONSORT algorithm for individualized dosing of follitropin alfa

In this randomized, controlled, open-label, phase IV study, ovarian response after a follitropin alfa starting dose determined by the CONSORT calculator was compared with a standard dose (150 IU). Normo-ovulatory women (aged 18–34 years) eligible for assisted reproductive techniques were recruited (23 centres: nine European countries and Chile); 200 women were randomized (CONSORT [n = 96]; standard dosing [n = 104]). Significantly lower mean daily (121.5 versus 167.4 IU; P < 0.001) and total (1288.5 versus 1810.0 IU; P < 0.001) doses of follitropin alfa were administered in the CONSORT group. Clinical pregnancy rates were CONSORT (36.0%) and standard dosing (35.5%); estimated difference (confidence interval 0.6%; −13.5 to 14.6). Ovarian hyperstimulation syndrome occurred in 6.3% and 12.5% of patients in the CONSORT and standard-dosing groups, respectively. The primary efficacy analysis found a significantly lower mean [SD] number of oocytes retrieved in the CONSORT (10.0 [5.6]; P = 0.037) versus standard-dosing group (11.8 [5.3]). Although the CONSORT calculator was statistically inferior to standard dosing in the number of oocytes retrieved, clinical pregnancy rates (fresh embryo transfers) were similar in both groups, and incidence of ovarian hyperstimulation syndrome was lower in the CONSORT group.

Ovarian response to recombinant human follicle-stimulating hormone: a randomized, antimüllerian hormone–stratified, dose–response trial in women undergoing in vitro fertilization/intracytoplasmic sperm injection

To evaluate the dose-response relationship of a novel recombinant human FSH (rhFSH; FE 999049) with respect to ovarian response in patients undergoing IVF/intracytoplasmic sperm injection treatment; and prospectively study the influence of initial antimüllerian hormone (AMH) concentrations. Randomized, controlled, assessor-blinded, AMH-stratified (low: 5.0-14.9 pmol/L [0.7-<2.1 ng/mL]; high: 15.0-44.9 pmol/L [2.1-6.3 ng/mL]) trial. Seven infertility centers in four countries. Two hundred sixty-five women aged ≤37 years. Controlled ovarian stimulation with either 5.2, 6.9, 8.6, 10.3, or 12.1 μg of rhFSH, or 11 μg (150 IU) of follitropin alfa in a GnRH antagonist cycle. Number of oocytes retrieved. The number of oocytes retrieved increased in an rhFSH dose-dependent manner, from 5.2 ± 3.3 oocytes with 5.2 μg/d to 12.2 ± 5.9 with 12.1 μg/d. The slopes of the rhFSH dose-response curves differed significantly between the two AMH strata, demonstrating that a 10% increase in dose resulted in 0.5 (95% confidence interval 0.2-0.7) and 1.0 (95% confidence interval 0.7-1.3) more oocytes in the low and high AMH stratum, respectively. Fertilization rate and blastocyst/oocyte ratio decreased significantly with increasing rhFSH doses in both AMH strata. No linear relationship was observed between rhFSH dose and number of blastocysts overall or by AMH strata. Five cases of ovarian hyperstimulation syndrome were reported for the three highest rhFSH doses and in the high AMH stratum. Increasing rhFSH doses results in a linear increase in number of oocytes retrieved in an AMH-dependent manner. The availability of blastocysts is less influenced by the rhFSH dose and AMH level. NCT01426386.

Single-arm, observational study of the ease of use of a redesigned pen device to deliver recombinant human follicle-stimulating hormone (follitropin alfa) for assisted reproductive technology treatment.

