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C Klipping - One of the best experts on this subject based on the ideXlab platform.

  • a prospective randomized pharmacodynamic study of quick starting a desogestrel progestin only pill following ulipristal acetate for emergency contraception
    Human Reproduction, 2015
    Co-Authors: Vivian Brache, Leila Cochon, Ingrid Duijkers, D P Levy, N Kapp, C Monteil, J L Abitbol, C Klipping
    Abstract:

    STUDY QUESTION: Is there a pharmacodynamic interaction between ulipristal acetate (UPA) 30 mg for emergency contraception and a daily progestin-only contraceptive pill desogestrel (DSG) 0.75 mg when initiated the next day? SUMMARY ANSWER: In this study DSG impaired the ability of UPA to delay ovulation but UPA had little impact on the onset of contraceptive effects due to DSG. WHAT IS KNOWN ALREADY: UPA is a progesterone receptor modulator used for emergency contraceptive (EC) at the dose of 30 mg. UPA delays ovulation by at least 5 days when administered in the mid to late follicular phase. In theory potent progestins could reactivate progesterone signaling that leads to follicle rupture thereby impacting the effectiveness of UPA as EC. In addition UPA could alter the onset of the contraceptive effect of progestin-containing contraceptives started immediately after UPA. STUDY DESIGN SIZE DURATION: A single-blind (for observer) placebo-controlled partial crossover study was conducted in two sites [Dominican Republic (DR) and the Netherlands (NDL)] over 11 months from October 2012 to September 2013. Healthy female volunteers participated in two of the three treatment cycles separated by a washout cycle. Treatment combinations studied were as follows: (i) a single 30 mg dose of UPA followed by 75 microg per day DSG for 20 days (ii) a single 30 mg dose of UPA followed by 20 days of placebo matching that of DSG (PLB2) or (iii) one tablet of placebo-matching UPA (PLB1) followed by 75 microg per day DSG for 20 days. Participants were randomized to one of the three treatment sequences (UPA + DSG/UPA + PLB2 PLB1 + DSG/UPA + DSG and UPA + PLB2/PLB1 + DSG) when a lead follicle was >/=14 to <16 mm diameter on transvaginal ultrasound imaging (TVU). PARTICIPANTS/MATERIAL SETTING METHODS: A total of 71 women were included and 49 were randomized to a first treatment combination of the three period sequences (20 in the DR and 29 in the NDL); 41 of the 49 continued and completed two treatment combinations (20 in the DR and 21 in the NDL). MAIN RESULTS AND THE ROLE OF CHANCE: Initiating DSG treatment the day after UPA significantly reduced the ovulation delaying effect of UPA (P = 0.0054). While ovulation occurred in only one of the 29 UPA-only cycles (3%) in the first 5 days it occurred in 13 of the 29 (45%) UPA + DSG cycles. LIMITATIONS REASONS FOR CAUTION: This was a small descriptive pharmacodynamic study in which some findings differed by study site. Distinguishing between a cystic corpus luteum and a luteinized unruptured follicle (LUF) by TVU was difficult in some cases; however the investigators reached consensus when the study was still blinded regarding ovulation based on hormone levels and careful review of daily TVU images. WIDER IMPLICATIONS OF THE FINDINGS: Initiating the use of a DSG progestin-only pill (POP) immediately after UPA reduces the ability of UPA to delay ovulation and thus may decrease its efficacy as EC. If starting a DSG POP after using UPA for EC and possibly any progestin-only method consideration should be given to delaying for at least 5 days after UPA intake in order to preserve the ovulation delaying effects of UPA. STUDY FUNDING/COMPETING INTERESTS: Funding was provided by HRA Pharma Paris France. V.B. has received funds for conducting Research studies and lectures for HRA Pharma. C.K. and I.J.M.D. are directors of a Contract Research Organization (Dinox) that received funds from HRA Pharma for the study conduct. D.L.P. N.K. C.M. and J.L.A. are HRA Pharma employees. L.C. has no conflict of interest in this work. TRIAL REGISTRATION NUMBER: EUDRACT No. 2012-002667-95. (c) The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions please email: journals.permissions@oup.com.

