Characterizing the exposure-response relationship of idecabtagene vicleucel in patients with relapsed/refractory multiple myeloma.

Idecabtagene vicleucel (ide-cel; bb2121) is a B-cell maturation antigen-directed chimeric antigen receptor (CAR) T cell therapy approved for treatment of patients with heavily pretreated relapsed and refractory multiple myeloma. This analysis evaluated exposure-response (ER) relationships of ide-cel with key efficacy end points and safety events. Ide-cel exposure data were available from 127 patients treated at target doses of 150, 300, or 450 × 106 CAR+ T cells from the phase II KarMMa study (NCT03361748). Key exposure metrics, including area under the curve of the transgene level from 0 to 28 days and maximum transgene level, were calculated using noncompartmental methods. Logistic regression models, using both linear and maximum response function of exposure on the logit scale, were evaluated to quantify observed ER trends, and modified by including statistically significant individual covariates in a stepwise regression analysis. There was wide overlap of exposures across the target doses. ER relationships were observed for the overall and complete response rates, with higher response rates associated with higher exposures. Model-based evaluations identified female sex and baseline serum monoclonal protein less than or equal to 10 g/L as predictive of a higher objective response rate and a higher complete response rate, respectively. ER relationships were observed for safety events of cytokine release syndrome requiring tocilizumab or corticosteroids. The established ER models were used to quantify the ide-cel dose-response, which showed a positive benefit-risk assessment for the range of ide-cel exposures associated with the target dose range of 150-450 × 106 CAR+ T cells.

Mobocertinib Dose Rationale in Patients with Metastatic NSCLC with EGFR Exon 20 Insertions: Exposure-Response Analyses of a Pivotal Phase I/II Study.

Mobocertinib is an oral tyrosine kinase inhibitor approved for treatment of patients with locally advanced or metastatic non-small cell lung cancer (mNSCLC) with epidermal growth factor receptor gene (EGFR) exon 20 insertion (ex20ins) mutations previously treated with platinum-based chemotherapy. These exposure-response analyses assessed potential relationships between exposure and efficacy or safety outcomes in platinum-pretreated patients with EGFRex20ins-positive mNSCLC who received mobocertinib 160 mg once daily (q.d.) in a pivotal phase I/II study. A statistically significant relationship between the independent review committee-assessed objective response rate and molar sum exposure to mobocertinib and its active metabolites (AP32960 and AP32914) was not discernable using a longitudinal model of clinical response driven by normalized dynamic molar sum exposure or a static model of best clinical response based on time-averaged molar sum exposure. However, the longitudinal model suggested a trend for decreased probability of response with the change in mobocertinib molar sum exposure between the 160- and 120-mg doses (odds ratio: 0.78; 95% confidence interval: 0.55-1.10; P = 0.156). Time-averaged molar sum exposure was a significant predictor of the rate of grade ≥ 3 treatment-emergent adverse events (AEs). Taken together, these exposure-efficacy and exposure-safety results support a favorable benefit-risk profile for the approved mobocertinib 160-mg q.d. dose and dose modification guidelines for patients experiencing AEs.

Forward and reverse translational approaches to predict efficacy of neutralizing respiratory syncytial virus (RSV) antibody prophylaxis.

BACKGROUND: Neutralizing mAbs can prevent communicable viral diseases. MK-1654 is a respiratory syncytial virus (RSV) F glycoprotein neutralizing monoclonal antibody (mAb) under development to prevent RSV infection in infants. Development and validation of methods to predict efficacious doses of neutralizing antibodies across patient populations exposed to a time-varying force of infection (i.e., seasonal variation) are necessary. METHODS: Five decades of clinical trial literature were leveraged to build a model-based meta-analysis (MBMA) describing the relationship between RSV serum neutralizing activity (SNA) and clinical endpoints. The MBMA was validated by backward translation to animal challenge experiments and forward translation to predict results of a recent RSV mAb trial. MBMA predictions were evaluated against a human trial of 70 participants who received either placebo or one of four dose-levels of MK-1654 and were challenged with RSV [NCT04086472]. The MBMA was used to perform clinical trial simulations and predict efficacy of MK-1654 in the infant target population. FINDINGS: The MBMA established a quantitative relationship between RSV SNA and clinical endpoints. This relationship was quantitatively consistent with animal model challenge experiments and results of a recently published clinical trial. Additionally, SNA elicited by increasing doses of MK-1654 in humans reduced RSV symptomatic infection rates with a quantitative relationship that approximated the MBMA. The MBMA indicated a high probability that a single dose of ≥ 75 mg of MK-1654 will result in prophylactic efficacy (> 75% for 5 months) in infants. INTERPRETATION: An MBMA approach can predict efficacy of neutralizing antibodies against RSV and potentially other respiratory pathogens.

