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A Randomized, Double-blind, Open for Active Comparator, Parallel-group, Multicenter Phase 2b Study to Assess the Efficacy and Safety of Three Different Doses of P2X3 Antagonist (BAY1817080) Versus Placebo and Elagolix 150 mg in Women With Symptomatic Endometriosis (SCHUMANN)

Assess efficacy and safety of three different doses of P2X3 antagonist in women with symptomatic endometriosis (SCHUMANN)

215

The majority (94.6%) of participants in the elagolix 150 mg arm were white since participants from Japan and China could not be randomized to elagolix. Age and body mass index (BMI) were generally well-balanced across treatment arms. The mean (SD) age was 34.64 (7.22) years, with 26.8% of participants in the age group <30 years, 50.3% of participants in the age group 30-40 years, and 23.0% of participants in the age group >40-55 years. The mean (SD) BMI was 25.54 (5.89) kg/m2. Slight imbalances between treatment groups were observed in mean worst pain, nonmenstrual pelvic pain (NMPP), and dysmenorrhea. The mean (SD) of mean worst pain, NMPP, and dysmenorrhea in the eliapixant 150 mg twice daily [BID] arm (6.63 [1.62], 6.45 [1.78], and 7.38 [1.39]) and elagolix 150 mg arm (6.38 [1.78], 6.18 [1.86], and 7.29 [1.84]) were higher compared to the other arms. Other endometriosis-specific baseline characteristics were generally comparable across treatment arms.

A total of 215 participants were randomized to 5 treatment arms (44 to eliapixant 25 mg BID, 44 to eliapixant 75 mg BID, 43 to eliapixant 150 mg BID, 43 to placebo, and 41 to elagolix 150 mg). Number of participants in each analysis set was as follows: Full analysis set (FAS) includes all 215 participants who were randomized to 5 treatment arms, which is less than planned in the protocol. Safety analysis set (SAF) includes 190 participants (88.4%) since 25 participants (11.6%) did not receive any study intervention and were excluded from SAF. Primary full analysis set (pFAS) includes 187 participants, which is 87.0% of the FAS population. Per protocol set (PPS) includes 183 participants, which is 85.1% of the FAS population. Primary per protocol set (pPPS) includes 160 participants, which is 74.4% of the FAS population. Pharmacokinetic Analysis Set (PKS) includes 189 participants, which is 87.9% of the FAS population.

There were no deaths and the number of participants with serious adverse event (SAEs) was low (1 participant in the eliapixant 25 mg BID arm, 2 participants in the eliapixant 75 mg BID arm, 3 participants in the eliapixant 150 mg BID arm, 1 participant in the placebo arm, and 2 participants in the elagolix 150 mg arm). 2 of these cases were assessed as related to study intervention by the investigator. The only eliapixant-related SAE was a case of moderate drug-induced liver injury of hepatocellular pattern (in the eliapixant 150 mg BID arm). The percentage of participants who permanently discontinued the study intervention was 2.6%. All the treatment emergent adverse events (TEAEs) leading to discontinuation of study intervention were reported by individual participants only. The overall frequency of participants with TEAEs was higher in the eliapixant 150 mg BID arm (76.3%), the placebo arm (73.0%), and the elagolix 150 mg arm (73.7%) than in the 2 lower-dosed eliapixant treatment arms. There was no specific event driving this difference across the treatment arms. Taste- and smell-related AEs were only observed in the eliapixant 150 mg BID arm (6 participants, 15.8%) and the placebo arm (3 participants, 8.1%). No mean increase in transaminases was observed in this study. A mean and median increase in antithrombin activity was observed in the eliapixant arms compared with the placebo arm, in line with similar findings from other Phase 1 and Phase 2 studies with eliapixant. However, no differences were observed in bleeding TEAEs between the treatment arms. A mean increase in alkaline phosphatase and fibrinogen was seen in the eliapixant arms, but not in the placebo arm, confirming similar changes in other Phase 2 studies with eliapixant. The clinical relevance of these findings remains unclear, as there was no difference between eliapixant and placebo with regard to potential clinical manifestations of such changes (e.g. frequency of TEAEs related to bleeding or thromboembolic events). No relevant mean changes were observed for vital signs (BMI, heart rate, diastolic and systolic blood pressure, weight).