  • the effects on ovarian activity of ulipristal acetate when quickstarting a combined oral contraceptive pill a prospective randomized double blind parallel arm placebo controlled study
    Human Reproduction, 2015
    Co-Authors: Sharon T Cameron, C Berger, L Michie, C Klipping, Kristina Gemzelldanielsson
    Abstract:

    STUDY QUESTION: What is the effect on ovarian activity of a preceding intake of ulipristal acetate (UPA) when starting a combined oral contraceptive (COC) in the mid- to late-follicular phase of the cycle? SUMMARY ANSWER: This study shows that UPA does not affect the ability of the COC to induce ovarian quiescence. WHAT IS KNOWN ALREADY: UPA is a progesterone receptor modulator that is available for emergency contraception (EC). In theory UPA could alter the effectiveness of hormonal contraception started immediately following it and vice versa. Current guidelines regarding quick starting a COC following UPA are based on expert opinion only. STUDY DESIGN SIZE DURATION: A double-blind randomized placebo-controlled trial was conducted at three separate sites Edinburgh (Scotland) Stockholm (Sweden) and Groningen (the Netherlands) over a 5-month period in 2012. Healthy female volunteers were randomized to take either UPA or an identically packaged placebo at mid-cycle (once a lead ovarian follicle was determined to be >13 mm on transvaginal ultrasound imaging). Participants were randomized by a computer-generated randomization schedule allocated by sequential sealed envelopes. All women then started 21 days of the same COC the following day. The study was designed to show non-inferiority of UPA compared with placebo in terms of the proportion of women attaining ovarian quiescence as measured by the Hoogland scoring system while taking COC. PARTICIPANTS/MATERIALS SETTING METHODS: A total of 76 women were recruited over the three sites Edinburgh (n = 18) Stockholm (n = 13) Groningen (n = 45) and received either UPA (n = 39) or placebo (n = 37). MAIN RESULTS AND THE ROLE OF CHANCE: There were no significant differences in demographic characteristics of women in the UPA and placebo groups. Among the 76 participants treated 47 (61.8%) reached quiescence and 25 (32.9%) ovulated. There were no significant differences between the groups in the odds ratio (OR) of reaching ovarian quiescence or not; OR 0.97 (95% CI: 0.39-2.46). All women who reached quiescence had done so after taking COCs for 14 days. LIMITATIONS REASONS FOR CAUTION: The main limitations of the study were that measurements of follicle size and blood tests were performed every 2-3 days and so it was not possible to determine the actual day that follicle rupture occurred for the women who ovulated. Furthermore the ultrasonography was conducted by a number of investigators at the sites which may introduce error in the form of inter-observer variability in measurements of follicle growth. Finally the findings of the study cannot be extrapolated to other combined hormonal methods of contraception such as the patch or ring nor to progestogen- only methods of contraception. WIDER IMPLICATIONS OF THE FINDINGS: This study provides evidence to suggest that UPA does not affect the ability of the COC to induce ovarian quiescence. However this study design cannot determine whether the COC affects the ability of UPA to delay ovulation. STUDY FUNDING/COMPETING INTERESTS: Funding was provided by HRA Pharma Paris France. C.K. S.T.C. and K.G.D. have received funds for conducting Research studies and lectures for HRA Pharma. C.K. is director of a Contract Research Organization (Dinox). The remaining authors declare no conflicts of interests. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov: NCT01569113. (c) The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions please email: journals.permissions@oup.com.

Arnaud Delobel - One of the best experts on this subject based on the ideXlab platform.

  • orthogonal liquid chromatography mass spectrometry methods for the comprehensive characterization of therapeutic glycoproteins from released glycans to intact protein level
    Journal of Chromatography A, 2017
    Co-Authors: Eric Largy, Gery Van Vyncht, Fabrice Cantais, Alain Beck, Arnaud Delobel
    Abstract:

    Proteins are increasingly used as therapeutics. Their characterization is challenging due to their size and inherent heterogeneity notably caused by post-translational modifications, among which glycosylation is probably the most prominent. The glycosylation profile of therapeutic proteins must therefore be thoroughly analyzed. Here, we illustrate how the use of a combination of various cutting-edge LC or LC/MS(/MS) methods, and operating at different levels of analysis allows the comprehensive characterization of both the N- and O-glycosylations of therapeutic proteins without the need for other approaches (capillary electrophoresis, MALDI-TOF). This workflow does not call for the use of highly specialized/custom hardware and software nor an extensive knowledge of glycan analysis. Most notably, we present the point of view of a Contract Research Organization, with the constraints associated to the work in a regulated environment (GxP). Two salient points of this work are i) the use of mixed-mode chromatography as a fast and straightforward mean of profiling N-glycans sialylation as well as an orthogonal method to separate N-glycans co-eluting in the HILIC mode; and ii) the use of widepore HILIC/MS to analyze challenging N/O-glycosylation profiles at both the peptide and subunit levels. A particular attention was given to the sample preparations in terms of duration, specificity, versatility, and robustness, as well as the ease of data processing.