Magnesium sulfate pharmacokinetics after intramuscular dosing in women with preeclampsia.

BACKGROUND: Current intramuscular magnesium dosing regimens in low and middle-income countries are based on indirect absorption parameters to inform pharmacokinetic and pharmacodynamic response. OBJECTIVE: To determine if therapeutic serum magnesium levels are obtained in women with severe preeclampsia receiving intramuscular administration of magnesium sulfate using the Pritchard regimen and to compare the key pharmacokinetic variables to those previously published. STUDY DESIGN: Serum magnesium levels were obtained at multiple time points at baseline and after magnesium sulfate administration from women with severe preeclampsia receiving the standard Pritchard regimen for seizure prophylaxis at Bayero University, Kano, Nigeria. The pharmacokinetic profiles were constructed for the study cohort and the updated pharmacokinetic model was compared with the one that was previously published. RESULTS: A total of 80 blood samples were collected from 20 women with severe preeclampsia (45 collected before childbirth and 35 collected after childbirth). After 11.5 hours of magnesium sulfate administration, 63% of women in the cohort had serum magnesium levels of ≥2.0 mmol/L. Data from women receiving the Pritchard regimen combined with data from women previously modeled after the receipt of intravenous magnesium sulfate were adequately described using a 2-compartment model with first-order absorption and linear elimination from the central compartment. All structural pharmacokinetic parameters including clearance, central volume of distribution, peripheral volume of distribution, and intercompartment clearance were adjusted for maternal weight, and the clearance was further adjusted for serum creatinine level and antepartum or postpartum status. The simulated pharmacokinetic profiles of the updated pharmacokinetic model and the previously published pharmacokinetic model are similar. In previously published pharmacokinetic modeling, absorption rate constant=0.32 and absolute bioavailability=0.86. In the updated pharmacokinetic model, absorption rate constant=0.45 and absolute bioavailability=0.91. CONCLUSION: These data support the use of the Pritchard regimen as acceptable to achieve therapeutic serum magnesium levels and support the reported simulation of serum magnesium levels and eclampsia response associated with different intramuscular regimens.

Meta-Analyses of Clinical Efficacy of Risankizumab and Adalimumab in Chronic Plaque Psoriasis: Supporting Evidence of Risankizumab Superiority.

Risankizumab, an anti-interleukin-23 monoclonal antibody, achieved significantly (P < 0.001) greater Psoriasis Area and Severity Index (PASI) and static Physician Global Assessment (sPGA) clear or almost clear (0/1) responses than adalimumab in a phase III trial in patients with moderate-to-severe psoriasis. Meta-analyses of the PASI 50, PASI 75, PASI 90, PASI 100, and sPGA0/1 responses after 16 weeks of treatment from eight (three for risankizumab and five for adalimumab) randomized, placebo-controlled trials were conducted to estimate the efficacy difference between risankizumab and adalimumab. For PASI 75, PASI 90, PASI 100, and sPGA0/1 responses, the estimated effect differences (95% confidence interval) between risankizumab and adalimumab were 15.2% (10.1%, 20.4%), 23.7% (15.7%, 31.2%), 20.8% (13.0%, 28.7%), and 20.1% (13.7%, 26.1%), respectively. These results were consistent with the observed efficacy difference from the head-to-head phase III trial, which was not included in the meta-analyses, providing independent, confirmatory evidence of the superior efficacy of risankizumab compared with adalimumab for treatment of moderate-to-severe psoriasis.

Maternal-Neonatal Raltegravir Population Pharmacokinetics Modeling: Implications for Initial Neonatal Dosing.

Raltegravir readily crosses the placenta to the fetus with maternal use during pregnancy. After birth, neonatal raltegravir elimination is highly variable and often extremely prolonged, with some neonates demonstrating rising profiles after birth despite removal from the source of extrinsic raltegravir. To establish an appropriate dosing regimen, an integrated maternal-neonatal pharmacokinetics model was built to predict raltegravir plasma concentrations in neonates with in utero raltegravir exposure. Postnatal age and body weight were used as structural covariates. The model predicted rising or decreasing neonatal elimination profiles based on the time of maternal drug administration relative to time of birth and degree of in utero drug disposition into the central and peripheral compartments. Based on this model, it is recommended to delay the first oral dose of raltegravir until 1-2 days of age in those neonates born to mothers who received raltegravir during pregnancy, labor, and delivery.

