Jan Endrikat

Ovulation inhibition with four variations of a four-phasic estradiol valerate/dienogest combined oral contraceptive : results of two prospective, randomized, open-label studies

BACKGROUND Attempts to improve the tolerability of combined oral contraceptives (COCs) have included the substitution of ethinylestradiol (EE) with 17beta-estradiol (E2). However, this has proved unsatisfactory, specifically in terms of cycle control. To improve upon the poor cycle control seen previously, E2 [in the form of estradiol valerate (E2V); 1 mg of E2V contains 0.76 mg of E2] was combined with dienogest (DNG) in a novel four-phasic regimen. In the current studies, the ovulation-inhibition potency of four variations of this regimen was assessed. STUDY DESIGN Two randomized, open-label, Phase II studies were performed. The first study compared two regimens (Regimens 1A and 2A) with similar dosages of DNG but different lengths of application. Having established in Study 1 that the length of application of Regimen 2A was most suitable, but that the dosages of DNG were too low for effective ovulation inhibition, a second study, which compared two regimens (Regimens 2B and 2C) with similar lengths of application but with increased dosages of DNG, was undertaken. The primary efficacy variable in both studies was the proportion of women with a Hoogland score of 5 or 6 during Cycle 2. RESULTS The full analysis set comprised 192 and 203 women in Studies 1 and 2, respectively. In Study 1, 10 women (10.9%) in Regimen 1A and 6 women (6.4%) in Regimen 2A had a Hoogland score of 5 or 6. In Study 2, three women (3.1%) in Regimen 2B and one woman (1.0%) in Regimen 2C had a Hoogland score of 5 or 6. There were no safety concerns with any of the regimens. CONCLUSION The results of these studies identified a four-phasic COC preparation comprising E2V/DNG that provides efficient ovulation inhibition. It is expected that this regimen will lead to an innovative COC containing E2 instead of EE.

A Canadian, multicentre study comparing the efficacy of a levonorgestrel-releasing intrauterine system to an oral contraceptive in women with idiopathic menorrhagia.

OBJECTIVES To evaluate the efficacy of a levonorgestrel-releasing intrauterine system (LNG-IUS) compared with a combined oral contraceptive containing 1 mg norethindrone acetate and 20 mg ethinyl estradiol (OC1/20) in reducing menstrual blood loss (MBL) in women with idiopathic menorrhagia. METHODS A prospective, randomized, open-label study was conducted in nine centres in Canada. Healthy women over 30 years of age suffering from idiopathic menorrhagia were treated either with LNG-IUS (n = 20) or with OC1/20 (n = 19) over 12 months. The primary endpoint was the change in MBL from baseline to 12 months. Secondary endpoints included treatment success (defined as a MBL score < 100 after 12 months), hemoglobin levels, and the menorrhagia severity score. RESULTS In both treatment groups, MBL decreased significantly from baseline to 12 months (P < 0.001). For the primary endpoint, the MBL score decreased significantly more in the LNG-IUS group (median from 228 to 13, mean percent change-83%) compared to the OC1/20 group (median from 290 to 72; mean percent change-68%) (P = 0.002) after 12 months. In the LNG-IUS group, 80% of subjects had treatment success compared with 36.8 % in the OC1/20 group (P < 0.009). Both treatments increased hemoglobin concentrations significantly between baseline and 12 months. The menorrhagia severity score was consistently lower in the LNG-IUS group at all study time points and was significantly lower (P = 0.045) at six months. Both treatments were well tolerated. CONCLUSION Both the LNG-IUS and the combined oral contraceptive effectively decreased menstrual blood loss in women with idiopathic menorrhagia. The overall clinical benefit was more pronounced with LNG-IUS than with OC1/20.

Safety of Gadobutrol: Results From 42 Clinical Phase II to IV Studies and Postmarketing Surveillance After 29 Million Applications.

