Efficacy and safety of eliapixant in endometriosis-associated pelvic pain: the randomized, placebo-controlled phase 2b SCHUMANN study.

BACKGROUND: The SCHUMANN study evaluated the efficacy and safety of the selective P2 × 3 antagonist eliapixant in patients with endometriosis-associated pelvic pain (EAPP). METHODS: SCHUMANN was a randomized, placebo- and active comparator-controlled, double-blind to placebo and open-label to comparator, parallel-group, multicenter, dose-finding phase 2b study. The participants were women with surgically diagnosed endometriosis who fulfilled defined EAPP criteria. Participants were randomized 1:1:1:1 to twice daily (BID) 25 mg, 75 mg, or 150 mg oral eliapixant or a placebo for 12 weeks. An exploratory once-daily elagolix 150 mg treatment group was also included. The primary endpoint was the absolute change in mean worst EAPP from baseline to the end of intervention (EOI). RESULTS: Overall, 215 participants were randomized for treatment (44 to eliapixant 25 mg, 44 to eliapixant 75 mg, 43 to eliapixant 150 mg, 43 to a placebo, and 41 to elagolix 150 mg). For safety reasons, the study was terminated early; both treatment and enrollment stopped immediately, producing less than 50% of the planned number of completers. The study found no significant differences in EAPP reduction from baseline between groups and no significant dose-response model. The elagolix 150 mg group showed better pain reduction than any of the other groups. No new safety signals were observed, relative to the previously known safety profile of eliapixant, which was generally well tolerated. However, one case of moderate and probably drug-induced liver injury in a participant receiving eliapixant 150 mg BID supported the association between eliapixant and a potential increase in liver function values, defined before the start of the phase 2 program. CONCLUSIONS: This study did not meet its primary objective as no statistically significant or clinically relevant differences in changes of mean worst EAPP from baseline were observed between treatment groups. The single observed case of moderate, probably drug-induced liver injury was the second case in the eliapixant phase 2 program conducted in the following indications: refractory or unexplained chronic cough, diabetic neuropathic pain, overactive bladder, and EAPP. Due to this, the benefit-risk ratio for the study was no longer considered to be positive. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04614246; registered November 3, 2020.

Hepatotoxicity of AKR1C3 Inhibitor BAY1128688: Findings from an Early Terminated Phase IIa Trial for the Treatment of Endometriosis.

INTRODUCTION: BAY1128688 is a selective inhibitor of aldo-keto reductase family 1 member C3 (AKR1C3), an enzyme implicated in the pathology of endometriosis and other disorders. In vivo animal studies suggested a potential therapeutic application of BAY1128688 in treating endometriosis. Early clinical studies in healthy volunteers supported the start of phase IIa. OBJECTIVE: This manuscript reports the results of a clinical trial (AKRENDO1) assessing the effects of BAY1128688 in adult premenopausal women with endometriosis-related pain symptoms over a 12-week treatment period. METHODS: Participants in this placebo-controlled, multicenter phase IIa clinical trial (NCT03373422) were randomized into one of five BAY1128688 treatment groups: 3 mg once daily (OD), 10 mg OD, 30 mg OD, 30 mg twice daily (BID), 60 mg BID; or a placebo group. The efficacy, safety, and tolerability of BAY1128688 were investigated. RESULTS: Dose-/exposure-dependent hepatotoxicity was observed following BAY1128688 treatment, characterized by elevations in serum alanine transferase (ALT) occurring at around 12 weeks of treatment and prompting premature trial termination. The reduced number of valid trial completers precludes conclusions regarding treatment efficacy. The pharmacokinetics and pharmacodynamics of BAY1128688 among participants with endometriosis were comparable with those previously found in healthy volunteers and were not predictive of the subsequent ALT elevations observed. CONCLUSIONS: The hepatotoxicity of BAY1128688 observed in AKRENDO1 was not predicted by animal studies nor by studies in healthy volunteers. However, in vitro interactions of BAY1128688 with bile salt transporters indicated a potential risk factor for hepatotoxicity at higher doses. This highlights the importance of in vitro mechanistic and transporter interaction studies in the assessment of hepatoxicity risk and suggests further mechanistic understanding is required. CLINICAL TRIAL REGISTRATION: NCT03373422 (date registered: November 23, 2017).

Efficacy and Safety of Eliapixant in Refractory Chronic Cough: The Randomized, Placebo-Controlled Phase 2b PAGANINI Study.