Alternative Magnesium Sulfate Dosing Regimens for Women With Preeclampsia: A Population Pharmacokinetic Exposure-Response Modeling and Simulation Study.

Magnesium sulfate is the anticonvulsant of choice for eclampsia prophylaxis and treatment; however, the recommended dosing regimens are costly and cumbersome and can be administered only by skilled health professionals. The objectives of this study were to develop a robust exposure-response model for the relationship between serum magnesium exposure and eclampsia using data from large studies of women with preeclampsia who received magnesium sulfate, and to predict eclampsia probabilities for standard and alternative (shorter treatment duration and/or fewer intramuscular injections) regimens. Exposure-response modeling and simulation were applied to existing data. A total of 10 280 women with preeclampsia who received magnesium sulfate or placebo were evaluated. An existing population pharmacokinetic model was used to estimate individual serum magnesium exposure. Logistic regression was applied to quantify the serum magnesium area under the curve-eclampsia rate relationship. Our exposure-response model-estimated eclampsia rates were comparable to observed rates. Several alternative regimens predicted magnesium peak concentration < 3.5 mmol/L (empiric safety threshold) and eclampsia rate ≤ 0.7% (observed response threshold), including 4 g intravenously plus 10 g intramuscularly followed by either 8 g intramuscularly every 6 hours × 3 doses or 10 g intramuscularly every 8 hours × 2 doses and 10 g intramuscularly every 8 hours × 3 doses. Several alternative magnesium sulfate regimens with comparable model-predicted efficacy and safety were identified that merit evaluation in confirmatory clinical trials.

Operating characteristics of stepwise covariate selection in pharmacometric modeling.

Stepwise covariate modeling (SCM) is a widely used tool in pharmacometric analyses to identify covariates that explain between-subject variability (BSV) in exposure and exposure-response relationships. However, this approach has several potential weaknesses, including over-estimated covariate effect and incorrect selection of covariates due to collinearity. In this work, we investigated the operating characteristics (i.e., accuracy, precision, and power) of SCM in a controlled setting by simulating sixteen scenarios with up to four covariate relationships. The SCM analysis showed a decrease in the power to detect the true covariates as model complexity increased. Furthermore, false highly correlated covariates were frequently selected in place of or in addition to the true covariates. Relative root mean square errors (RMRSE) ranged from 1 to 51% for the fixed effects parameters, increased with the number of covariates included in the model, and were slightly higher than the RMRSE obtained with a simple re-estimation exercise with the true model (i.e., stochastic simulation and estimation). RMRSE for BSV increased with the number of covariates included in the model, with a covariance parameter RMRSE of almost 135% in the most complex scenario. Loose boundary conditions on the continuous covariate power relation appeared to have an impact on the covariate model selection in SCM. A stricter boundary condition helped achieve high power (> 90%), even in the most complex scenario. Finally, reducing the sample size in terms of number of subjects or number of samples proved to have an impact on the power to detect the correct model.

Population Pharmacokinetic Modeling to Evaluate Standard Magnesium Sulfate Treatments and Alternative Dosing Regimens for Women With Preeclampsia.

Magnesium sulfate is the standard therapy for prevention and treatment of eclampsia. Two standard dosing regimens require either continuous intravenous infusion or frequent, large-volume intramuscular injections, which may preclude patients from receiving optimal care. This project sought to identify alternative, potentially more convenient, but similarly effective dosing regimens that could be used in restrictive clinical settings. A 2-compartment population pharmacokinetic (PK) model was developed to characterize serial PK data from 92 pregnant women with preeclampsia who received magnesium sulfate. Body weight and serum creatinine concentration had a significant impact on magnesium PK. The final PK model was used to simulate magnesium concentration profiles for the 2 standard regimens and several simplified alternative dosing regimens. The simulations suggest that intravenous regimens with loading doses of 8 g over 60 minutes followed by 2 g/h for 10 hours and 12 g over 120 minutes followed by 2 g/h for 8 hours (same total dose as the standard intravenous regimen but shorter treatment duration) would result in magnesium concentrations below the toxic range. For the intramuscular regimens, higher maintenance doses given less frequently (4 g intravenously + 10-g intramuscular loading doses with maintenance doses of 8 g every 6 hours or 10 g every 8 hours for 24 hours) or removal of the intravenous loading dose (eg, 10 g intramusculary every 8 hours for 24 hours) may be reasonable alternatives. In addition, individualized dose adjustments based on body weight and serum creatinine were proposed for the standard regimens.