ObjectiveThe aim of this study was to provide a systematic safety analysis of gadobutrol after more than 29 million applications in clinical routine. Materials and MethodsForty-two clinical development phase II to IV studies on gadobutrol or comparator and the postmarketing safety surveillance database for gadobutrol (1998–2015) were analyzed. Adverse events (AEs) and drug-related AEs were evaluated in the clinical development database and spontaneous adverse drug reactions (ADRs) in the postmarketing database. Subgroup analyses were run on patients with special medical history and on patients of different age groups. ResultsIn the clinical development studies, 6809 and 2184 patients received gadobutrol or comparators, respectively. The incidence of drug-related AEs was 3.5% for both groups. With the exception of nausea (0.7% related cases in both groups), all other drug-related AEs were 0.3% or less in both groups. Hypersensitivity reactions were sporadic (<0.1%). Patients with history of allergies to contrast agents experienced slightly more drug-related AEs. No differences were seen between age groups.The overall reporting rate of ADRs from postmarketing surveillance was 0.05%. The most frequent ADRs were anaphylactoid/hypersensitivity reactions, nausea, vomiting, and dyspnea.For 3 single-agent reports of nephrogenic systemic fibrosis, using a conservative approach, association with gadobutrol could not be excluded. ConclusionsGadobutrol is well tolerated and has a favorable safety profile for patients of all age groups.

Ovulation inhibition doses of progestins: a systematic review of the available literature and of marketed preparations worldwide ☆

BACKGROUND The objective of this analysis was to provide a comprehensive review of ovulation inhibition data of progestins currently available worldwide. This analysis may serve as a reference tool for research on new progestin molecules. STUDY DESIGN We used literature search engines to detect data of progestin monotherapies on ovulation inhibition in humans. Only treatments with stable dosing during a cycle were accepted. In a second step, we tried to estimate the 99% ovulation inhibiting doses and their fiducial confidence limits using the probit dose-response model. Finally, we analyzed the progestin doses of combined oral contraceptives currently on the market. RESULTS We found original data on 29 marketed and nonmarketed progestins in a total of 60 publications, published between 1956 and May 2010. Details on methods used for determining ovulation, number of doses and daily dose of each tested progestin, number of subjects, cycles and ovulations are summarized in a table. We designed one example of a dose-response curve using the statistical model. For most progestins, literature data were insufficient for this purpose. A total of 13 progestins are components of oral contraceptives currently on the market worldwide, five of them in combination with 20 mcg ethinyl estradiol (EE). CONCLUSION This review provides a comprehensive overview of all progestins ever tested for their ovulation inhibition potency and a summary of all preparations currently on the world market, including their regimens and their combinations with EE.

A Canadian multicentre prospective study on the effects of an oral contraceptive containing 3 mg drospirenone and 30 μg ethinyl oestradiol on somatic and psychological symptoms related to water retention and on body weight

Objectives To evaluate the effects of an oral contraceptive containing 3 mg drospirenone (DRSP) and 30 μg ethinyl oestradiol (EE) on somatic and psychological symptoms related to water retention, and on body weight. Methods This prospective study was performed in 26 centres in Canada over six treatment cycles. The first primary efficacy variable was the individual change in the water retention score of the Moos Menstrual Distress Questionnaire (MDQ) from baseline to the final examination in women with significant somatic symptoms related to water retention (n = 43). The second primary target variable was the change in body weight (n = 305). Results Forty-three women met the criteria for the first primary target variable. In the premenstrual phase, the score decreased from 6.49 (SEM 0.45) at baseline to 3.19 (SEM 0.54) at the final examination (p = 0.0001). The data for the menstrual phase were 4.70 (SEM 0.30) at baseline and 2.35 (SEM 0.32) at the final examination (p < 0.0001). Baseline data from 299 women were assessed for the second primary target variable. Body weight did not change significantly, having increased only by 0.14 kg (SEM 0.13) at the final visit (p = 0.3082). Conclusion An oral contraceptive containing 3 mg DRSP and 30 μg EE significantly reduced the clinical symptoms of water retention. Body weight did not change.

Gadobutrol in renally impaired patients : results of the GRIP study

Objective The aim of this study was to assess the potential risk of gadobutrol-enhanced magnetic resonance imaging (MRI) in patients with moderate to severe renal impairment for the development of nephrogenic systemic fibrosis (NSF). Materials and Methods We performed a prospective, international, multicenter, open-label study in 55 centers. Patients with moderate to severe renal impairment scheduled for any gadobutrol-enhanced MRI were included. All patients received a single intravenous bolus injection of gadobutrol at a dose of 0.1 mmol/kg body weight. The primary target variable was the number of patients who develop NSF within a 2-year follow-up period. Results A total of 908 patients were enrolled, including 586 with moderate and 284 with severe renal impairment who are at highest risk for developing NSF. The mean time since renal disease diagnosis was 1.83 and 5.49 years in the moderate and severe renal impairment cohort, respectively. Overall, 184 patients (20.3%) underwent further contrast-enhanced MRI with other gadolinium-based contrast agents within the 2-year follow-up. No patient developed symptoms conclusive of NSF. Conclusions No safety concerns with gadobutrol in patients with moderate to severe renal impairment were identified. There were no NSF cases.