INTRODUCTION: The PAGANINI study evaluated the efficacy and safety of the selective P2X3 antagonist eliapixant in patients with refractory chronic cough (RCC). METHODS: PAGANINI was a randomized, double-blind, parallel-group, placebo-controlled, multicenter, dose-finding, phase 2b study. Adults with RCC lasting ≥ 12 months and cough severity ≥ 40 mm on a visual analog scale at screening were enrolled. Participants were randomized 1:1:1:1 to twice-daily 25 mg, 75 mg, or 150 mg oral eliapixant or placebo for 12 weeks. The primary endpoint was change from baseline in 24-h cough count after 12 weeks of intervention. RESULTS: Overall, 310 participants were randomized to twice-daily eliapixant 25 mg (n = 75), 75 mg (n = 78), 150 mg (n = 80), or placebo (n = 77). A statistically significant dose-response signal with eliapixant was detected for the primary endpoint (all dose-response models, adjusted p < 0.1; one-sided). Adverse events (AEs) were reported in 39 (51%) participants with placebo and 43-51 (57-65%) participants receiving eliapixant. The most common AE was dysgeusia, occurring in 1% (n = 1) of the placebo group and 1-16% (n = 1-13) of the eliapixant groups in a dose-related manner. One case of a moderate drug-induced liver injury occurred in a participant receiving 150 mg twice-daily eliapixant. CONCLUSION: Eliapixant demonstrated efficacy and a favorable taste tolerability profile in RCC. However, a drug-induced liver injury contributed to intensified liver monitoring in clinical trials with eliapixant and discontinuation of the entire development program in all indications by Bayer AG. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04562155; registered September 18, 2020.

Surgical Outcomes in Patients With Endometriosis: A Systematic Review.

OBJECTIVE: Among women treated surgically for endometriosis-associated pain, comprehensive data are lacking on the proportions of patients who experience little or no symptom relief, develop recurrent symptoms, or require further surgical treatment for endometriosis. The aim of this study was to assess the efficacy of surgical procedures used to treat endometriosis-associated pain. METHODS: Medline and Embase were searched on October 13, 2016. Articles referring to women undergoing surgery for the treatment of endometriosis-associated pain were screened by two independent investigators. For each included treatment arm, data were extracted for the proportion of patients reporting partial or no improvement after surgery for endometriosis-associated pain, pain recurrence, or requirement for further surgery. RESULTS: A total of 38 studies were included. Most studies did not report relevant outcomes to evaluate pain (71.1%) and recurrent surgery (68.4%). Of the women who underwent lesion excision, 11.8% reported no improvement in pain, and 22.6% underwent further surgery. Postoperative pain, recurrent pain, and adverse events were reported by 34.3%, 28.7%, and 14.8%, respectively, of patients who underwent excision or ablation of endometriosis combined with pelvic denervation and in 25.0%, 15.8%, and 8.1% of women who underwent lesion excision alone. Of the patients who were treated surgically for deep endometriosis affecting the bowel and/or bladder, 7.0% experienced recurrent symptoms, and 4.1% underwent further surgery. CONCLUSION: This review supports the findings of previous studies and highlights the need for standardized reporting and more detailed follow-up after surgery for endometriosis-associated pain.

Dienogest for Treatment of Endometriosis in Chinese Women: A Placebo-Controlled, Randomized, Double-Blind Phase 3 Study.

BACKGROUND: Dienogest is a progestin with demonstrated efficacy in the treatment of endometriosis in European women. The objective of this study was to evaluate the efficacy and safety of dienogest in Chinese women. PATIENTS AND METHODS: This 24-week, randomized, double-blind, placebo-controlled multicenter (n = 23) study evaluated the efficacy and safety of 2 mg dienogest once daily in 255 Chinese women aged 18-45 years with laparoscopically diagnosed endometriosis and an endometriosis-associated pelvic pain (EAPP) score ≥30 mm on a 0-100 mm visual analog scale. The primary efficacy variable was absolute change in EAPP from baseline to week 24. Secondary efficacy variables included proportions of responders and intake of supportive analgesic medication. Safety variables included adverse events (AEs), laboratory parameters, and bleeding patterns. Bone mineral density (BMD) was evaluated in a subset of 140 women. RESULTS: After 24 weeks of treatment, the difference between treatment arms for mean reduction in EAPP was statistically significant in favor of dienogest (-24.54 mm; 95% CI -29.93 to -19.15; p < 0.0001). Secondary efficacy analyses supported the significant superiority of dienogest over placebo. Dienogest was well tolerated, with few AEs associated with therapy. Dienogest had no effect on BMD levels after 24 weeks of treatment. CONCLUSIONS: Dienogest 2 mg once daily for 24 weeks was superior to placebo in reducing EAPP and was safe and well tolerated in Chinese women with endometriosis. The results are consistent with studies previously conducted in European women.