Population pharmacokinetics and exposure-response of osimertinib in patients with non-small cell lung cancer.

AIMS: To develop a population (pop) pharmacokinetic (PK) model for osimertinib (AZD9291) and its metabolite (AZ5104) and investigate the exposure-response relationships for selected efficacy and safety parameters. METHODS: PK, safety and efficacy data were collected from two non-small cell lung cancer (NSCLC) patient studies (n = 748) and one healthy volunteer study (n = 32), after single or multiple once-daily dosing of 20-240 mg osimertinib. Nonlinear mixed effects modelling was used to characterise the popPK. Individual exposure values were used to investigate the relationship with response evaluation criteria in solid tumours (RECIST 1.1) efficacy parameters and key safety parameters (rash, diarrhoea, QTcF). RESULTS: A popPK model that adequately described osimertinib and its metabolite AZ5104 in a joint manner was developed. Body weight, serum albumin and ethnicity were identified as significant covariates on PK in the analysis, but were not found to have a clinically relevant impact on osimertinib exposure. No relationship was identified between exposure and efficacy over the dose range studied. A linear relationship was observed between exposure and the occurrence of rash or diarrhoea, and between concentration and QTcF, with a predicted mean (upper 90% confidence interval) increase of 14.2 (15.8) ms at the maximum concentration for an 80 mg once-daily dose at steady state. CONCLUSIONS: PopPK and exposure-response models were developed for osimertinib and AZ5104. There was no relationship between exposure and efficacy but a linear relationship between exposure and safety endpoints (rash, diarrhoea and QTcF) was observed.

Large, comparative, randomized double-blind trial confirming noninferiority of pregnancy rates for corifollitropin alfa compared with recombinant follicle-stimulating hormone in a gonadotropin-releasing hormone antagonist controlled ovarian stimulation protocol in older patients undergoing in vitro fertilization.

OBJECTIVE: To compare corifollitropin alfa with recombinant FSH treatment in terms of the vital pregnancy rate in older patients undergoing IVF. DESIGN: Phase 3 randomized, double-blind, noninferiority trial. SETTING: Multicenter trial. PATIENT(S): A total of 1,390 women aged 35-42 years. INTERVENTION(S): A single injection of 150 µg of corifollitropin alfa or daily 300 IU of recombinant FSH for the first 7 days then daily recombinant FSH until three follicles reach ≥17 mm in size. Ganirelix was started on stimulation day 5 up to and including the day of recombinant hCG administration. If available, two good quality embryos were transferred on day 3. MAIN OUTCOME MEASURE(S): Vital pregnancy rate (PR), number of oocytes, and live birth rate. RESULT(S): Vital PRs per started cycle were 23.9% in the corifollitropin alfa group and 26.9% in the recombinant FSH group, with an estimated difference (95% confidence interval) of -3.0% (-7.4 to 1.4). The mean (SD) number of recovered oocytes per started cycle was 10.7 (7.2) and 10.3 (6.8) in the corifollitropin alfa and the recombinant FSH groups, respectively, with an estimated difference of 0.5 (-0.2 to 1.2). The live birth rates per started cycle were 21.3% in the corifollitropin alfa group and 23.4% in the recombinant FSH group, with an estimated difference (95% confidence interval) -2.3% (-6.5 to 1.9). The incidence of serious adverse events was 0.4% versus 2.7% in the corifollitropin alfa and recombinant FSH groups, respectively, and of ovarian hyperstimulation syndrome (OHSS; all grades) was 1.7% in both groups. CONCLUSION(S): Treatment with corifollitropin alfa was proven noninferior to daily recombinant FSH with respect to vital PRs, number of oocytes retrieved, and live birth rates, and was generally well tolerated. CLINICAL TRIAL REGISTRATION NUMBER: NCT01144416.

Comparative analysis of the effects of nomegestrol acetate/17 ß-estradiol and drospirenone/ethinylestradiol on premenstrual and menstrual symptoms and dysmenorrhea.

