Hum. Reprod. Advance Access published online on August 6, 2008
Human Reproduction, doi:10.1093/humrep/den288
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A randomized dose–response trial of a single injection of corifollitropin alfa to sustain multifollicular growth during controlled ovarian stimulation
1 Correspondence address. Norbert Koper, Global Clinical Development Department, NV Organon, a part of Schering-Plough Corporation, Molenstraat 110, PO Box 20, 5340 BH Oss, The Netherlands. E-mail: norbert.koper{at}spcorp.com
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionThe Corifollitropin Alfa Dose...FundingAcknowledgementsReferences |
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BACKGROUND: This study primarily investigated the dose–response relationship of corifollitropin alfa to initiate multifollicular development for the first 7 days of controlled ovarian stimulation (COS).
METHODS: Women aged 20–39 years undergoing COS for in vitro fertilization or intracytoplasmic sperm injection were randomized to a single dose of corifollitropin alfa 60, 120 or 180 µg, or daily injections of 150 IU recombinant follicle-stimulating hormone (rFSH). Patients treated with corifollitropin alfa started fixed daily treatment with 150 IU rFSH on stimulation Day 8. Patients received a GnRH antagonist (ganirelix 0.25 mg/day) from stimulation Day 5 until the day of human chorionic gonadotrophin.
RESULTS: Pharmacokinetics of corifollitropin alfa were dose-proportional. The main reason for not having embryo transfer was insufficient ovarian response in 30.8, 2.6, 3.8 and 7.4% of patients in the corifollitropin alfa 60, 120, 180 µg and rFSH groups, respectively. On Day 8, the mean (standard deviation) number of follicles 
11 mm was 6.8 (4.4), 10.1 (6.1) and 12.8 (7.5), respectively. The number of cumulus–oocyte complexes retrieved showed a clear dose–response relationship (P < 0.0001), being 5.2 (5.5), 10.3 (6.3) and 12.5 (8.0) in the three dose groups, respectively.
CONCLUSIONS: A single injection of corifollitropin alfa induces dose-related increase in multifollicular development and in the number of retrieved oocytes. The optimal dose for a 1-week interval is higher than 60 µg and lower than 180 µg and will be selected based on modelling and simulation taking into account insufficient stimulation as well as overstimulation. Clinical Trials gov: NCT00598208 [ClinicalTrials.gov] .
Key words: corifollitropin alfa/rFSH/controlled ovarian stimulation/IVF/sustained follicle stimulant
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionThe Corifollitropin Alfa Dose...FundingAcknowledgementsReferences |
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Current treatment regimens for controlled ovarian stimulation (COS) in women undergoing in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) usually require daily self-injection of follicle-stimulating hormone (FSH). Although advances in methods of FSH administration (e.g. self-injection with pen devices) have helped to lessen the burden for patients, the need for daily FSH injections is still present. New gonadotrophin preparations with longer half-lives are being developed that may lower the frequency of FSH administration (Fares et al., 1992
; Duijkers et al., 2002; Klein et al., 2003; Perlman et al., 2003). When combined with the advantages of gonadotrophin-releasing hormone (GnRH) antagonist regimens (Hohmann et al., 2003; Kolibianakis et al., 2006; Tarlatzis et al., 2006; Heijnen et al., 2007), the development of new clinical protocols that can provide similar success rates with fewer injections may help reduce the treatment burden to further enhance the acceptability for patients undergoing COS.
Corifollitropin alfa (Org 36286, NV Organon, a part of Schering-Plough Corporation, Oss, the Netherlands), a sustained follicle stimulant, is a novel recombinant fertility hormone which consists of the 
-subunit of human FSH and a hybrid subunit consisting of the carboxy terminal peptide (CTP) of the β-subunit of human chorionic gonadotrophin (hCG) coupled with the FSH β-subunit. This molecular structure includes O-linked carbohydrate chains at the CTP, which results in an increased half-life in vivo compared with recombinant FSH (rFSH) (Fares et al., 1992). Previous studies in hypogonadotrophic hypogonadal men, pituitary-suppressed healthy women and women with anovulatory infertility have indicated that the terminal half-life of corifollitropin alfa is approximately twice that of rFSH (Bouloux et al., 2001; Duijkers et al., 2002; Balen et al., 2004). These studies have also shown that administration of corifollitropin alfa is safe and well-tolerated and does not result in antibody formation (Bouloux et al., 2001; Duijkers et al., 2002; Balen et al., 2004).