Reevaluating response and failure of medical treatment of endometriosis: a systematic review.

OBJECTIVE: To assess patient response rates to medical therapies used to treat endometriosis-associated pain. DESIGN: A systematic review with the use of Medline and Embase. SETTING: Not applicable. PATIENT(S): Women receiving medical therapy to treat endometriosis. INTERVENTIONS(S): None. MAIN OUTCOME MEASURE(S): The proportions of patients who: experienced no reduction in endometriosis-associated pain symptoms; had pain symptoms remaining at the end of the treatment period; had pain recurrence after treatment cessation; experienced an increase or no change in disease score during the study; were satisfied with treatment; and discontinued therapy owing to adverse events or lack of efficacy. The change in pain symptom severity experienced during and after treatment, as measured on the visual analog scale, was also assessed. RESULT(S): In total, 58 articles describing 125 treatment arms met the inclusion criteria. Data for the response of endometriosis-associated pain symptoms to treatment were presented in only 29 articles. The median proportions of women with no reduction in pain were 11%-19%; at the end of treatment, 5%-59% had pain remaining; and after follow-up, 17%-34% had experienced recurrence of pain symptoms after treatment cessation. After median study durations of 2-24 months, the median discontinuation rates due to adverse events or lack of efficacy were 5%-16%. CONCLUSION(S): Few studies of medical therapies for endometriosis report outcomes that are relevant to patients, and many women gain only limited or intermittent benefit from treatment.

Dienogest 2 mg Daily in the Treatment of Adolescents with Clinically Suspected Endometriosis: The VISanne Study to Assess Safety in ADOlescents.

STUDY OBJECTIVE: To study the safety and efficacy of dienogest 2 mg in adolescents with suspected endometriosis. DESIGN: A 52-week, open-label, single-arm study. SETTING: In 21 study centers, in 6 European countries. PARTICIPANTS: Adolescents aged 12 to younger than 18 years with clinically suspected or laparoscopically confirmed endometriosis. INTERVENTIONS: Dienogest 2 mg once daily. MAIN OUTCOME MEASURES: The primary end point was relative change in lumbar spine (L2-L4) bone mineral density (BMD) measured using dual-energy x-ray absorptiometry. A key secondary end point was change in endometriosis-associated pain assessed using a visual analogue scale. RESULTS: Of 120 patients screened, 111 comprised the full-analysis set (ie, patients who took ≥1 dose of study drug and had ≥1 post-treatment observation) and 97 (87.4%) completed the study. Mean lumbar BMD at baseline was 1.1046 (SD, 0.1550) g/cm2. At the end of dienogest treatment (EOT; defined as at 52 weeks or premature study discontinuation), mean relative change in BMD from baseline was -1.2% (SD, 2.3%; n = 103). Follow-up measurement 6 months after EOT in the subgroup with decreased BMD at EOT (n = 60) showed partial recovery in lumbar BMD (mean change from baseline: -2.3% at EOT, -0.6% 6 months after EOT). Mean endometriosis-associated pain score was 64.3 (SD, 19.1) mm at baseline and decreased to 9.0 (SD, 13.9) mm by week 48. CONCLUSION: In adolescents with suspected endometriosis, dienogest 2 mg for 52 weeks was associated with a decrease in lumbar BMD, followed by partial recovery after treatment discontinuation. Endometriosis-associated pain was substantially reduced during treatment. Because bone accretion is critical during adolescence, results of the VISanne study to assess safety in ADOlescents (VISADO) study highlights the need for tailored treatment in this population, taking into account the expected efficacy on endometriosis-associated pain and an individual's risk factors for osteoporosis.

A randomized, double-blind, placebo-controlled study of the lowest effective dose of drospirenone with 17ß-estradiol for moderate to severe vasomotor symptoms in postmenopausal women.

