Patients' and clinicians' perspectives on item importance, scoring, and clinically meaningful differences for the Endometriosis Symptom Diary (ESD) and Endometriosis Impact Scale (EIS).

BACKGROUND: The Endometriosis Symptom Diary (ESD) and Endometriosis Impact Scale (EIS) are patient-reported outcome measures developed to evaluate efficacy in clinical trials and clinical practice. The ESD is a daily electronic diary assessing symptom severity; the EIS is a weekly electronic diary assessing symptom impact. This study explored the importance of symptoms (ESD items) and impacts (EIS domains), perspectives on scoring algorithms, and clinically important difference (CID) thresholds to inform clinical trial score interpretation. METHODS: Endometriosis patients in Germany (n = 8) and the US (n = 17), and expert clinicians (n = 4) in Germany, the US, Spain, and Finland participated in semi-structured qualitative interviews comprising structured tasks. Interview transcripts were analyzed using thematic analysis techniques. RESULTS: Quality and severity of endometriosis-associated pelvic pain varied considerably among patients; some experienced pelvic pain daily, others during menstrual bleeding (dysmenorrhea) only. Patients and clinicians ranked "worst pelvic pain" as the most meaningful pain concept assessed by the ESD, followed by constant and short-term pelvic pain. Preferences for summarizing daily pain scores over the 28-day menstrual cycle depended on individuals' experience of pain: patients experiencing pain daily preferred scores summarizing data for all 28 days; patients primarily experiencing pain during selected days, and their treating clinicians preferred scores based on the most severe pain days. Initial CID exploration for the "worst pelvic pain" 0-10 numerical rating scale (0-10 NRS) revealed that, for most patients, a 2- or 3-point reduction was considered meaningful, depending on baseline severity. Patients and clinicians ranked "emotional well-being" and "limitations in physical activities" as the most important EIS domains. CONCLUSIONS: This study informs the use of the ESD and EIS as clinically relevant measures of endometriosis symptoms and their impact. Findings from the ESD highlight the importance of individual-patient assessment of pain experience and identify "worst pelvic pain" as the most meaningful symptom assessed. Aggregating scores over the 28-day menstrual cycle may inform meaningful endpoints for clinical trials. Diverse EIS concepts (e.g. impact on emotional well-being and physical activities) are meaningful to patients and clinicians, emphasizing the importance of evaluating the impact on both to comprehensively assess treatment efficacy and decisions. TRIAL REGISTRATION: Not applicable. Qualitative, non-interventional study; registration not required.

A Systematic Approach for Post Hoc Subgroup Analyses With Applications in Clinical Case Studies.

BACKGROUND: The analysis of subgroups in clinical trials is essential to assess differences in treatment effects for distinct patient clusters, that is, to detect patients with greater treatment benefit or patients where the treatment seems to be ineffective. METHODS: The software application subscreen (R package) has been developed to analyze the population of clinical trials in minute detail. The aim was to efficiently calculate point estimates (eg, hazard ratios) for multiple subgroups to identify groups that potentially differ from the overall trial result. The approach intentionally avoids inferential statistics such as P values or confidence intervals but intends to encourage discussions enriched with external evidence (eg, from other studies) about the exploratory results, which can be accompanied by further statistical methods in subsequent analyses. The subscreen application was applied to 2 clinical study data sets and used in a simulation study to demonstrate its usefulness. RESULTS: The visualization of numerous combined subgroups illustrates the homogeneity or heterogeneity of potentially all subgroup estimates with the overall result. With this, the application leads to more targeted planning of future trials. CONCLUSION: This described approach supports the current trend and requirements for the investigation of subgroup effects as discussed in the EMA draft guidance for subgroup analyses in confirmatory clinical trials (EMA 2014). The lack of a convenient tool to answer spontaneous questions from different perspectives can hinder an efficient discussion, especially in joint interdisciplinary study teams. With the new application, an easily executed but powerful tool is provided to fill this gap.