OBJECTIVES: To compare premenstrual and menstrual symptoms in healthy women using nomegestrol acetate/17ß-estradiol (NOMAC/E2) and drospirenone/ethinylestradiol (DRSP/EE) via the Moos Menstrual Distress Questionnaire Form C (MDQ-C). METHODS: Women completed the MDQ-C at baseline and after completion of cycles 1, 3, 6 and 13, for the premenstrual (four days before most recent flow) and menstrual (most recent flow) phases in two randomized controlled trials. Treatment effects of NOMAC/E2 and DRSP/EE on the t-scores of eight MDQ-C symptom domains from 3522 women were examined, and the effects of both treatments on the score for cramps from 1779 women with moderate to severe cramps at baseline. Longitudinal data analysis methods were applied in both analyses. RESULTS: NOMAC/E2 users experienced a significant improvement in Pain, Water Retention, Negative Affect, Impaired Concentration and Behaviour Change domain scores in the menstrual phase compared with DRSP/EE users (p < 0.001 for all comparisons). However, Arousal (emotional and mental) scores worsened with NOMAC/E2 but not with DRSP/EE. Women with moderate to severe cramps experienced an improvement in the cramps score with NOMAC/E2 and DRSP/EE. CONCLUSIONS: NOMAC/E2 was effective in reducing most premenstrual and menstrual symptoms, and was associated with significantly greater improvements in many MDQ-C domain scores compared with DRSP/EE. ( ClinicalTrials.gov: NCT00413062 and NCT00511199).

Prognostic models for high and low ovarian responses in controlled ovarian stimulation using a GnRH antagonist protocol.

STUDY QUESTION: Can predictors of low and high ovarian responses be identified in patients undergoing controlled ovarian stimulation (COS) in a GnRH antagonist protocol? SUMMARY ANSWER: Common prognostic factors for high and low ovarian responses were female age, antral follicle count (AFC) and basal serum FSH and LH. WHAT IS KNOWN ALREADY: Predictors of ovarian response have been identified in GnRH agonist protocols. With the introduction of GnRH antagonists to prevent premature LH rises during COS, and the gradual shift in use of long GnRH agonist to short GnRH antagonist protocols, there is a need for data on the predictability of ovarian response in GnRH antagonist cycles. STUDY DESIGN, SIZE, DURATION: A retrospective analysis of data from the Engage trial and validation with the Xpect trial. Prognostic models were constructed for high (>18 oocytes retrieved) and low (<6 oocytes retrieved) ovarian response. Model building was based on the recombinant FSH (rFSH) arm (n = 747) of the Engage trial. Multivariable logistic regression models were constructed in a stepwise fashion (P < 0.15 for entry). Validation based on calibration was performed in patients with equivalent treatment (n = 199) in the Xpect trial. PARTICIPANTS/MATERIALS, SETTING, METHODS: Infertile women with an indication for COS prior to IVF. The Engage and Xpect trials included patients of similar ethnic origins from North America and Europe who had regular menstrual cycles. The main causes of infertility were male factor, tubal factor and endometriosis. MAIN RESULTS AND THE ROLE OF CHANCE: In the Engage trial, 18.3% of patients had a high and 12.7% had a low ovarian response. Age, AFC, serum FSH and serum LH at stimulation Day 1 were prognostic for both high and low ovarian responses. Higher AFC and LH were associated with an increased chance of high ovarian response. Older age and higher FSH correlated with an increased chance of low ovarian response. Region (North America/Europe) and BMI were prognostic for high ovarian response, and serum estradiol at stimulation Day 1 was associated with low ovarian response. The area under the receiver operating characteristic (ROC) curve (AUC) for the model for a high ovarian response was 0.82. Sensitivity and specificity were 0.82 and 0.73; positive and negative predictive values were 0.40 and 0.95, respectively. The AUC for the model for a low ovarian response was 0.80. Sensitivity and specificity were 0.77 and 0.73, respectively; positive and negative predictive values were 0.29 and 0.96, respectively. In Xpect, 19.1% of patients were high ovarian responders and 16.1% were low ovarian responders. The slope of the calibration line was 0.81 and 1.35 for high and low ovarian responses, respectively, both not statistically different from 1.0. In summary, common prognostic factors for high and low ovarian responses were female age, AFC and basal serum FSH and LH. Simple multivariable models are presented that are able to predict both a too low or too high ovarian response in patients treated with a GnRH antagonist protocol and daily rFSH. LIMITATIONS, REASONS FOR CAUTION: Anti-Müllerian hormone was not included in the prediction modelling. WIDER IMPLICATIONS OF THE FINDINGS: The findings will help with the identification of patients at risk of a too high or too low ovarian response and individualization of COS treatment. STUDY FUNDING/COMPETING INTERESTS: Financial support for this study and the editorial work was provided by Merck, Sharp & Dohme Corp. (MSD), a subsidiary of Merck & Co. Inc., Whitehouse Station, NJ, USA. F.J.B. received a grant from CVZ to his institution; P.J.M.V. and H.W. are employees of MSD, and B.M.J.L.M. was an employee of MSD at the time of development of this manuscript. TRIAL REGISTRATION NUMBERS: NCT 00696800 and NCT00778999.

