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Apeldoorn, Netherlands

Andersen A.N.,Copenhagen University | Witjes H.,Biostatistics and Research Decision science | Gordon K.,Merck And Co. | Mannaerts B.,Global Clinical Research
Human Reproduction | Year: 2011

Background: Prediction of ovarian response prior to the first controlled ovarian stimulation (COS) cycle is useful in determining the optimal starting dose of recombinant FSH (rFSH). However, potentially predictive factors may be subject to inter-cycle variability and many patients are pre-treated with oral contraceptives (OC) for scheduling purposes. Our objective was to determine predictive factors of ovarian response for patients undergoing COS with rFSH in a gonadotrophin-releasing hormone antagonist protocol and to determine the inter-cycle variability of these factors.Methods: In this multinational trial, 442 patients were randomized to receive either OC treatment or no treatment prior to their first COS cycle. For candidate predictive factors, patient characteristics were collected at screening, and endocrine and sonographic data were collected during the early follicular phase of the two subsequent cycles. A treatment regimen of 200 IU rFSH and 0.25 mg ganirelix was applied during the second cycle. Predictive factors of ovarian response and of too low (<6 oocytes) or too high (>18 oocytes) ovarian responses were determined using stepwise linear regression and stepwise logistic regression, respectively.Results: Anti-Mllerian hormone (AMH) and basal FSH were statistically significant predictors of the number of oocytes retrieved and of an excessive ovarian response. For low ovarian response, AMH was the only significant predictive factor. In the non-OC group, the predictive value was higher than in the OC group and higher at the early follicular phase of the stimulation cycle than of the previous cycle. The inter-cycle variation for AMH was low compared with the inter-cycle variation of other hormones. Between the two groups, there were no differences in the number or quality of embryos obtained or transferred, but the implantation rate was significantly lower in the OC group (24.1 versus 30.1, P 0.03), resulting in an ongoing pregnancy rate of 26.3 compared with 35.7 in the non-OC group (P 0.05). Conclusions: The best predictive model of ovarian response was in the non-OC group and included both AMH and basal FSH determined at the early follicular phase of the stimulation cycle. In the proceeding cycle, AMH alone had sufficient predictive value since it was not affected by inter-cycle variability or OC pretreatment.Clinical trial identifier: NCT00778999. © 2011 The Author. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. Source


Doody K.J.,Center for Assisted Reproduction | Devroey P.,Universitair Ziekenhuis Brussel | Leader A.,University of Ottawa | Witjes H.,Biostatistics and Research Decision science | Mannaerts B.M.,Global Clinical Research
Reproductive BioMedicine Online | Year: 2011

The relationship between endogenous LH concentrations and ongoing pregnancy rates among normogonadotrophic patients undergoing ovarian stimulation in a gonadotrophin-releasing hormone antagonist protocol were examined. In the Engage trial, 1506 patients received corifollitropin alfa (150 μg) or daily recombinant FSH (rFSH) (200 IU) for the first 7 days of stimulation with 0.25 mg ganirelix from stimulation day 5. Patients were retrospectively stratified by serum LH percentiles (<25th, 25th-75th and >75th) on stimulation day 8 and day of human chorionic gonadotrophin administration. Odds ratios (OR) with and without adjustment for predictive factors for ongoing pregnancy were estimated. LH concentration was not associated with pregnancy rates in either treatment arm, in contrast to ovarian response and serum progesterone. With adjustment for these predictors and age, OR (95% confidence interval) for ongoing pregnancy on stimulation day 8 for LH categories P75 versus ≤P75 and P75 were 0.75 (0.53-1.06), 1.26 (0.87-1.83) and 0.70 (0.46-1.09) in the corifollitropin alfa arm and 0.80 (0.54-1.17), 1.28 (0.87-1.87) and 0.73 (0.46-1.16) in the rFSH arm respectively. There was also no significant difference in pregnancy rates between LH categories on day of human chorionic gonadotrophin administration with either treatment. During ovarian stimulation for IVF/intracytoplasmic sperm injection, circulating concentrations of LH should not become too high or too low as the development of mature eggs and the likelihood of ongoing pregnancy may be negatively affected. Gonadotrophin-releasing hormone (GnRH) analogues are applied to prevent premature LH rises but certain regimens may result in relatively low circulating LH concentrations. To examine the relationship between circulating LH concentrations and ongoing pregnancy rates in a GnRH antagonist protocol, data from a large randomized trial, Engage, were retrospectively analysed. In this trial, 1506 patients received corifollitropin alfa or daily recombinant FSH for the first 7 days of stimulation and ganirelix (a GnRH antagonist) from stimulation day 5 onwards. Patients were grouped by their LH concentration (low, normal or high) on stimulation day 8 and the day of human chorionic gonadotrophin (HCG) administration to trigger final egg maturation. The chance of ongoing pregnancy by LH category, with or without adjustment for other factors affecting pregnancy was calculated. There was no significant difference in the chance of pregnancy between patients in the different LH categories, regardless of the day of assessment or the treatment group. In contrast, circulating progesterone (another hormone produced by mature follicles) and the number of eggs retrieved clearly affected the chance of pregnancy. These analyses showed that ongoing pregnancy rates are not influenced by either low or high circulating LH concentrations when using a GnRH antagonist protocol. © 2011, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved. Source