OBJECTIVE: This study aims to investigate the efficacy and safety of daily drospirenone/17ß-estradiol in two low-dose combinations (0.25 mg/0.5 mg and 0.5 mg/0.5 mg, respectively) versus 17ß-estradiol (0.3 mg) or placebo in postmenopausal women with moderate to severe vasomotor symptoms. METHODS: Seven hundred thirty-five postmenopausal women aged 40 years or older who experienced a minimum of 7 to 8 moderate to severe hot flushes per day, or 50 to 60 moderate to severe hot flushes per week, participated in a 12-week, double-blind, randomized, placebo-controlled study. The primary efficacy variables were mean changes from baseline to weeks 4 and 12 in the weekly frequency and weekly mean daily severity of moderate to severe hot flushes recorded daily by the participants on diary cards. RESULTS: All active treatments were significantly more effective than placebo for the primary efficacy variables for drospirenone/17ß-estradiol (P < 0.0001), and for 17ß-estradiol (P < 0.01) at 4 and 12 weeks. Efficacy was greater for both low-dose drospirenone/17ß-estradiol combinations versus the lower-dose 17ß-estradiol. Change in vaginal pH and vaginal maturation index showed significant improvements (with P values versus placebo of <0.0001 and P ≤ 0.0028, respectively), and exploratory analysis of the Clinical Global Impressions scale score indicated an overall satisfaction of women with active treatments. All active treatments were generally well tolerated with low rates of adverse event-related dropouts, and the safety profile of drospirenone/17ß-estradiol in both low-dose combinations was consistent with previous studies. CONCLUSIONS: Drospirenone 0.25 mg/17ß-estradiol 0.5 mg is concluded to be the lowest dose with demonstrated efficacy in the treatment of postmenopausal women with moderate to severe vasomotor symptoms.

Population pharmacokinetic/pharmacodynamic evaluation of low-dose drospirenone with 17ß-estradiol in postmenopausal women with moderate to severe vasomotor symptoms.

OBJECTIVE: This study aims to characterize the pharmacokinetics/pharmacodynamics of drospirenone and estradiol in the treatment of postmenopausal women with moderate to severe vasomotor symptoms and to explore the relationship between the serum exposures of estradiol and drospirenone and efficacy, measured by reductions in moderate to severe hot flushes. METHODS: Participants in a 12-week, double-blind, randomized, placebo-controlled study of daily drospirenone/estradiol in two low-dose combinations (0.25 mg/0.5 mg and 0.5 mg/0.5 mg), estradiol (0.3 mg), or placebo provided infrequent serum samples for pharmacokinetic analysis of estradiol and drospirenone, with additional frequent sampling during 24 hours in a study subset. RESULTS: Estradiol steady-state serum concentrations were described by a one-compartmental model with first-order elimination and zero-order absorption. The pharmacokinetics of drospirenone was described by a linear open two-compartment model with first-order elimination kinetics from the central compartment and delayed first-order absorption kinetics. A total of 1,516 serum estradiol concentrations and 736 serum drospirenone concentrations (n = 251) from 383 women were evaluated. Baseline estradiol concentrations increased with rising body mass index, and apparent clearance of estradiol at steady state was 39% higher in smokers versus nonsmokers. The serum exposures of both estradiol and drospirenone affected efficacy, as analyzed by a generalized linear model. Smoking had a negative effect on the efficacy of hormone therapy. CONCLUSIONS: The efficacy of low-dose drospirenone/estradiol for reducing vasomotor symptoms correlates with the serum exposure of estradiol and, for the first time, the serum exposure of drospirenone. Smoking adversely affects the clearance of estradiol and the efficacy of treatment.

An empirically validated responder definition for the reduction of moderate to severe hot flushes in postmenopausal women.

OBJECTIVE: The aim of this study was to derive an empirically validated definition of treatment responders for the reduction of moderate to severe hot flushes in postmenopausal women. METHODS: This study used prospective blinded data analysis from a placebo-controlled study to investigate the efficacy of a treatment of moderate to severe hot flushes in postmenopausal women. Seven hundred ten postmenopausal women with at least 50 moderate to severe hot flushes per week participated in the study. The participants recorded the number of moderate to severe hot flushes each day in a diary. They also assessed their satisfaction with treatment on a Clinical Global Impression-improvement rating scale. Changes in the weekly number of moderate to severe hot flushes were compared with participants' self-assessments to derive an empirically validated minimal clinically important difference. This anchor-based value was compared with the conventional half-SD rule for minimal clinically important difference in participant-reported outcomes. RESULTS: Anchor- and distribution-based minimal clinically important differences between "no change/worse" and "minimally improved" were an absolute reduction of 19.1 and 18.6 in the weekly number of moderate to severe hot flushes, respectively. In addition, the threshold between "minimally improved" compared with "much improved or better" was determined, based on the anchor method, as an absolute reduction of 40.3 in the weekly number of moderate to severe hot flushes. CONCLUSIONS: A responder was defined as having at least an improvement of 19.1 hot flushes per week at week 4 and an improvement of 40.3 hot flushes per week at week 12.