  • therapeutic antibody glycosylation analysis a Contract Research Organization perspective in the frame of batch release or comparability support
    Methods of Molecular Biology, 2013
    Co-Authors: Arnaud Delobel, Fabrice Cantais, Anicet Catrain, Erell Dereux, Gery Van Vyncht
    Abstract:

    Abstract Glycosylation of the Fc moiety of a monoclonal antibody is a heterogeneous posttranslational process considered as a critical quality attribute of the purified drug substance due to its major impact on safety and efficacy (i.e., immunogenicity, CDC or ADCC effector functions, etc.). Glycosylation should thus be addressed for batch-to-batch comparability and for drug substance characterization, in terms of identity and/or purity testing. We present below a set of efficient, performing and complementary analytical tests that can be used alone or in combination, depending on the information needed and available laboratory instrumentation. The results obtained using these techniques for "global" glycosylation profile, N-glycans profiling, monosaccharides, and sialic acids determination are presented for the Trastuzumab (Herceptin)-humanized mAb produced in CHO.

Jerome Lemoine - One of the best experts on this subject based on the ideXlab platform.

  • clinical quantitation of prostate specific antigen biomarker in the low nanogram milliliter range by conventional bore liquid chromatography tandem mass spectrometry multiple reaction monitoring coupling and correlation with elisa tests
    Molecular & Cellular Proteomics, 2009
    Co-Authors: Tanguy Fortin, Arnaud Salvador, Jean Philippe Charrier, Cristof Lenz, Xavier Lacoux, Aymeric Morla, Genevieve Choquetkastylevsky, Jerome Lemoine
    Abstract:

    Used for years across a wide range of pathologies, proteomics studies based on semiquantitative mass spectrometry of proteins have already led to the discovery of numerous protein biomarker candidates. Often tens of putative biomarkers have been described for a single disease, but the subsequent phase of clinical evaluation on large cohorts for each candidate is clearly the bottleneck as revealed by the meager number of newly approved biomarkers for clinical use. One of the critical limitations of discovery work flows arises when no antibody is available to initiate an immunoassay because 1–3 years are required to conceive de novo a reliable immunoassay. Such a delay is a serious drawback when tens of putative markers are concerned. Quantitation of small organic molecules by mass spectrometry has been used extensively for years in the field of environmental contaminant analysis or pharmacokinetic profiling of drug candidates during clinical studies. More recently, absolute quantitation of proteins using mass spectrometry by single (SRM)1 or multiple reaction monitoring (MRM) and stable isotope dilution has thus naturally emerged as an alternative to immunoassays. Basically the absolute quantitation of a protein is provided by the integration of the specific MRM signals corresponding, respectively, to a proteotypic peptide (1) obtained from enzymatic hydrolysis of the target protein (usually by trypsin) and to its synthetic stable isotope-labeled isotopomer (2). The validation criteria of an MS-based method in terms of accuracy and precision are relatively easy to fulfill when addressing small molecules or proteins below 10 kDa in plasma or serum. Indeed they may be easily extracted from the bulk of high molecular mass proteins simply by selective precipitation. The quantitation of higher molecular mass proteins has proven to be more challenging because of the complexity and large dynamic range of proteins in e.g. plasma. In a pioneering study Anderson and Hunter (3) successfully demonstrated generation of a multiplexed assay for proteins covering high (tens to hundreds of micrograms/milliliter) to medium (hundreds of nanograms/milliliter to a few micrograms/milliliter) abundance ranges in plasma when combined with immunodepletion. However, these ranges remain problematic because clinically relevant biomarkers are usually present in plasma or serum in the low nanogram/milliliter range or below. To significantly improve the limit of quantitation (LOQ) of LC-MRM mass spectrometry, Keshishian et al. (4) evaluated a combination of immunodepletion of the most abundant plasma or serum proteins with strong cation exchange (SCX) chromatography for sample preparation prior to LC-MRM analysis. LOQs in the 1–10 ng/ml range were obtained with a coefficient of variation from 3 to 15% for five exogenous non-human proteins and the human prostate-specific antigen (PSA) protein spiked together into immunodepleted plasma from a healthy female donor. Very recently, a new approach using product ion scanning on a linear ion trap was proposed by Diamandis and co-workers (5) that allowed reaching a limit of quantitation of 1 ng/ml for PSA spiked into control plasma. This study marked a gain in sensitivity compared with previous attempts by others on similar instrumentation (6–9) but applied immunopurification of the target protein. Interestingly all the strategies published to date have been dealing with analytical development of work flows for the validation of biomarker candidates using microbore, nanoflow chromatography. Nanoflow is without any doubt appealing over conventional microflow during the proteomics discovery phase when the amount of biological material, for instance from a tumor biopsy, is often limited. Nonetheless this technique inherently still suffers from a lack of robustness and requires skilled personnel to be operational on a daily basis. As a consequence, nanoflow chromatography is not easily adaptable for the high throughput analysis environment encountered in clinical laboratories or good laboratory practice-certified or Contract Research Organization companies where hundreds of samples are handled per day. In such Organizations only microflow separations using 1- or 2-mm-internal diameter HPLC columns are compatible with the requirements of robustness and sample throughput. Therefore, the present work was centered on how a simple work flow could, in the near future, enable the large scale verification phase of putative biomarkers in the ng/ml of plasma range by the use of conventional LC equipment, i.e. using a 2-mm-internal diameter HPLC column. To address this question, we have considered that the absolute quantitation of PSA in true clinical samples could represent a challenging model. Combining immunodepletion of serum albumin and peptide fractionation simply by solid phase extraction (SPE), we were able to demonstrate for the first time the absolute quantitation of PSA by LC-MRM mass spectrometry in clinical serum samples of patients with benign prostate hyperplasia (BPH) or prostate cancer (PCa) within concentrations ranging from 4 to 30 ng/ml. Furthermore a good correlation was observed between the clinical ELISA tests and the mass spectrometry-based assays. We believe that these results are an unprecedented demonstration that the clinical relevance of putative biomarkers issued from proteomics investigation may now be confidently evaluated in the ng/ml range by robust coupling between conventional bore LC and mass spectrometry.