In a previous smaller study of corifollitropin alfa in women scheduled for IVF or ICSI, single doses of 120, 180 or 240 µg induced and maintained multiple follicular growth for 1 week in a GnRH antagonist protocol (Devroey et al., 2004). However, the outcome of this first trial showed that corifollitropin alfa was effective in the dose range of 120–240 µg, but that the dosages tested were too high to demonstrate a significant dose–response relationship. In addition, the amount of additional rFSH needed to reach the stage of hCG administration was similar in each of the corifollitropin alfa dose groups. The current study in women undergoing COS for IVF or ICSI was designed to investigate the dose–response relationship with respect to the number of oocytes retrieved following a single injection of corifollitropin alfa over a lower dose range (60–180 µg). The outcome of this investigation allowed subsequent modelling and simulation to identify the optimal dose of corifollitropin alfa in a 1-week regimen. A reference group of subjects treated with daily fixed 150 IU rFSH was used only as a positive control for a standard (mild) GnRH antagonist treatment regimen.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionThe Corifollitropin Alfa Dose...FundingAcknowledgementsReferences |
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This was a multicentre, open-label, randomized study with three doses of corifollitropin alfa (60, 120 and 180 µg) in a COS regimen for IVF or ICSI. The primary objective of this study was to investigate the dose–response relationship of corifollitropin alfa. A treatment arm with rFSH was included for reference only. The study was approved by the Health Authority and Independent Medical Ethics Committee for each centre and conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Guidelines and Good Clinical Practice. Written informed consent was provided by all patients.
Patients
Patients were women aged 20–39 years with a normal menstrual cycle (24–35 days) and a body mass index of 17–31 kg/m2 with an indication for COS before IVF or ICSI. Women with a history of ovarian hyperstimulation syndrome (OHSS), polycystic ovary syndrome (PCOS) or any endocrine abnormality were excluded. Other exclusion criteria included a previous poor response to FSH or human menopausal gonadotrophin (hMG), more than three unsuccessful COS cycles since last ongoing pregnancy, fewer than two ovaries, abnormal hormone levels during Days 2–7 of the menstrual cycle, use of hormonal preparations within 1 month before treatment or previous use of corifollitropin alfa.
Study design
Patients were randomized after evaluation of screening data to confirm eligibility. Randomization to one of the four treatment groups (1:1:1:1 ratio) was stratified by age (<32 or 32 years) and by centre using a central remote allocation procedure using a fixed block size of four and a minimization algorithm combined with randomly permutated blocks. Patients randomized to corifollitropin alfa started ovarian stimulation on Day 2 or 3 of their menstrual cycle with a single subcutaneous (SC) dose of 60, 120 or 180 µg. This was followed 1 week later (treatment Day 8) by a fixed daily dose of SC rFSH 150 IU (follitropin beta, Follistim® AQ/Puregon®, NV Organon) up to the day of hCG administration. Patients in the reference group received a fixed daily dose of SC rFSH 150 IU from cycle Days 2 or 3 up to the day of hCG. FSH administration on the day of hCG was optional for all patients. To prevent premature luteinizing hormone (LH) surges, patients were treated with a fixed GnRH antagonist regimen of SC ganirelix 0.25 mg (ganirelix acetate injection, Orgalutran®, NV Organon) from stimulation Day 5 up to and including the day of hCG. Maximum total treatment duration was 19 days. To induce final oocyte maturation, hCG 10 000 IU (Pregnyl®, NV Organon) were to be given when three follicles 17 mm were observed by ultrasound scan (USS). Approximately 30–36 h thereafter, oocyte retrieval followed by IVF or ICSI was performed. At embryo transfer, which took place 2–5 days after oocyte retrieval, up to three embryos could be transferred. All patients received daily progesterone for luteal phase support for at least 2 weeks or until menses. Outcomes achieved with spare, frozen embryos were reported during the first year after treatment.