PurposeEvaluation of patients’ ease of use of the redesigned, disposable, ready-to-use follitropin alfa pen during controlled ovarian stimulation for assisted reproductive technology.MethodsThis single-center, observational, open-label, single-arm study recruited infertile normo-ovulatory women (aged 18–45 years). Nurses trained patients to self-administer recombinant human follicle-stimulating hormone daily using the follitropin alfa pen (300 IU, 450 IU, and 900 IU). Before treatment, patients completed Questionnaire A. Following self-administered treatment, on stimulation days 5–6 and 7–8 (within a day of receiving recombinant human chorionic gonadotropin), patients completed Questionnaire B. Nurses completed an ease-of-learning/teaching questionnaire. The primary endpoint was proportion of patients rating the pen as “easy/very easy” to use (Questionnaire B) on the final visit before recombinant human chorionic gonadotropin. Secondary endpoints included: proportion of patients rating the follitropin alfa pen as easy to learn, use, prepare, deliver, and dispose of (Questionnaires A and B). Proportions (95% confidence intervals [CIs]) were provided for primary and secondary endpoints. Adverse events were reported descriptively.ResultsEighty-six patients received recombinant human follicle-stimulating hormone. Of the 72 patients who had completed the overall assessment questions, 66 (91.7%; 95% CI =82.7%–96.9%) found the pen “easy” to use. Also, 70/86 (81.4%) patients “strongly agreed/agreed” that, overall, it was easy to learn how to use the pen; 72/86 (83.7%) “strongly agreed/agreed” that easily understandable, verbal information was provided; and 70/86 (81.4%) were confident about using the pen correctly. In total, 24/26 nurses (92.3%; 95% CI =74.9%–99.1%) rated the pen as easy to use. Clinical pregnancy rate/patient/cycle/embryo transfer was 37%. Twenty-six ovarian hyperstimulation syndrome events were reported (none severe; 16 patients [19%]); of these, 13 occurred at embryo transfer.ConclusionIn this observational study, patients had a high acceptance of the redesigned follitropin alfa pen, with most finding it very easy/easy to use. Assisted reproductive technology nurses found the pen very easy/easy to teach.

Gonal-f RFF® Redi-ject™: Optimization of Use with Simulated Use Testing and Human Factors Engineering

Gonal-f RFF® Redi-ject™: Optimization of Use with Simulated Use Testing and Human Factors Engineering

A large, multicentre, observational, post-marketing surveillance study of the 2:1 formulation of follitropin alfa and lutropin alfa in routine clinical practice for assisted reproductive technology

BackgroundFollicle-stimulating hormone (FSH) and luteinizing hormone (LH) both have a role to play in follicular development during the natural menstrual cycle. LH supplementation during controlled ovarian stimulation (COS) for assisted reproductive technology (ART) is used for patients with hypogonadotropic hypogonadism. However, the use of exogenous LH in COS in normogonadotropic women undergoing ART is the subject of debate. The aim of this study was to investigate characteristics of infertile women who received the 2:1 formulation of follitropin alfa and lutropin alfa (indicated for stimulation of follicular development in women with severe LH and FSH deficiency) in German clinical practice.MethodsA 3-year, multicentre, open-label, observational/non-interventional, post-marketing surveillance study of women (21-45 years) undergoing ART. Primary endpoint: reason for prescribing the 2:1 formulation of follitropin alfa and lutropin alfa. Secondary variables included: COS duration/dose; oocytes retrieved; fertilization; clinical pregnancy; ovarian hyperstimulation syndrome (OHSS).ResultsIn total, 2220 cycles were assessed; at least one reason for prescribing the 2:1 formulation was given in 1834/2220 (82.6%) cycles. Most common reasons were: poor ovarian response (POR) (39.4%), low baseline LH (17.8%), and age (13.8%). COS: mean dose of the 2:1 formulation on first day, 183.1/91.5 IU; mean duration, 10.8 days. In 2173/2220 (97.9%) cycles, human chorionic gonadotrophin was administered. Oocyte pick-up (OPU) was attempted in 2108/2220 (95.0%) cycles; mean (standard deviation) 8.0 (5.4) oocytes retrieved/OPU cycle. Fertilization (≥1 oocyte fertilized) rates: in vitro fertilization (IVF), 391/439 (89.1%) cycles; intracytoplasmic sperm injection (ICSI)/IVF + ICSI, 1524/1613 (94.5%) cycles. Clinical pregnancy rate: all cycles, 25.9%; embryo transfer cycles, 31.3%. OHSS: hospitalization for OHSS, 8 (0.36%) cycles, Grade 2, 60 (2.7%), and Grade 3, 1 (0.05%).ConclusionsIn German routine clinical practice, the most common reasons for using the 2:1 formulation of follitropin alfa and lutropin alfa for women undergoing ART were POR, low baseline LH, and age. Severe OHSS incidence was low and similar to that reported previously.Trial registrationClinicaltrials.gov NCT01112618

Ovarian Stimulation with Urofollitropin (uFSH) Results in a Lower Yield of Oocytes Compared to Recombinant FSH (rFSH), Nevertheless, uFSH is at Least as Effective as rFSH in Younger Patients: Preliminary Results of a Retrospective Study with Antagonist Protocols in an IVF/ICSI Program