Short follicular phase of stimulation following corifollitropin alfa or daily recombinant FSH treatment does not compromise clinical outcome: a retrospective analysis of the Engage trial.

To evaluate whether a short follicular phase of ovarian stimulation compromises the chance of pregnancy, subjects from a double-blind, randomized trial treated with a single dose of corifollitropin alfa (n=756) or daily recombinant FSH (n=750) were categorized as early responders if three follicles ≥17 mm were reached and human chorionic gonadotrophin (HCG) was administered prior to or on stimulation day 8, and as normal responders if three follicles ≥17 mm were reached and HCG was administered after stimulation day 8. In the corifollitropin alfa and recombinant FSH groups, 23.2% and 29.1%, respectively, were early responders (P=0.01). Regardless of the treatment group, the initial ovarian response was higher in early responders, but with two extra days of stimulation, the number and size of follicles on the day of HCG in the normal responders was similar to those of the early responders. The number of oocytes was similar in both response groups following corifollitropin alfa treatment (13.6 versus 14.5) and recombinant FSH treatment (12.8, both groups). The ongoing pregnancy rates were comparable for early and normal responders regardless of the treatment group, supporting successful outcome following a stimulation period of only 1 week.

Progesterone elevation does not compromise pregnancy rates in high responders: a pooled analysis of in vitro fertilization patients treated with recombinant follicle-stimulating hormone/gonadotropin-releasing hormone antagonist in six trials.

OBJECTIVE: To compare the impact of elevated P during the late follicular phase on the chance of pregnancy in low, normal, and high responders. DESIGN: Retrospective combined analysis from six clinical trials. SETTING: IVF centers. PATIENT(S): Women up to 39 years of age with a regular menstrual cycle and an indication for ovarian stimulation before IVF/intracytoplasmic sperm injection. INTERVENTION(S): Ovarian stimulation with recombinant (r) FSH in a GnRH antagonist protocol. MAIN OUTCOME MEASURE(S): Ongoing pregnancy rates (OPRs) assessed with the use of univariate and multivariate analyses according to serum P levels ≤ 1.5 ng/mL versus >1.5 ng/mL on the day of hCG administration and compared among low (1-5 oocytes), normal (6-18 oocytes), and high (>18 oocytes) responders. RESULT(S): A total of 157/1,866 women (8.4%; 95% confidence interval [CI] 7.2%-9.8%) had elevated P. Incidence of elevated P increased from 4.5% in low responders to 19.0% in high responders. Overall, OPRs were significantly lower in women with elevated P. Per started cycle, the >1.5 to ≤ 1.5 ng/mL adjusted odds ratio was 0.55 (95% CI 0.37-0.81). OPRs were not impaired in high responders with P elevation and were significantly higher compared with normal responders with P elevation. CONCLUSION(S): The incidence of elevated P increases with ovarian response, and elevated P at a threshold of 1.5 ng/mL is independently associated with a decreased chance of pregnancy in low to normal responders, but not in high responders, when using an rFSH/GnRH antagonist protocol.

Clinical impact of LH rises prior to and during ganirelix treatment started on day 5 or on day 6 of ovarian stimulation.