David L Cooper - One of the best experts on this subject based on the ideXlab platform.

  • a novel supplemental approach to capturing post marketing safety information on recombinant factor viia in acquired hemophilia the acquired hemophilia surveillance project
    Journal of Blood Medicine, 2014
    Co-Authors: Steven R Lentz, Anand Tandra, Robert Gut, David L Cooper
    Abstract:

    Dear editor Acquired hemophilia (AH) is a rare (incidence is 1 per 1.5 million) but often severe bleeding disorder characterized by autoantibodies to coagulation factor VIII (FVIII). It is associated with life-threatening bleeding and ~20% mortality.1,2 Recombinant factor VIIa (rFVIIa; NovoSeven® RT, Novo Nordisk A/S, Bagsvaerd, Denmark) received an indication from the US Food and Drug Administration (FDA) in October 2006 for the treatment of bleeding episodes and the prevention of bleeding in surgical interventions or invasive procedures in patients with AH.3 The approval of rFVIIa for AH was supported by data collected through the Hemostasis and Thrombosis Research Society (HTRS) Registry since the product’s original approval in 1999. The HTRS Registry is a longitudinal US database created by the Society in collaboration with Novo Nordisk to study treatment strategies for patients with bleeding disorders and to provide post-marketing surveillance. It was adapted in 2006 to fulfill a 5-year commitment by Novo Nordisk to the FDA to provide surveillance around AH. AH affects only about 350 patients per year in the US and many patients are treated outside of the federally designated and funded hemophilia treatment center (HTC) network by hematologists, hematologist/oncologists, and other hospital-based physicians. Many hospitals and most of the ~140 HTCs do not frequently see patients with this disorder, or else see them so rarely that maintaining active IRB renewals and trained staff to participate in the HTRS Registry over 5 years would be considered burdensome. In addition, requests for consultation on such patients from those who first see the patients (emergency medicine, hospitalists, critical care, obstetrics/gynecology, rheumatology) may originate within the hematology staff at any hospital and may be limited to phone consultation with a remote hematologist, thus limiting the amount of data available to the hematologist regarding patient treatment and outcomes. The objective of the Acquired Hemophilia Surveillance (AHS) project was to implement a simple IRB-exempt case report surveillance system to document the at-risk population exposed to rFVIIa and to capture data on the incidence of adverse events (AEs), particularly thromboembolic events (TEs) in these patients. It was specifically targeted to healthcare professionals (HCPs), including non-hematologists who did not belong to HTRS or who were based at HTCs that were resource constrained from considering HTRS participation. This AHS system was launched in April 2008 as a one-page fax-in reporting system maintained by Novo Nordisk. In June 2008, it was converted to a secured web-based platform located at novosevensurveillance.com by Outcome Sciences (Cambridge, MA, USA), a third-party Contract Research Organization that also entered the preliminary faxed-in reports and maintained the database. The AHS web portal allowed for simple electronic entry of demographic and treatment information on acquired hemophilia cases, with the addition of a full safety report form where applicable. AHS takes advantage of the HIPAA exclusion for collection of safety information (45 CFR §164.512(b)(iii)(D)). Reporting HCPs were provided fair market compensation per case entry. Field-based medical liaisons were integrally involved in obtaining information about potential AH cases from visits to HTC and non-HTC sites where they discussed both the HTRS Registry (primary goal) and the AHS project (secondary goal) with HCPs as a means of contributing AH information for post-marketing safety. Medical liaisons distributed copies of a “dear doctor” letter describing the AH post-marketing safety requirement and the AHS project, magnets with the HTRS and AHS project contact numbers, and other supporting materials. Bleed data collected from AHS between April 2008 and 30 November 2011 were analyzed for the safety of rFVIIa treatment in patients with AH. Information on demographics, rFVIIa dosing (entered via an optional free text field) and incidence of thrombotic events was collected and reported using descriptive statistics. Reporting HCPs were required to complete an affirmation about presence/absence of adverse events, and if reporting adverse events to complete a detailed safety