Objective: Differences in the mode of action between recombinant FSH (rFSH) and urinary derived FSH (uFSH) have been reported in cycles down-regulated by agonists. The aim of our study was to determine, if these differences also exist in cycles down-regulated by antagonists. Method: Antagonist cycles performed between 2009 - 2012 were divided into two groups: 1. Cycles stimulated with rFSH preparations: Follitropin alfa (n=203) and Follitropin beta (n=443) and 2. Cycles stimu- lated with Urofollitropin (n=405). Cetrorelix or Ganirelix were used as antagonists. All patients received 75 IU hMG additionally from day 6 of stimulation onwards up to the day of hCG administration. A logistic regression analysis was conducted to find the most significant parameters predicting hCG-positive pregnancy for 2471 IVF cycles. The results demonstrated that the predictors such as age of patients and number of cycles ever per- formed made negative contributions and number of oocytes retrieved and number of embryos transferred made positive contributions to prediction. Taking this into consideration, comparable groups could be created by including only first- ever IVF cycles with more than 10 oocytes retrieved and 2 embryos transferred. Thus, the final sample for comparison included 98 patients in the rFSH-group and 27 patients in the uFSH group. Results: There were no differences in basic personal data and gonadotropin consumption between the groups. Stimulation with rFSH resulted in a higher yield of oocytes compared to uFSH (15,6 vs. 14,4), however, the results of the following reproductive outcome parameters were all in favor of uFSH when rFSH and uFSH were compared: oocyte maturation rate (76.5% vs. 79.0 %), fertilization rate (53,6% vs. 58,6%), embryo score 4 rate (25,7% vs.. 31,1%), hCG-positive pregnancy rate (43,9% vs. 59,3%), clinical pregnancy rate (33,7% vs. 44,4%), embryo-cryopreservation rate (19,3% vs. 30,5%) and abortion rate (14,0% vs. 12,5%). Conclusions: These results seem to support the concept that uFSH produces fewer oocytes than rFSH, but the oocytes produced by uFSH are, on an average, of better quality than those produced by rFSH. Basic studies have shown that dif- ferent FSH isoforms with different elimination kinetics in the two gonadotropin preparations could be responsible for the different effects. However, the results have to be confirmed by well designed prospective randomized studies.

A randomized, assessor-blind, dose-response trial in patients undergoing controlled ovarian stimulation for IVF/ICSI with a novel recombinant FSH preparation (FE 999049) derived from a human cell-line

To establish the relationship between the dose of FE 999049, a novel recombinant FSH derived from a human cell-line (PER.C6) and the number of oocytes retrieved, and to characterize it according to serum AMH. Randomized, controlled, assessor-blind, multicentre, dose-response trial in 265 IVF/ICSI patients undergoing controlled ovarian stimulation with one of five doses of FE 999049 (Ferring Pharmaceuticals) or one dose of follitropin alfa (GONAL-F, EMD Serono) (NCT01426386). Patients were randomized to fixed doses of 5.2, 6.9, 8.6, 10.3 or 12.1 μg/day FE 999049 (N=222) or follitropin alfa 11 μg/day (150 IU/day) (N=43). Randomization was stratified by serum AMH (low: 5.0-14.9 pmol/L, high: 15.0-44.9 pmol/L; Beckmann-Coulter Gen 2 ELISA). Stimulation was carried out in a GnRH antagonist cycle (ganirelix 0.25 mg/day from day 6). Triggering was done when ≥3 follicles ≥17 mm. Ongoing pregnancy was determined 10-11 weeks after compulsory single blastocyst transfer. There was a significant (p<0.001) dose-response relationship for FE 999049 with respect to number of oocytes retrieved; overall and for each AMH strata. Increasing the FE 999049 dose with 10% led to an increase of 1 oocyte (95% CI: 0.65-1.30) in the high AMH stratum and 0.5 oocyte (95% CI: 0.22-0.72) in the low AMH stratum. The dose-response curves were significantly (p<0.05) different for the two strata, with 31-97% more oocytes in the high AMH stratum across FE 999049 doses. The percentage of FE 999049 patients with extreme responses (i.e. <4 or ≥20 oocytes) followed a U-shaped dose-response curve. No linear relationship was observed between FE 999049 dose and number of blastocysts, but rather a threshold relationship. The ongoing pregnancy rate was 35% for FE 999049 and unrelated to dose. A significant dose-response relationship was established between FE 999049 and number of oocytes retrieved with significantly different slopes for the low and high AMH strata.