A Systematic Approach for Post Hoc Subgroup Analyses With Applications in Clinical Case Studies.

BACKGROUND: The analysis of subgroups in clinical trials is essential to assess differences in treatment effects for distinct patient clusters, that is, to detect patients with greater treatment benefit or patients where the treatment seems to be ineffective. METHODS: The software application subscreen (R package) has been developed to analyze the population of clinical trials in minute detail. The aim was to efficiently calculate point estimates (eg, hazard ratios) for multiple subgroups to identify groups that potentially differ from the overall trial result. The approach intentionally avoids inferential statistics such as P values or confidence intervals but intends to encourage discussions enriched with external evidence (eg, from other studies) about the exploratory results, which can be accompanied by further statistical methods in subsequent analyses. The subscreen application was applied to 2 clinical study data sets and used in a simulation study to demonstrate its usefulness. RESULTS: The visualization of numerous combined subgroups illustrates the homogeneity or heterogeneity of potentially all subgroup estimates with the overall result. With this, the application leads to more targeted planning of future trials. CONCLUSION: This described approach supports the current trend and requirements for the investigation of subgroup effects as discussed in the EMA draft guidance for subgroup analyses in confirmatory clinical trials (EMA 2014). The lack of a convenient tool to answer spontaneous questions from different perspectives can hinder an efficient discussion, especially in joint interdisciplinary study teams. With the new application, an easily executed but powerful tool is provided to fill this gap.

Absence of Drug-Drug Interaction of Anastrozole on Levonorgestrel Delivered Simultaneously by an Intravaginal Ring: Results of a Phase 2 Trial.

Intravaginal rings (IVRs) are an established option for continuous administration of drugs in women. The combination of anastrozole (ATZ) and levonorgestrel (LNG) in an IVR with an intended 4-week wearing period has been considered for long-term treatment of endometriosis-associated pelvic pain. A randomized, parallel-group, multicenter phase 2b study to assess the efficacy and safety of different dose combinations in women with symptomatic endometriosis has recently been performed. This paper will focus on the investigation of pharmacokinetic (PK) effects of ATZ on LNG using data collected from this study. Two hundred sixteen patients were randomized to the treatment group with IVRs releasing LNG 40 µg/day alone or in combination with ATZ 300 µg/day, 600 µg/day, or 1050 µg/day for 12 weeks. PK blood samples were taken before dosing and before IVR replacement or removal (days 28, 56, and 84). The primary PK parameter was the plasma concentration in apparent steady state of ATZ and LNG at the end of each IVR wearing period. Results of PK analysis demonstrate that ATZ concentrations increased proportionally with increasing dose (geometric mean values of 7.85, 15.48, and 22.61 µg/L at 300, 600, and 1050 µg/day nominal release, respectively). All point estimates for LNG concentration in apparent steady state ratios between the mono and combination IVR groups were close to 1, and the 90% confidence interval limits were in the 0.80 to 1.25 range (1.01 [0.85-1.19], 1.03 [0.88-1.20], 0.94 [0.80-1.10]). In conclusion, our data indicate there is no evidence of drug-drug interaction of ATZ on LNG.

Efficacy, safety and tolerability of the CCR1 antagonist BAY 86-5047 for the treatment of endometriosis-associated pelvic pain: a randomized controlled trial.