Pituitary ovarian and additional contraceptive effects of an estradiol-based combined oral contraceptive: results of a randomized open-label study.

BACKGROUND The estrogen step-down/progestogen step-up 28-day estradiol valerate/dienogest (E(2)V/DNG) oral contraceptive effectively inhibits ovulation; however, limited data are available regarding its effects on estradiol (E2), progesterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) or its additional extraovarian contraceptive effects. STUDY DESIGN In this secondary analysis, 100 women received E(2)V 3 mg on days 1-2, E(2)V 2 mg/DNG 2 mg on days 3-7, E(2)V 2 mg/DNG 3 mg on days 8-24, E(2)V 1 mg on days 25-26 and placebo on days 27-28 for one treatment cycle. Measures included the presence/absence of cervical mucus; endometrial thickness; and serum E2, progesterone, and gonadotropin levels. RESULTS E2, progesterone, LH and FSH levels did not exhibit the typical ovulatory increase and remained relatively stable during the cycle. E(2)V/DNG reduced mean maximal endometrial thickness and proportion of women with visible cervical mucus. All parameters returned to pretreatment levels during the posttreatment cycle. CONCLUSION E(2)V/DNG provides extraovarian contraceptive effects (reducing endometrial thickness and cervical mucus production) in addition to inhibiting ovulation, assuring contraceptive efficacy.

Chromosomal abnormalities in fetuses with ultrasonographically detected neural tube defects.

We analyzed the karyotype of fetuses with ultrasonographically detected neural tube defects (NTDs). In our study, we included a total of 194 fetuses with NTDs. We analyzed the type of NTD, the karyotype, maternal age, fetal gestational age at diagnosis, and fetal sex. Of the 194 fetuses with NTDs, 87 were anencephalic and 107 had other, nonanencephalic, NTDs. A total of 12 fetuses were shown to have chromosomal abnormalities. Three of 87 anencephalic fetuses (3.45%) had chromosomal abnormalities. The sex ratio for anencephalic fetuses was 65.5% : 34.5% for female and male fetuses. Nine of 107 fetuses with other NTDs (8.41%) had chromosomal abnormalities. Seven fetuses had isolated NTDs and a further seven fetuses had additional ultrasonographic anomalies. Two of the latter had abnormal karyotypes. The sex ratio of all other NTD cases was 67.3% : 32.7% for female and male fetuses. The high number of chromosomal abnormalities justifies prenatal karyotyping in all fetuses with ultrasonographically diagnosed NTDs.

Safety of gadoxetate disodium: Results from the clinical phase II–III development program and postmarketing surveillance

To summarize the safety data of gadoxetate disodium, reported in 12 Phase II and III clinical development studies and in the postmarketing surveillance database.

Axillary ultrasound for breast cancer staging: an attempt to identify clinical/histopathological factors impacting diagnostic performance.

Aim To assess the diagnostic value of pre-surgery axillary ultrasound for nodal staging in patients with primary breast cancer and to identify clinical/histopathological factors impacting diagnostic performance. Study Design Single-center, retrospective chart analysis. We assessed sensitivity, specificity, and positive and negative predictive value of clinical examination as well as axillary ultrasound vs. clinical examination alone. The histopathological results were the standard of truth. In addition, we analyzed clinical and histopathological factors regarding their potential to impact sensitivity and specificity. Results We enrolled a total of 172 women in the study. Sensitivity of clinical examination plus ultrasound was significantly higher than for clinical examination alone (58% vs. 31.6%). Specificity and positive predictive value were similar while the negative predictive value increased from 63.4% to 73% when additionally applying ultrasound. Sensitivity and specificity of axillary ultrasound were impacted by tumor size (P = 0.2/0.04), suspicious axillary palpation (P < 0.01/<0.01), number of affected lymph nodes (P < 0.01/-) and distant metastases (P = 0.04/<0.01). All other factors had no impact. Conclusion Since pre-surgery axillary nodal staging is currently used to determine disease management, axillary ultrasound is a useful add-on tool in the diagnostic armamentarium for breast cancer patients. Tumor size, suspicious axillary palpation, number of affected lymph nodes and distant metastases increase diagnostic performance of this diagnostic modality.