information form consistent with the data required to complete a standard MedWatch report. From April 2008 through 30 November 2011, 38 individual HCPs submitted 99 case reports (including 65 treated with rFVIIa) via facsimile or electronic data capture interface. The reports were from both HTCs (44) and non-HTCs (48), and more commonly from centers that did not participate in HTRS (84) than did participate (8). Of the 99 patients, 41 (41%) were male and 58 (59%) were female. The mean age was 66.6 years (range 16.4 to 97.3 years). The most common underlying conditions were autoimmune (34 patients), malignancy (12 patients), and post-partum (5 patients). The mean (SD) anti-VIII titer was 154.5 (453.7) Bethesda units (BU) and the median (range) anti-VIII titer was 35 (1–3,789) BU. Factor VIII levels were reported for 93 of the 99 patients. Fifty-eight percent (57/99) of the subjects had reported factor VIII levels ≤1%. The mean (median) factor VIII level in 36 remaining patients (≥1% FVIII levels) was 8.1% (4.0%) with a range of 1.8%–50%. The mean (median) reported discrete bleeding episodes per patient was 4.3 (2.0) with a range of 0–100 episodes since the time of AH diagnosis. Most of these episodes were spontaneous (84 patients), surgical (14 patients), or related to a procedure (12 patients). Details on specific bleeding episodes were not captured in this brief report format. The use of rFVIIa was indicated in 65 case reports (83%), including 50 first-line treated cases (77%), 14 second-line treated cases (22%), and one with unspecified line of treatment. A bypassing agent other than rFVIIa was indicated to have been used in 13 case reports (17%). No bypassing agent was indicated to have been used in 21 case reports. The acquired hemophilia condition was reported to have been resolved in 51 cases (52%) and not resolved in 30 cases (30%). Resolution was reported as “unsure” in 17 cases and not reported for one case. The mean (median) time to acquired hemophilia resolution was 7.5 (2.0) months with a range of 1–52 months. There were five reported deaths. There were 13 cases for which the mortality status was reported as “unsure.” In the 65 cases where rFVIIa was used, the reporters affirmed that none of the patients suffered an adverse event that was considered possibly/probably related to rFVIIa. Therefore, there was no detailed treatment and outcome information requested or provided on adverse events. Reports of dosing as a write-in field, most with limited detail, suggest that full treatment records were not available or reviewed during the preparation of many of these reports, and some patients might have been treated at facilities outside the reporting sites. Since many of the reports also reflect that patients experienced multiple episodes (mean 4.3 per patient), the interpretation of general information provided in response to a single question on efficacy at 24 and 72 hours remains unclear. Among the 50 patients who received rFVIIa as first-line treatment and had outcomes reported, 47 and 46 were reported to have “excellent/good” or “fair/partially effective” outcome at 24 and 72 hours. Among the 14 patients who received rFVIIa as second-line treatment and had outcomes reported, 12 were reported to have an “excellent/good” or “fair/partially effective” outcome at 24 and 72 hours. For rare disorders or rare complications of common disorders, the standard post-marketing surveillance approach of an IRB-approved observational or product registry may have significant limitations and barriers at the site-implementation level. AHS provides an innovative approach to augment data from formal post-marketing registries under a HIPAA exclusion for HTCs, hematology/oncology practices, and even primary hospital-based treating physicians/pharmacists (emergency room, intensive care unit, post-partum unit) to capture basic surveillance data for AH patients exposed to rFVIIa. AHS was not designed to provide registry-level data, but rather to capture 25% to 50% of identified case reports where registry data entry would not occur. Medical liaisons can play an important role in the identification of patients with rare disorders or complications and can provide information about the primary PMS registry and/or backup systems. The AHS project reaffirms the safety of rFVIIa and the low rate of thrombotic complications. However, AHS lacks the detailed information available through traditional Research registries at large centers, such as data on individual bleeds, treatment of individual bleeding episodes, rFVIIa dosing, time to hemostasis, and the relationship of immunosuppressive treatments to AH resolution.