Assessments
Before the start of ovarian stimulation, pregnancy was excluded by means of an hCG test. A blood sample was obtained for hormone assessments, and USS was performed. Patients returned to the clinic for USS and blood sampling on Days 3 and 5, and then daily up to and including the day of hCG. Additional blood samples to assess hormone levels were collected on the day of oocyte retrieval, on the day of embryo transfer and 2 weeks after embryo transfer.
Validated immunoassays (Devroey et al., 2004) were performed at a central laboratory to measure serum levels of FSH, LH, estradiol (E2), progesterone (NV Organon, Waltrop, Germany), inhibin-B, corifollitropin alfa and antibodies against corifollitropin alfa.
Statistics
The sample size was based on the primary objective to investigate the dose–response relationship for the number of cumulus–oocyte complexes retrieved (primary endpoint). Assuming a linear dose–response model with log-dose as explanatory variable, with a positive slope of 3.3 (implying a difference of four oocytes between the lowest and highest corifollitropin alfa doses) and a standard deviation (SD) of seven oocytes, a sample size of 80 patients per group was sufficient to detect a positive dose–response with a power of 90% at the 0.05 significance level.
The number of cumulus–oocyte complexes retrieved was defined as the primary outcome parameter for this trial and analyzed accordingly. The number of cumulus–oocyte complexes retrieved was analyzed per started cycle (number set to zero for patients without oocyte retrieval) and per oocyte retrieval. The dose–response was investigated using the log-dose effect in an analysis of covariance (ANCOVA) model, with log-dose as covariate and centre as factor. The treatment effect on the number of oocytes was also evaluated using an analysis of variance (ANOVA) model with centre and treatment as factors. Confidence intervals of the differences between each corifollitropin alfa dose group and the rFSH reference group were calculated using this model.
In addition, the number of follicles and E2 levels on Day 8 were analyzed using the ANCOVA model, with log-dose as covariate and centre as factor.
Other variables that were evaluated included dose of rFSH required, number and size of follicles, serum hormone levels, fertilization rate, number and quality of embryos obtained and transferred, and pregnancy rates. Descriptive summary statistics were calculated for these parameters. Formal statistical comparisons between the corifollitropin alfa and rFSH treatment groups were not planned or performed for these other parameters.
All efficacy analyses were based on the intent-to-treat (ITT) population, which included all randomized patients who received corifollitropin alfa or at least one dose of rFSH. One patient randomized to the 60 µg group was mistakenly treated with rFSH instead. This patient is included within the corifollitropin alfa 60 µg group for ITT analyses.
The pharmacokinetics of corifollitropin alfa were assessed using a one-compartment model with first-order absorption, first-order elimination and body weight as covariate and a non-linear mixed-effects model program (NONMEM) was used for the analysis. Population (mean) and individual parameter estimates were determined.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionThe Corifollitropin Alfa Dose...FundingAcknowledgementsReferences |
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A total of 325 patients were randomized at 17 centres across Europe (Fig. 1), 315 of whom received treatment. Non-treated patients dropped out because of spontaneous pregnancy or personal reasons. Treatment groups had comparable demographic and fertility characteristics at baseline (Table I). Mean age (SD) of the patients in this study was 32.1 (3.7) years, mean body weight (SD) was 64.5 (9.1) kg and mean body mass index (SD) was 23.0 (3.0) kg/m2. Mean serum hormone levels were similar in all treatment groups at screening.
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Thirty-nine patients who started ovarian stimulation with corifollitropin alfa or rFSH did not receive hCG, most of whom (n = 23) were in the corifollitropin alfa 60 µg group (Table I). Overall, 34 patients in the 60 µg group (44%), seven in the 120 µg group (9%), nine in the 180 µg group (11%) and 15 in the rFSH group (19%) were discontinued (i.e. cycle cancelled) before embryo transfer. The main reason for cycle cancellation was insufficient ovarian response; occurring in 30.8, 2.6, 3.8 and 7.4% of patients in the corifollitropin alfa 60, 120, 180 µg and rFSH groups, respectively.