BACKGROUND: We sought to evaluate the incidence and clinical impact of luteinizing hormone (LH) rises prior to and during gonadotropin-releasing hormone (GnRH) antagonist treatment started on day 5 or 6 of ovarian stimulation with recombinant follicle-stimulating hormone (rFSH). METHODS: Pooled data from three trials with the GnRH antagonist ganirelix started on day 5 (n = 961) and from five trials with ganirelix started on day 6 (n = 1135) of ovarian stimulation with rFSH were retrospectively analyzed. RESULTS: The incidence of LH rises (LH ≥ 10.0 IU/L) prior to ganirelix treatment was 2.3% and 6.6% on ganirelix start days 5 and 6, respectively (P < 0.01). During ganirelix treatment this incidence was 1.2% and 2.3%, respectively (P = 0.06). Women with LH rise on day 5 or 6 had a higher ovarian response with more oocytes recovered, mean ± SD, 12.9 ± 8.5 versus no LH rise, 10.2 ± 6.4 (P < 0.01). In women with and without LH rise prior to ganirelix treatment the ongoing pregnancy rates were similar (26.0% vs 29.9%; odds ratio [OR], 0.89; 95% confidence interval [CI], 0.55-1.44). Women with LH rise during ganirelix treatment had a lower ovarian response with 7.5 ± 6.7 oocytes recovered versus no LH rise, 10.2 ± 6.4 (P = 0.02) and a tendancy for a lower chance of ongoing pregnancy (16.7% vs 29.9%; OR, 0.52; 95% CI, 0.21-1.26). CONCLUSIONS: The incidence of early and late LH rises was low but may be further reduced by initiating ganirelix on stimulation day 5 rather than on day 6. In contrast to women with an early LH rise, women with a late LH rise may have a reduced chance of ongoing pregnancy.

Corifollitropin alfa or rFSH treatment flexibility options for controlled ovarian stimulation: a post hoc analysis of the Engage trial.

BACKGROUND: We sought to determine the impact of treatment flexibility on clinical outcomes in either a corifollitropin alfa or recombinant follicle-stimulating hormone (rFSH) protocol. METHODS: Post hoc analysis of a prospective, multicenter, randomized, double-blind, double-dummy non-inferiority clinical trial (Engage). Efficacy outcomes were assessed on patients from the Engage trial who started treatment on menstrual cycle day 2 versus menstrual cycle day 3, patients who received rFSH step-down or fixed-dose rFSH, patients who received rFSH on the day of human chorionic gonadotropin (hCG) compared with those who did not, and patients who received hCG when the criterion was reached versus those with a 1-day delay. RESULTS: The effect of each of the treatment flexibility options on ongoing pregnancy rate was not significant. The estimated difference (95% confidence interval) in ongoing pregnancy rate was -4.3% (-9.4%, 0.8%) for patients who started ovarian stimulation on cycle day 2 versus day 3, 1.8% (-4.1%, 7.6%) for patients who received hCG on the day the hCG criterion was met versus 1 day after, 3.2% (-2.1%, 8.6%) for patients who received rFSH on the day of hCG administration versus those who did not, and -5.8% (-13.0%, 1.4%) for patients who received a reduced versus fixed-dose of rFSH from day 8. CONCLUSIONS: Treatment flexibility of ovarian stimulation does not substantially affect the clinical outcome in patients' treatment following initiation of ovarian stimulation with either corifollitropin alfa or with daily rFSH in a gonadotropin-releasing hormone antagonist protocol. TRIAL REGISTRATION: Trial was registered under ClinicalTrials.gov identifier NCT00696800.

High ovarian response does not jeopardize ongoing pregnancy rates and increases cumulative pregnancy rates in a GnRH-antagonist protocol.