At Week 12 (end of intervention [EOI]), the mean (SD) changes in mean worst EAPP from baseline were -1.56 (1.35) in the eliapixant 25 mg BID arm, -2.12 (2.66) in the eliapixant 75 mg BID arm, -1.88 (2.03) in the eliapixant 150 mg BID arm, and -1.89 (1.91) in the placebo arm (pPPS). The least square-mean (LS-mean, SE) of change obtained by mixed model repeated measures (MMRM) from baseline to Week 12 (EOI) were -1.63 (0.38) in the eliapixant 25 mg BID arm, -2.13 (0.41) in the eliapixant 75 mg BID arm, -1.96 (0.41) in the eliapixant 150 mg BID arm, and -1.94 (0.38) in the placebo arm. Overall, no significant difference was observed across treatment arms. At Week 12 (EOI) the adjusted p-value for Emax 1, Emax 2, SigEmax 1, and SigEmax2 candidate models were 0.5266, 0.4679, 0.4052, and 0.4082. No significant dose response model was found. The least square-mean (SE) of change in worst EAPP from baseline to Week 12 (EOI) in the elagolix 150 mg arm (-2.69 [0.41]) was lower than other treatment arms (-1.60 [0.40] in the eliapixant 25 mg BID arm, -2.07 [0.42] in the eliapixant 75 mg BID arm, -1.97 [0.42] in the eliapixant 150 mg BID arm, and -1.89 [0.40] in the placebo arm), which means that elagolix 150 mg arm showed a better pain reduction at EOI visit than other treatment arms (PPS). Difference of least square-mean (SE) of change (pairwise comparison between treatment arms and placebo arm) obtained by MMRM in mean worst EAPP from baseline to Week 12 (EOI) were 0.29 (0.54) in the eliapixant 25 mg BID arm, -0.18 (0.55) in the eliapixant 75 mg BID arm, and -0.08 (0.56) in the eliapixant 150 mg BID arm compared with the placebo arm. Overall, no significant difference was observed between eliapixant treatment arms compared with placebo arm.

Number of completers of this study was <50% of the planned number due to early termination. Mean worst EAPP reductions were observed at Week 12 for all treatment groups and no significant differences were observed across treatment arms. No significant dose response model was found at any time point. Thus, the study did not meet the primary objective. No new safety signals relative to the known safety profile of eliapixant were observed and eliapixant was generally well tolerated in the study.

July. 03, 2023

No

https://jrct.niph.go.jp/latest-detail/jRCT2031210001

Myoishi Masashi

Bayer Yakuhin, Ltd.

2-4-9 Umeda, Kita-ku, Osaka, Osaka

byl_ct_contact@bayer.com

Contact Dedicated

Bayer Yakuhin, Ltd.

2-4-9 Umeda, Kita-ku, Osaka, Osaka

+81-6-6133-6363

byl_ct_contact@bayer.com

Complete

Mar. 31, 2021

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

treatment purpose

-Participant must be => 18 years of age at the time of signing the informed consent
-Visually-confirmed endometriosis: detection of endometriotic lesions during laparoscopy or laparotomy (with or without pathological diagnosis) within 10 years but no less than 8 weeks from Visit 1a (surgically diagnosed endometriosis). For Japan only and limited to no more than half of all randomized Japanese participants: the diagnosis can be based on previous imaging (i.e. endometriosis lesion detected by ultrasound or MRI). If the participant was diagnosed by ultrasound, the lesion must be visualized again by ultrasound at the screening visit. If the participant was diagnosed by MRI, the diagnosis must have been made within 12 months before Visit 1a (clinically diagnosed endometriosis).
-Both sub-criteria regarding pain symptoms must be fulfilled:
--At Visit 1a, participant presents self-reported moderate to severe pain which - based on the judgement of the investigator - carries a reasonable likelihood to translate into a severity of pain symptoms sufficient to fulfil the eligibility criterion and be caused by endometriosis, and
--During the screening period at least 24 daily ESD entries during the 28 consecutive days starting on the first day with menstrual bleeding at or after Visit 1a and entries in the ESD item 1a ('worst pain' on the daily numerical rating scale) sum up to 98 or more.
-Willingness to use standardized rescue pain medications for EAPP (i.e. ibuprofen, acetaminophen and tramadol) and not use any prophylactic pain medication, according to investigator's instruction
-Ability to swallow the study intervention, i.e., the different kinds of tablets, as complete units
-Good general health (except for findings related to endometriosis) as proven by medical history, physical and gynecological examinations and laboratory test results
-Normal or clinically insignificant cervical cytology not requiring further follow-up:
--A cervical cytology sample has to be obtained during screening, or
--A documented normal result has to be available from cervical cytology conducted within 12 months prior to Visit 1a.
--Human papilloma virus (HPV) testing in participants with atypical squamous cells of unknown significance (ASCUS) will be used as an adjunctive test automatically. Participants with ASCUS can be included if they are negative for high-risk HPV strains.