INTRODUCTION: Antagonism of CC chemokine receptor type 1 (CCR1) may provide a novel treatment approach for women with symptomatic endometriosis. Studies of CCR1 antagonists in these patients have not been reported. MATERIAL AND METHODS: Women (n = 110; 18-45 years) with symptomatic endometriosis were randomized to BAY 86-5047 or placebo for 12 weeks. Pelvic pain was assessed using the visual analogue scale (VAS) and women recorded the intake of pain medication in a diary. The primary efficacy outcome was a composite of the absolute change in VAS score and the cumulative change in consumption of analgesics between baseline and the end of treatment. Safety assessments included adverse events, blood and urine evaluation and electrocardiography. RESULTS: Mean VAS scores decreased from 64.8 mm at baseline to 49.2 mm at week 12 in the BAY 86-5047 group and from 67.2 mm to 47.8 mm in the placebo group. The proportion of women using analgesics decreased from 33.9% to 11.5% or from 44.4% to 15.4% for patients who received BAY 86-5047 or placebo, respectively. There was no significant difference between the two treatment groups in terms of change in VAS scores (p = 0.45) or intake of analgesics (p = 0.82). A three-step sensitivity analysis failed to show superiority of BAY 86-5047 over placebo (p = 0.67). BAY 86-5047 was well tolerated and no significant safety concerns arose during the study. CONCLUSIONS: Based on these results, BAY 86-5047 is unlikely to be useful in the treatment of women with endometriosis-associated pelvic pain.

Model-Based Dose Selection for Intravaginal Ring Formulations Releasing Anastrozole and Levonorgestrel Intended for the Treatment of Endometriosis Symptoms.

Pharmacokinetics (PK) of anastrozole (ATZ) and levonorgestrel (LNG) released from an intravaginal ring (IVR) intended to treat endometriosis symptoms were characterized, and the exposure-response relationship focusing on the development of large ovarian follicle-like structures was investigated by modeling and simulation to support dose selection for further studies. A population PK analysis and simulations were performed for ATZ and LNG based on clinical phase 1 study data from 66 healthy women. A PK/PD model was developed to predict the probability of a maximum follicle size ≥30 mm and the potential contribution of ATZ beside the known LNG effects. Population PK models for ATZ and LNG were established where the interaction of LNG with sex hormone-binding globulin (SHBG) as well as a stimulating effect of estradiol on SHBG were considered. Furthermore, simulations showed that doses of 40 µg/d LNG combined with 300, 600, or 1050 µg/d ATZ reached anticipated exposure levels for both drugs, facilitating selection of ATZ and LNG doses in the phase 2 dose-finding study. The main driver for the effect on maximum follicle size appears to be unbound LNG exposure. A 50% probability of maximum follicle size ≥30 mm was estimated for 40 µg/d LNG based on the exposure-response analysis. ATZ in the dose range investigated does not increase the risk for ovarian cysts as occurs with LNG at a dose that does not inhibit ovulation.

Characterization of anastrozole effects, delivered by an intravaginal ring in cynomolgus monkeys.

STUDY QUESTION: Is it feasible to deliver anastrozole (ATZ), an aromatase inhibitor (AI), by a vaginal polymer-based drug delivery system in the cynomolgus monkey (Macaca fascicularis) to describe the pharmacokinetic profile? SUMMARY ANSWER: The present study showed the effective release of ATZ into the systemic circulation from intravaginal rings in cynomolgus monkeys. WHAT IS KNOWN ALREADY: ATZ is a marketed drug with well documented pharmacological and safety profiles for oral administration. Aromatase is the key enzyme catalyzing estrogen biosynthesis and is overexpressed in endometriotic lesions. AIs show therapeutic efficacy in endometriosis in exploratory clinical trials. STUDY DESIGN, SIZE, DURATION: The pharmacokinetics of the in vivo release and the pharmacodynamic activity of ATZ released by intravaginal rings (IVR) were investigated in healthy cycling female cynomolgus monkeys in three different dose groups (n = 5) for one menstrual cycle. PARTICIPANTS/MATERIALS, SETTING, METHODS: IVRs for the cynomolgus monkey, releasing three different doses of ATZ were designed and tested for in vitro/in vivo release for up to 42 days. For pharmacokinetic and pharmacodynamic evaluation, plasma samples were taken once daily from Day 1 to 3 and then every third day until menses occurred (17-42 days). MAIN RESULTS AND THE ROLE OF CHANCE: ATZ was shown to be compatible with the IVR drug delivery system. An average in vivo release of 277 µg/day/animal of ATZ for one menstrual cycle was effective in causing a decrease of systemic estradiol (E2) levels by ∼30% without inducing counter regulation such as the elevation of FSH or the formation of ovarian cysts. LIMITATIONS, REASONS FOR CAUTION: The study was limited to three dose groups in which only the highest dose decreased the E2 level. Hence, additional research with IVRs releasing higher amounts of ATZ is required to define the threshold for an ATZ-dependent ovarian stimulation in cynomolgus monkeys. WIDER IMPLICATIONS OF THE FINDINGS: The release rate administered from IVRs is sufficient and in a range that supports feasibility of IVR administration of ATZ as a new approach for long-term therapy of estrogen-dependent diseases such as endometriosis in human.