STUDY QUESTION: Is the ovarian response to controlled ovarian stimulation (COS) related to the ongoing pregnancy rate when taking into account the main covariates affecting the probabilities of pregnancy following fresh embryo transfer? SUMMARY ANSWER: In patients treated with corifollitropin alfa or daily recombinant FSH (rFSH) in a GnRH-antagonist protocol, a high ovarian response did not compromise ongoing pregnancy rates and increased cumulative pregnancy rates following fresh and frozen-thawed embryo transfer. WHAT IS KNOWN AND WHAT THIS PAPER ADDS: A strong association between the number of oocytes and pregnancy rates has been described but this is the first comprehensive analysis assessing important confounders that might affect pregnancy rates. STUDY DESIGN: In a large, prospective, double-blind, randomized trial (Engage; n = 1506), patients were treated with either a single dose of 150 µg corifollitropin alfa or daily 200 IU rFSH for the first 7 days of COS in a GnRH-antagonist (ganirelix) protocol. In this retrospective analysis, patients were categorized into five groups according to the number of oocytes retrieved (0-5, 6-9, 10-13, 14-18 and >18 oocytes). The number of good-quality embryos obtained and transferred, as well as the ongoing pregnancy rates, live birth rates and cumulative ongoing pregnancy rates per started cycle by group were evaluated. Univariate analysis was performed to identify factors that predict the chance of ongoing pregnancy. Logistic regression analysis on the dependent variables ongoing pregnancy and cumulative ongoing pregnancy, respectively, including oocyte category as an independent factor in the model, was performed by treatment group (corifollitropin alfa and rFSH) and overall. The likelihood of ongoing pregnancy and cumulative ongoing pregnancy was then evaluated taking into account ovarian response as well as other identified significant predictors of success. PARTICIPANTS AND SETTING: In total, 1506 patients had been randomized in a ratio of 1:1 to either of the treatment groups. Patients were aged ≤ 36 years and had a body weight >60 kg. MAIN RESULTS AND THE ROLE OF CHANCE: The ongoing pregnancy rates per started cycle increased in the corifollitropin alfa and rFSH groups from 31.9 and 31.3%, respectively, in the lowest response group (0-5 oocytes) to 41.9 and 43.4% in the highest response group (>18 oocytes) with a significant linear trend (P = 0.04). The cumulative pregnancy rates taking frozen-thawed embryo transfers into account increased from 33.0 and 31.3% to 60.8 and 55.9% in the corifollitropin alfa and rFSH groups, respectively. Univariate logistic regression analyses of ongoing pregnancy showed significant effects for the following factors: embryo transfer (double or single, P < 0.01), region of treatment (North America or Europe, P < 0.01), progesterone level on the day of hCG (>1.5 or ≤ 1.5 ng/ml, P < 0.01), start day of the stimulation (cycle day 2 or 3, P = 0.02) and age (P = 0.04). Logistic regression analysis of ongoing pregnancy using 10-13 oocytes as the reference category, per treatment group and overall revealed estimated odds ratios (OR) close to 1.0 versus the reference, without statistically significant differences with and without adjustment for significant predictive factors affecting pregnancy rates. Unadjusted OR for cumulative pregnancy reflected significantly lower odds of pregnancy for the lowest response group and significantly higher odds of pregnancy for the highest response group in comparison with the reference. When adjusted for the predictive factors, the cumulative ongoing pregnancy OR (95% confidence interval) of the highest response group versus the reference group was 1.87 (1.34-2.59) when the data of both treatment groups were pooled. BIAS, CONFOUNDING AND OTHER REASONS FOR CAUTION: The number of covariates included in the final model was limited to five major factors and not all other potentially significant predictive factors were available for evaluation. GENERALIZABILITY TO OTHER POPULATIONS: This analysis is limited to IVF patients with a regular menstrual cycle up to 36 years of age and a body weight >60 and ≤ 90 kg treated with a GnRH-antagonist protocol and cannot be extrapolated to other patient populations or treatment regimens.

A comparison of live birth rates and cumulative ongoing pregnancy rates between Europe and North America after ovarian stimulation with corifollitropin alfa or recombinant follicle-stimulating hormone.

OBJECTIVE: To compare live birth rates after fresh embryo transfer (ET) and cumulative ongoing pregnancy rates after fresh ET and frozen-thawed (ET) between continents and overall after one treatment cycle with corifollitropin alfa or recombinant FSH. DESIGN: Double-blind, multicenter, randomized controlled trial. SETTING: Fourteen centers in North America (NA); 20 in Europe (EU). PATIENT(S): 804 NA patients and 702 EU patients. INTERVENTION(S): Patients >60 kg received a single dose of corifollitropin alfa or daily rFSH for the first 7 days of controlled ovarian stimulation. MAIN OUTCOME MEASURE(S): Live birth rates. RESULT(S): Within each continent no differences were noted between the two treatment groups; however, between continents, the cumulative ongoing pregnancy rate and live birth rate were considerably higher in NA than in EU. The live birth rate in NA was 39.2% in both treatment groups compared with 31.5% and 28.8% in EU after corifollitropin alfa and rFSH treatment, respectively. Considering the number of embryos transferred, the live birth rate per ET was still higher in NA than in EU (42.7% v.s 36.8% with corifollitropin alfa and 41.6% vs. 30.9% with rFSH). Overall live birth rates after fresh ET were 35.6% and 34.4% (estimated difference 1.1% [95% confidence interval -3.7-5.8]), and the estimated cumulative live birth rates were 43.4% and 41.3% with corifollitropin alfa and rFSH, respectively. CONCLUSION(S): Live birth rates and cumulative pregnancy rates were higher in NA than in EU after treatment with either corifollitropin alfa or daily rFSH; both treatment protocols provided equal success rates. CLINICALTRIALS.GOV IDENTIFIERS: NCT00703014 and NCT00702273.