-Current pregnancy or less than 3 months since delivery, abortion or stop of lactation before Visit 1a
-Hypersensitivity to any ingredient of the study intervention and/or the standardized rescue medications
-Known osteoporosis
-History of a low trauma fracture
-Contraindications for elagolix or the standardized rescue medications
-Current malignancy or history of cancer (exception: basal cell or squamous cell carcinoma of the skin) within the last 5 years prior to Visit 1a
-Any other disease or condition that, according to the investigator, can compromise the function of the body systems and could result in altered absorption, excessive accumulation, impaired metabolism, or altered excretion of the study intervention (e.g. chronic bowel diseases, Crohn's disease and ulcerative colitis)
-Menopause or signs of menopausal transition, such as absence of regular menstrual cycles based on investigator's judgment (absence of information regarding menstrual bleeding pattern e.g. due to long term use of hormonal contraception is not an exclusion criterion)
-Any disease or condition that may worsen during the study period according to the assessment and opinion of the investigator
-Abnormal uterine bleeding in terms of regularity or heaviness (with the exception of heavy menstrual bleeding that does not require treatment)
-Any findings that require further diagnostic procedures to avoid harm to the participant (e.g. ovarian tumors of uncertain origin or pelvic masses of unclear etiology)
-Any serious or unstable diseases or medical conditions,
including psychiatric disorders, that might interfere with the

conduct of the study or the interpretation of the result, including for example:
--history of hysterectomy and/or bilateral oophorectomy
--any conditions considered to contribute significantly to pelvic pain by the investigator, e.g. fibromyalgia, uterine fibroids, irritable bowel syndrome or other bowel disorders
--any other underlying diseases requiring regular use of pain medication (e.g. migraine)
--history of or current anxiety or depression unless stable with or without medical treatment>= 6 months before Visit 1a
-Major surgery scheduled during the study period
-Non-responsiveness of EAPP to earlier treatment with GnRH-agonists or GnRH-antagonists, based on the judgement of the investigator
-SARS-CoV-2- positive virus RNA test within 4 weeks prior to Visit 1a reported by participant, regardless of whether the participant had symptoms
-History of COVID-19 infection with persistent/ongoing symptoms
-Contact with SARS-CoV-2- positive or COVID-19 patient within the last 4 weeks prior to Visit 1a
-Intake of medication prohibited due to potential drug-drug interaction
-Use of other treatments that might interfere with the conduct of the study or the interpretation of the results, including:
--hormonal medications
--other treatments intended for endometriosis/pelvic pain during participation in the study, including the use of herbal products or traditional Chinese medicine for symptom relief, with the exception of the standardized rescue pain medications
-Simultaneous participation in another clinical trial with investigational medicinal product(s). Participation in another trial 3 months prior to Visit 1a that might have an impact on the study objectives, at the discretion of the investigator
-Previous assignment to study intervention (randomization) in this study (allowing previously randomized participants to be re-included into the study may lead to bias)
-Laboratory values outside the inclusion range (specified in the laboratory manual) and considered clinically relevant

Female

symptomatic endometriosis

Each participant will receive one of three oral doses (150 mg, 75 mg, 25 mg) of BAY 1817080, placebo or 150 mg of elagolix twice daily (elagolix: once daily) over a 12-week intervention period.

Absolute change in mean worst EAPP from baseline to end of intervention [ Time Frame: At baseline (last 28 days before start of study drug) and at day 57-84 (+3) ]

Number of participants with treatment-emergent adverse events [ Time Frame: Up to 98 days ]

+81-3-3448-6154

Jan. 19, 2021

Austria/Belgium/Bulgaria/Canada/China/Czechia/Estonia/Finland/Germany/Greece/Hungary/Italy/Latvia/Lithuania/Norway/Poland/Slovakia/Spain/United States