Controlled ovarian stimulation
Median duration of stimulation in the corifollitropin groups was 10–11 days. The total amount of rFSH required from Day 8 to reach the criteria of hCG administration was 600 IU (4 days), 450 IU (3 days) and 300 IU (2 days) in the 60, 120 and 180 µg groups, respectively. In the rFSH reference group, the median duration of stimulation was 10 days and the total amount of rFSH administered was 1350 IU.
Pharmacokinetics
Pharmacokinetic parameters for corifollitropin alfa are summarized in Table II. Maximum serum concentration (Cmax) and area under the curve from time zero to infinity (AUC0-
) of corifollitropin alfa were dose-proportional within the range 60–180 µg, whereas terminal half-life (mean 65–66 h) was independent of dose. Actual serum levels of corifollitropin alfa are plotted together with population-predicted curves for a patient with a body weight of 65 kg in Fig. 2. Corifollitropin alfa exposure showed an inverse relationship with body weight, which was found to be a significant covariate of clearance and volume of distribution. Using population-predicted parameters, Cmax and AUC0- were shown to be almost twice as high in a 50 kg body weight patient compared with a patient with a body weight of 80 kg, as depicted in the lower panel of Table II.
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Follicular dynamics
From start of COS to treatment Day 6, the number and size of follicles were comparable between groups. However, from Day 6 onwards, the number of follicles
11 mm was higher in the corifollitropin alfa 120 and 180 µg groups compared with the 60 µg group. On Day 8, before administration of rFSH, the mean (SD) number of follicles 11 mm showed a dose-related increase (P < 0.001) and was 6.8 (4.4), 10.1 (6.1) and 12.8 (7.5) in the 60, 120 and 180 µg groups, respectively. On the day of hCG administration, this dose-related response was still apparent, and the mean (SD) number of follicles was, respectively, 11.4 (5.3), 13.5 (6.5) and 16.4 (7.2) (Fig. 3).
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Serum hormones during the follicular and luteal phases
Median serum levels of LH, E2 and inhibin-B for all patients who received hCG are shown in Fig. 4. After an initial decline in all groups, serum levels of LH increased from Day 3 to 5 in the corifollitropin alfa groups while continuing to decline in the rFSH group until Day 6. After the start of ganirelix treatment on stimulation Day 5, LH levels decreased in the corifollitropin alfa groups until Day 9, whereas there was a slight increase in the rFSH group from Day 6 to 9. Median serum LH levels on the day of hCG were 1.1, 0.8 and 0.8 IU/l in the corifollitropin alfa 60, 120 and 180 µg groups, respectively, and 1.5 IU/l in the rFSH group.
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On stimulation Day 5, premature LH rises (
10 IU/l) were experienced by 12 patients before starting ganirelix (corifollitropin alfa 60 µg, n = 1; 120 µg, n = 3 and 180 µg, n = 8), 11 of whom also had concomitant rises in serum progesterone levels (3.18 nmol/l). Ten of these patients had a subsequent embryo transfer, of whom four became pregnant (one miscarried). LH rises were also observed in five patients after starting ganirelix (corifollitropin alfa 60 µg, n = 3; rFSH, n = 2). Three of these patients underwent embryo transfer but none became pregnant.
Median serum E2 levels increased more rapidly in the corifollitropin alfa groups compared with the rFSH group during the first 6 days of stimulation. Between Day 6 and 8, levels declined in the 60 µg group, reached a plateau in the 120 µg group and continued to increase in the 180 µg group. On Day 8, serum E2 levels showed a dose-related increase (P < 0.001). After the start of daily rFSH on Day 8, serum E2 levels increased in all corifollitropin alfa groups. On day of hCG, serum E2 levels were similar in the 60, 120 µg and rFSH groups, but 
1.5-fold higher in the 180 µg group.