Defining a minimal clinically important difference for endometriosis-associated pelvic pain measured on a visual analog scale: analyses of two placebo-controlled, randomized trials.

BACKGROUND: When comparing active treatments, a non-inferiority (or one-sided equivalence) study design is often used. This design requires the definition of a non-inferiority margin, the threshold value of clinical relevance. In recent studies, a non-inferiority margin of 15 mm has been used for the change in endometriosis-associated pelvic pain (EAPP) on a visual analog scale (VAS). However, this value was derived from other chronic painful conditions and its validation in EAPP was lacking. METHODS: Data were analyzed from two placebo-controlled studies of active treatments in endometriosis, including 281 patients with laparoscopically-confirmed endometriosis and moderate-to-severe EAPP. Patients recorded EAPP on a VAS at baseline and the end of treatment. Patients also assessed their satisfaction with treatment on a modified Clinical Global Impression scale. Changes in VAS score were compared with patients' self-assessments to derive an empirically validated non-inferiority margin. This anchor-based value was compared to a non-inferiority margin derived using the conventional half standard deviation rule for minimal clinically important difference (MCID) in patient-reported outcomes. RESULTS: Anchor-based and distribution-based MCIDs were-7.8 mm and-8.6 mm, respectively. CONCLUSIONS: An empirically validated non-inferiority margin of 10 mm for EAPP measured on a VAS is appropriate to compare treatments in endometriosis.

Supernatants of HIV-infected immune cells affect the barrier function of human HT-29/B6 intestinal epithelial cells.

OBJECTIVES: Characterization of the diarrhoea-inducing effect of altered cytokine production in HIV infection. METHODS: Monocyte-derived macrophages (MDM) were infected with macrophagetropic (SF162) and lymphocytotropic (IIIB) HIV-1 strains and cocultured with autologous peripheral blood mononuclear cells (PBMC). After 24 h the supernatants were collected and tested for their immunoreactive levels of cytokines by enzyme-linked immunosorbent assay. The effects of the supernatants and the respective recombinant human cytokines on barrier function of HT-29/B6 cells were determined. RESULTS: Infection of MDM with HIV-1 SF162 or IIIB led to increased production of tumour necrosis factor-alpha (TNFalpha), interleukin-1-beta, interferon-alpha and interferon-gamma after cell-cell contact with PBMC. Supernatants of infected cells decreased transepithelial resistance (R(t)), with higher effects on R(t) in HIV IIIB infection, which was due to higher cytokine concentrations. The effect was not due to cytotoxicity (negative LDH assay) or epithelial monolayer disruption [zonula occludens protein-1 (ZO-1) immunofluorescence staining]. The effect of HIV-1 IIIB coculture supernatants could be mimicked by the respective recombinant human cytokines. TNFalpha is an effector cytokine, because inhibition of TNFalpha by its soluble receptor decreased the effect of the supernatants on transepithelial resistance. Conductance scanning indicated the cytokine-induced barrier defect to be due to both, induction of epithelial apoptoses and tight junction alterations. CONCLUSIONS: Cell-cell interaction of HIV-infected macrophages with PBMC leads to a release of cytokines sufficient to alter intestinal epithelial barrier function. The main effect was mediated by TNFalpha inducing a leak-flux which may contribute to the diarrhoea by HIV per se (HIV-enteropathy).