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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


Brueckmann B.,Massachusetts General Hospital | Sasaki N.,Massachusetts General Hospital | Grobara P.,Biostatistics and Research Decision science | Li M.K.,Sharp Corporation | And 16 more authors.
British Journal of Anaesthesia | Year: 2015

Background This study aimed to investigate whether reversal of rocuronium-induced neuromuscular blockade with sugammadex reduced the incidence of residual blockade and facilitated operating room discharge readiness. Methods Adult patients undergoing abdominal surgery received rocuronium, followed by randomized allocation to sugammadex (2 or 4 mg kg-1) or usual care (neostigmine/glycopyrrolate, dosing per usual care practice) for reversal of neuromuscular blockade. Timing of reversal agent administration was based on the providers' clinical judgement. Primary endpoint was the presence of residual neuromuscular blockade at PACU admission, defined as a train-of-four (TOF) ratio <0.9, using TOF-Watch® SX. Key secondary endpoint was time between reversal agent administration and operating room discharge-readiness; analysed with analysis of covariance. Results Of 154 patients randomized, 150 had a TOF value measured at PACU entry. Zero out of 74 sugammadex patients and 33 out of 76 (43.4%) usual care patients had TOF-Watch® SX-assessed residual neuromuscular blockade at PACU admission (odds ratio 0.0, 95% CI [0-0.06], P<0.0001). Of these 33 usual care patients, 2 also had clinical evidence of partial paralysis. Time between reversal agent administration and operating room discharge-readiness was shorter for sugammadex vs usual care (14.7 vs 18.6 min respectively; P=0.02). Conclusions After abdominal surgery, sugammadex reversal eliminated residual neuromuscular blockade in the PACU, and shortened the time from start of study medication administration to the time the patient was ready for discharge from the operating room. © The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. Source


Fletcher C.,Amgen | Driessen S.,Abbott Laboratories | Burger H.U.,Hoffmann-La Roche | Gerlinger C.,Bayer AG | And 2 more authors.
Pharmaceutical Statistics | Year: 2013

The European Federation of Statisticians in the Pharmaceutical Industry (EFSPI) believes access to clinical trial data should be implemented in a way that supports good research, avoids misuse of such data, lies within the scope of the original informed consent and fully protects patient confidentiality. In principle, EFSPI supports responsible data sharing. EFSPI acknowledges it is in the interest of patients that their data are handled in a strictly confidential manner to avoid misuse under all possible circumstances. It is also in the interest of the altruistic nature of patients participating in trials that such data will be used for further development of science as much as possible applying good statistical principles. This paper summarises EFSPI's position on access to clinical trial data. The position was developed during the European Medicines Agency (EMA) advisory process and before the draft EMA policy on publication and access to clinical trial data was released for consultation; however, the EFSPI's position remains unchanged following the release of the draft policy. Finally, EFSPI supports a need for further guidance to be provided on important technical aspects relating to re-analyses and additional analyses of clinical trial data, for example, multiplicity, meta-analysis, subgroup analyses and publication bias. Copyright © 2013 John Wiley & Sons, Ltd. Copyright © 2013 John Wiley & Sons, Ltd. Source


Griesinger G.,University of Lubeck | Shapiro D.B.,Reproductive Biology Associates | Kolibianakis E.M.,Aristotle University of Thessaloniki | Witjes H.,Biostatistics and Research Decision science | Mannaerts B.M.,Merck And Co.
Reproductive BioMedicine Online | Year: 2011

The association between endogenous LH concentrations during ovarian stimulation in a gonadotrophin-releasing hormone (GnRH) antagonist protocol and pregnancy likelihood was examined in a large combined analysis of individualized patient data obtained after treatment with recombinant FSH and a GnRH antagonist prior to IVF/intracytoplasmic sperm injection. Data from 1764 patients from six randomized controlled trials were pooled for retrospective analysis. Ongoing pregnancy and miscarriage rates for patients stratified by LH percentiles were assessed. Patients in the lowest LH quartile (P75). With adjustment for identified predictive factors of pregnancy, estimated odds ratios (95% confidence interval) for ongoing pregnancy for LH categories P75 versus ≤P75 and P75 were 0.96 (0.75-1.22), 1.13 (0.88-1.45) and 0.89 (0.66-1.21) on stimulation day 8, and 0.96 (0.76-1.21), 1.03 (0.82-1.30) and 0.95 (0.72-1.26) on the day of human chorionic gonadotrophin, respectively. No significant differences in pregnancy or miscarriage rates between the LH categories were observed. Endogenous LH concentrations have no association with the likelihood of ongoing pregnancy in women undergoing ovarian stimulation using a recombinant FSH/GnRH antagonist protocol. Circulating concentrations of LH are suppressed during ovarian stimulation for IVF/intracytoplasmic sperm injection with either gonadotrophin-releasing hormone (GnRH) agonists or antagonists to prevent premature LH rises. The association between circulating LH concentrations during ovarian stimulation and the likelihood of pregnancy was examined in a large combined analysis of individualized patient data obtained after treatment with recombinant FSH to stimulate multifollicular development and a GnRH antagonist (ganirelix) to prevent LH surges. Data from 1764 patients from six randomized controlled trials were pooled for retrospective analysis. Patients were divided into three groups based on their circulating LH concentrations being either low, normal or high on stimulation day 8 and on the day of human chorionic gonadotrophin (HCG) administration, and their ongoing pregnancy and miscarriage rates were calculated. Patients with low LH concentrations were in general younger, had a higher ovarian reserve and more retrieved eggs than patients with high LH concentrations. With adjustment for factors known to affect pregnancy, the chance of ongoing pregnancy was not lower for patients with low or high LH concentrations on stimulation day 8 or day of HCG administration. No significant differences in miscarriage rates between the LH categories were observed either. This combined analysis confirms that the concentrations of circulating LH during GnRH antagonist treatment do not affect the likelihood of ongoing pregnancy in women undergoing ovarian stimulation with recombinant FSH. © 2011, Reproductive Healthcare Ltd. Published by Elsevier Ltd. 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

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