De Greef R.,Merck Research Labs | Zandvliet A.S.,Merck Research Labs | De Haan A.F.J.,Biostatistics and Research Decision science BARDS | Ijzerman-Boon P.C.,Biostatistics and Research Decision science BARDS | And 2 more authors.
Clinical Pharmacology and Therapeutics | Year: 2010

In controlled ovarian stimulation (COS), a single subcutaneous dose of corifollitropin alfa is used to initiate and sustain multifollicular growth for 7 days. The objective of this study was to determine the optimal dose of corifollitropin alfa. A pharmacokinetic model was developed to describe the time profile of corifollitropin alfa concentrations. Multiple parameters reflecting ovarian response were included in a pharmacokinetic-pharmacodynamic (PK-PD) model framework. An early decline in serum inhibin B was shown to be a sensitive marker for COS failure. Simulations were performed to select the lowest corifollitropin alfa dose that would result in a minimal cancellation rate: 100μg for a group of women weighing 60kg and 150μg for a group of women weighing 60kg. With these doses, the predicted mean number of oocytes per started COS cycle was similar in the two groups, i.e., 12.1 and 13.2, respectively. The selected doses were tested in prospective clinical trials and were proven to be adequate. © 2010 American Society for Clinical Pharmacology and Therapeutics. Source


Lebbe C.,University Paris Diderot | Weber J.S.,H. Lee Moffitt Cancer Center and Research Institute | Maio M.,University of Siena | Neyns B.,Universitair Ziekenhuis Brussel | And 7 more authors.
Annals of oncology : official journal of the European Society for Medical Oncology / ESMO | Year: 2014