Median serum inhibin-B levels followed a similar pattern as serum E2 levels, with an initial rise in all groups. From Day 6 onwards, serum inhibin-B levels continued to increase in the 180 µg group and daily rFSH group, whereas inhibin-B reached a plateau from Day 6 to 8 in the 120 µg group and decreased in the 60 µg group.
Clinical outcomes
The number of cumulus–oocyte complexes retrieved after treatment with corifollitropin alfa showed a clear dose–response relationship (Pslope < 0.0001) (Fig. 5). The mean (SD) number of oocytes retrieved per started cycle was 5.2 (5.5), 10.3 (6.3) and 12.5 (8.0) in the corifollitropin alfa 60, 120 and 180 µg dose groups, respectively (Table III). Statistical testing indicated that all differences between the corifollitropin alfa groups reached significance [120 versus 60 µg: P < 0.0001, 95% confidence interval (CI) (3.07, 7.15); 180 versus 60 µg: P < 0.0001, 95% CI (5.37, 9.42) and 180 versus 120 µg: P = 0.028, 95% CI (0.25, 4.32)]. In the rFSH group, the mean number of oocytes (SD) was 7.7 (6.3), which was statistically significantly higher than in the 60 µg group [P = 0.009, 95% CI (0.69, 4.72)], but statistically significantly lower than in the 120 µg [P = 0.020, 95% CI (–4.43, –0.39)] and 180 µg [P < 0.0001, 95% CI (–6.71, –2.69)] dose groups, when tested using the ANOVA model.
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Other clinical outcome parameters are summarized in Table III. The mean number of good-quality (Grade I and II) embryos obtained was higher in the 120 and 180 µg groups. The incidence of single embryo transfer of one good-quality embryo across the groups ranged from 37 to 53% and implantation rate ranged from 17 to 21%. In total, 46 ongoing pregnancies were achieved (corifollitropin alfa 60 µg, n = 12; 120 µg, n = 12; 180 µg, n = 11; rFSH, n = 11) and the percentage of ongoing pregnancies per transfer ranged from 16 to 27%. Ongoing pregnancies included nine sets of twins, one in the corifollitropin alfa 60 µg group, five in the 120 µg group, two in the 180 µg group and one in the rFSH group. Cumulative pregnancy rate, including fresh and cryopreserved embryos, was slightly higher in the corifollitropin alfa 120 and 180 µg groups.
Safety
In total, 13 subjects experienced 16 serious adverse events, including ectopic pregnancy, salmonellosis, mild pelvic pain, ovarian cyst, appendicitis, peritonitis and hyperemesis, all of which were considered by the investigator and study sponsor as unlikely to be related to study treatment. Six reports of OHSS were classed as serious adverse events, two in each of the corifollitropin alfa 120 and 180 µg groups and two in the rFSH group, all of which were considered possibly or probably related to study treatment. They included two severe cases (Grade III), one in the 120 µg group and one in the rFSH group, three moderate cases (Grade II) and one mild case (Grade I). Other serious adverse events considered at least possibly related to study treatment were a high-risk triple pregnancy in the 180 µg group and a report of severe pelvic pain in the rFSH group. Treatment with corifollitropin alfa did not induce hypersensitivity reactions, or antibodies against corifollitropin alfa.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionThe Corifollitropin Alfa Dose...FundingAcknowledgementsReferences |
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This study shows that a single injection of a new recombinant fertility hormone, corifollitropin alfa, can induce and sustain multifollicular growth for an entire week in women undergoing COS for IVF or ICSI. A single dose of corifollitropin alfa resulted in a dose-dependent, statistically significant increase in the number of cumulus–oocyte complexes retrieved over the dose range of 60–180 µg. This is consistent with the only previous smaller study of corifollitropin alfa in IVF patients, in which higher doses of 120–240 µg were tested (Devroey et al., 2004
). In the current study, per started cycle, fewer cumulus–oocyte complexes were retrieved with 60 µg corifollitropin alfa compared with fixed 150 IU rFSH. The high cycle cancellation rate in the 60 µg group before hCG administration (30% and before embryo transfer 44%) indicates that this dose is too low to support the first 7 days of COS. Cancellation rates with the higher corifollitropin alfa doses (9 and 11% with 120 and 180 µg, respectively) are consistent with those generally observed in COS protocols. However, the cancellation rate with daily rFSH was comparatively high (7% before hCG; 19% before embryo transfer), mainly due to insufficient ovarian response. This can be explained by the protocolized 150 IU regimen of rFSH, which implied that the dose could not be increased during stimulation if it appeared to be too low for a specific patient. The protocolized dosing regimen may also account for the relatively low number of oocytes retrieved in the rFSH group.