Kristina Gemzelldanielsson - One of the best experts on this subject based on the ideXlab platform.

  • the effects on ovarian activity of ulipristal acetate when quickstarting a combined oral contraceptive pill a prospective randomized double blind parallel arm placebo controlled study
    Human Reproduction, 2015
    Co-Authors: Sharon T Cameron, C Berger, L Michie, C Klipping, Kristina Gemzelldanielsson
    Abstract:

    STUDY QUESTION: What is the effect on ovarian activity of a preceding intake of ulipristal acetate (UPA) when starting a combined oral contraceptive (COC) in the mid- to late-follicular phase of the cycle? SUMMARY ANSWER: This study shows that UPA does not affect the ability of the COC to induce ovarian quiescence. WHAT IS KNOWN ALREADY: UPA is a progesterone receptor modulator that is available for emergency contraception (EC). In theory UPA could alter the effectiveness of hormonal contraception started immediately following it and vice versa. Current guidelines regarding quick starting a COC following UPA are based on expert opinion only. STUDY DESIGN SIZE DURATION: A double-blind randomized placebo-controlled trial was conducted at three separate sites Edinburgh (Scotland) Stockholm (Sweden) and Groningen (the Netherlands) over a 5-month period in 2012. Healthy female volunteers were randomized to take either UPA or an identically packaged placebo at mid-cycle (once a lead ovarian follicle was determined to be >13 mm on transvaginal ultrasound imaging). Participants were randomized by a computer-generated randomization schedule allocated by sequential sealed envelopes. All women then started 21 days of the same COC the following day. The study was designed to show non-inferiority of UPA compared with placebo in terms of the proportion of women attaining ovarian quiescence as measured by the Hoogland scoring system while taking COC. PARTICIPANTS/MATERIALS SETTING METHODS: A total of 76 women were recruited over the three sites Edinburgh (n = 18) Stockholm (n = 13) Groningen (n = 45) and received either UPA (n = 39) or placebo (n = 37). MAIN RESULTS AND THE ROLE OF CHANCE: There were no significant differences in demographic characteristics of women in the UPA and placebo groups. Among the 76 participants treated 47 (61.8%) reached quiescence and 25 (32.9%) ovulated. There were no significant differences between the groups in the odds ratio (OR) of reaching ovarian quiescence or not; OR 0.97 (95% CI: 0.39-2.46). All women who reached quiescence had done so after taking COCs for 14 days. LIMITATIONS REASONS FOR CAUTION: The main limitations of the study were that measurements of follicle size and blood tests were performed every 2-3 days and so it was not possible to determine the actual day that follicle rupture occurred for the women who ovulated. Furthermore the ultrasonography was conducted by a number of investigators at the sites which may introduce error in the form of inter-observer variability in measurements of follicle growth. Finally the findings of the study cannot be extrapolated to other combined hormonal methods of contraception such as the patch or ring nor to progestogen- only methods of contraception. WIDER IMPLICATIONS OF THE FINDINGS: This study provides evidence to suggest that UPA does not affect the ability of the COC to induce ovarian quiescence. However this study design cannot determine whether the COC affects the ability of UPA to delay ovulation. STUDY FUNDING/COMPETING INTERESTS: Funding was provided by HRA Pharma Paris France. C.K. S.T.C. and K.G.D. have received funds for conducting Research studies and lectures for HRA Pharma. C.K. is director of a Contract Research Organization (Dinox). The remaining authors declare no conflicts of interests. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov: NCT01569113. (c) The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions please email: journals.permissions@oup.com.