BACKGROUND: This report provides a survival update at a follow-up of >5 years (5.5-6 years) for patients with advanced melanoma who previously received ipilimumab in phase II clinical trials. Safety and efficacy data following ipilimumab retreatment are also reported.PATIENTS AND METHODS: Patients who previously received ipilimumab 0.3, 3, or 10 mg/kg in one of six phase II trials (CA184-004, CA184-007, CA184-008, CA184-022, MDX010-08, and MDX010-15) were eligible to enroll in the companion study, CA184-025. Upon enrollment, patients initially received ipilimumab retreatment, extended maintenance therapy, or were followed for survival only. Overall survival (OS) rates were evaluated in patients from studies CA184-004, CA184-007, CA184-008, and CA184-022. Safety and best overall response during ipilimumab retreatment at 10 mg/kg were assessed in study CA184-025.RESULTS: Five-year OS rates for previously treated patients who received ipilimumab induction at 0.3, 3, or 10 mg/kg were 12.3%, 12.3%-16.5%, and 15.5%-28.4%, respectively. Five-year OS rates for treatment-naive patients who received ipilimumab induction at 3 or 10 mg/kg were 26.8% and 21.4%-49.5%, respectively. Little to no change in OS was observed from year 5 up to year 6. The objective response rate among retreated patients was 23%. Grade 3/4 immune-related adverse events occurred in 25%, 5.9%, and 13.2% of retreated patients who initially received ipilimumab 0.3, 3, and 10 mg/kg, with the most common being observed in the skin (4.2%, 2.9%, 3.8%) and gastrointestinal tract (12.5%, 2.9%, 3.8%), respectively.CONCLUSIONS: At a follow-up of 5-6 years, ipilimumab continues to demonstrate durable, long-term survival in a proportion of patients with advanced melanoma. In some patients, ipilimumab retreatment can re-establish disease control with a safety profile that is comparable with that observed during ipilimumab induction. Further studies are needed to determine the contribution of ipilimumab retreatment to OS.CLINICALTRIALSGOV: NCT00162123. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com. Source


Fauser B.C.J.M.,University Utrecht | Alper M.M.,Harvard University | Ledger W.,University of Sheffield | Schoolcraft W.B.,Colorado Center for Reproductive Medicine | And 2 more authors.
Reproductive BioMedicine Online | Year: 2010

A single injection of corifollitropin alfa can replace seven daily injections of recombinant FSH (rFSH) using a gonadotrophin-releasing hormone antagonist protocol in ovarian stimulation prior to IVF or intracytoplasmic sperm injection. This double-blind randomized controlled trial assessed the pharmacokinetics and pharmacodynamics of 150 μg corifollitropin alfa versus daily 200 IU rFSH in 1509 patients. Comparative analyses were performed on serum concentrations of FSH immunoreactivity (pharmacokinetics), and the number and size of growing follicles, and inhibin B and oestradiol concentrations as biomarkers of ovarian response (pharmacodynamics). The rate of follicular development was similar in both treatment groups. By stimulation day 8, 33% of patients treated with corifollitropin alfa reached the criterion for human chorionic gonadotrophin (HCG) injection. The number of follicles ≥11 mm was slightly higher after corifollitropin alfa compared with daily rFSH at stimulation day 8 (difference, 1.2; 95% confidence interval (CI) 0.5-1.8; P < 0.01) and on the day of HCG injection (difference, 2.1; 95% CI 1.4-2.8; P < 0.01). The rise of inhibin B and oestradiol concentrations was similar in both treatment groups. Although the pharmacokinetics of corifollitropin alfa and rFSH are quite different their pharmacodynamic profiles at the dosages used are similar. A single injection of corifollitropin alfa can replace seven daily injections of recombinant FSH (rFSH) using a gonadotrophin-releasing hormone antagonist protocol in ovarian stimulation prior to IVF or intracytoplasmic sperm injection. The objective of this study was to compare the pharmacokinetics and pharmacodynamics of corifollitropin alfa versus daily rFSH. A total of 1509 patients were randomized in a double-blind, controlled trial to either a single injection of 150 μg corifollitropin alfa or to daily injections of 200 IU rFSH for the first 7 days of ovarian stimulation. Serum levels of FSH immunoreactivity were analysed (pharmacokinetic analysis), together with the number and size of growing follicles and serum inhibin B and oestradiol concentrations as biomarkers of the ovarian response (pharmacodynamic analysis). Serum FSH immunoreactivity levels were higher up to stimulation day 5 for corifollitropin alfa compared with the daily rFSH regimen but were similar from day 8 onwards, when patients started rFSH if the criteria for human chorionic gonadotrophin were not yet reached. Corifollitropin alfa treatment resulted in a similar growth rate of follicles though a slightly higher number of follicles were recruited compared with daily rFSH. It is concluded that the pharmacokinetics of corifollitropin alfa and rFSH are quite different but their induced pharmacodynamic effects at the dosages used are similar. © 2010, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved. Source

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