The open-label design of this study was deemed appropriate from a methodological perspective in view of the relatively objective and robust primary endpoint, number of oocytes retrieved, and within strict protocolized boundaries defining stimulation start-, dosing- and stop-criteria. Further studies are required to compare clinical outcomes with corifollitropin alfa and daily rFSH regimens.
Other clinical outcomes were generally comparable between the corifollitropin alfa groups. The overall pregnancy rate in the treatment cycles was relatively low, but comparable between all groups, including the daily rFSH reference group. Further analyses were hampered due to the small sample size, especially when looking at subpopulations (e.g. number of embryos transferred, day of embryo transfer, variation in luteal phase support), and did not reveal a clear explanation for this finding. The total number of embryos and number of good-quality embryos were higher with corifollitropin alfa 120 and 180 µg, possibly reflecting the higher oocyte yield in these groups. This may explain the slightly higher cumulative pregnancy rates in these groups, since more good-quality embryos may have been available for cryopreservation. Reliable estimation of the ongoing pregnancy rate following treatment with the corifollitropin alfa compared with rFSH will come from an adequately powered clinical trial using a similar patient population. The primary endpoint of this currently ongoing phase III trial is ongoing pregnancy.
Patients treated with corifollitropin alfa started daily rFSH treatment on Day 8 in order to reach the criteria for hCG administration. This was achieved with a median of just three injections of rFSH in the corifollitropin alfa 120 µg group and two injections in the 180 µg group. Although the 120 µg group required more daily rFSH than the 180 µg group, median duration of ovarian stimulation was the same (10 days) in both groups because the final dose of rFSH could have been given either on the day of hCG or the day before. This observation confirms previous findings, in which, on average, three daily injections of rFSH were required after a single injection of corifollitropin alfa (Devroey et al., 2004).
The occurrence of early increases in serum LH levels before the start of GnRH antagonist treatment was low but LH levels were assessed only once at stimulation Day 5. As described previously in patients treated with different starting doses of rFSH in a GnRH antagonist protocol (Out et al., 2004), the incidence of early LH rises was dose-dependent. Most of these patients (8/12) were treated with corifollitropin alfa 180 µg and all but one also had a rise in serum progesterone, indicating premature luteinization. The incidence of premature LH rise reported here is lower than that seen in the previous corifollitropin alfa IVF study, in which flexible initiation of GnRH antagonist administration (given when first follicle 14 mm) was associated with premature LH rises in 17.6% of corifollitropin alfa-treated patients and 8.3% of rFSH-treated patients (Devroey et al., 2004). However, the incidence is similar to that observed in previous studies using both fixed and flexible GnRH antagonist protocols in patients treated with daily rFSH 150 IU (The European Orgalutran Study Group et al., 2000; European and Middle East Orgalutran Study Group, 2001). As also reported in the previous corifollitropin alfa IVF study, the pregnancy rate among patients with premature luteinization did not appear to be reduced, though the numbers included were small (four out of 12 patients).
The pharmacokinetics of corifollitropin alfa showed dose-proportionality over the range 60–180 µg. Terminal half-life was similar in all dose groups (65–66 h) and is consistent with results of previous studies in pituitary-suppressed female volunteers and IVF patients (Duijkers et al., 2002; Devroey et al., 2004). Body weight had a significant impact on exposure to corifollitropin alfa, expressed as Cmax and AUC0-. A comparable effect of body weight on rFSH exposure during daily rFSH treatment has previously been shown (Mannaerts et al., 1996). Results of this study suggest that the exposure of subjects with different body weights should be taken into account in final dose selection of corifollitropin alfa for phase III studies.
The optimal dose of corifollitropin alfa is mainly determined by the predefined time interval (1 week) that a single administration needs to support multiple follicular growth. Clearly, cancellation due to insufficient circulating FSH should be prevented as well as overstimulation. Reflections of insufficient bioactive FSH are not only actual cancellations due to insufficient ovarian response, but also declining levels of serum inhibin-B during stimulation. Accordingly, the 60 µg dose is too low for the subset of subjects included in this trial. Based on the outcome of this trial and subsequent modelling and simulation, taking into account the body weight (exposure) of subjects, the optimal dose of corifollitropin alfa could be estimated. The outcome of simulations (not included in this manuscript) may also predict the number of oocytes that will be retrieved.
Treatment with a single injection of corifollitropin alfa was safe and well tolerated. The number of cases of OHSS was low and comparable with that reported for current rFSH regimens. Corifollitropin alfa was also shown to be non-immunogenic, with no antibody formation or hypersensitivity reaction being observed.
In conclusion, a single dose of corifollitropin alfa can sustain multifollicular growth for an entire week. This trial demonstrates that the optimal dose of corifollitropin alfa in a 1-week regimen is higher than 60 µg and lower than 180 µg. Treatment with corifollitropin alfa potentially offers the convenience of more injection-free days for patients undergoing COS for IVF and ICSI.
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The Corifollitropin Alfa Dose-finding Study Group |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionThe Corifollitropin Alfa Dose...FundingAcknowledgementsReferences |
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T. Åbyholm, H.F. Rikshospitalet, Oslo, Norway; A.N. Andersen, Rigshospitalet, Copenhagen, Denmark; A.H. Balen, Assisted Conception Unit, Leeds General Infirmary, Leeds, UK; D.D.M. Braat, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; P. Devroey, Academisch Ziekenhuis, Vrije Universiteit Brussel, Brussels, Belgium; T.H. D’Hooghe, Universitair Ziekenhuis Leuven, Leuven, Belgium; R. Felberbaum, Universitätsklinikum Lübeck, Lübeck, Germany; B.J.C.M. Fauser, Erasmus Medisch Centrum, Rotterdam and Utrecht, The Netherlands; M. Fridström, Fertilitsenheten, Huddinge Universitetssjukhus, Stockholm, Sweden; T. Hillensjö, Fertilitets Centrum, Carlanderska Sjukhuset, Göteborg, Sweden; C. Keck, Universitäts-Frauenklinik II, Freiburg, Germany; H. Kurunmäki, Felicitas-Klinikka, Helsinki, Finland; S. Lindenberg, Nordica Fertility Clinic and Research Center, Copenhagen, Denmark; W. Ombelet, Ziekenhuis Oost Limburg Campus Sint Jan (Genk), Genk, Belgium; J. Tapanainen, Department of Obstetrics and Gynecology, Oulu University Hospital, Oulu, Finland; E. Varila, AVA-Klinikka, Tampere, Finland; H. Wramsby, IVF Kliniken, St Görans Sjukhus, Stockholm, Sweden; N.P. Koper, A.F.J. de Haan, M.J. Struÿs, B.M. Mannaerts, NV Organon, Oss, The Netherlands.
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Funding |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionThe Corifollitropin Alfa Dose...FundingAcknowledgementsReferences |
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Financial support was provided by NV Organon, Oss, The Netherlands.
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Acknowledgements |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionThe Corifollitropin Alfa Dose...FundingAcknowledgementsReferences |
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Editorial assistance was provided by Andy Bond at Prime Medica (Knutsford, Cheshire, UK). The design and conduct of the study, as well as analysis of the study data and opinions, conclusions and interpretation of the data, were the responsibility of the authors.
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Footnotes |
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Results from this study have been presented at the 22nd Annual Meeting of the European Society for Human Reproduction & Embryology, Prague, Czech Republic, 18–21 June 2006. 
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Submitted on November 26, 2007; resubmitted on June 23, 2008; accepted on June 30, 2008.
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