A Phase 1b/2 Trial Evaluating the Safety, Pharmacokinetics, and Efficacy of EP-104GI in Adults With Eosinophilic Esophagitis (RESOLVE)
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 117
- 试验地点
- 19
- 主要终点
- Dose Escalation- Incidence of treatment emergent adverse events (TEAEs)
研究概览
简要总结
A Phase 1b/2 study to explore the safety, efficacy and pharmacokinetics of EP-104GI in adults with eosinophilic esophagitis (EoE). Endoscopic and histologic assessments will also be evaluated to understand the local effects of EP-104GI on eosinophilic EoE disease activity. Approximately 27 to 33 participants will be enrolled in dose escalation: 3-6 participants per dose cohort. The number of participants enrolled in escalation will depend on the number of dose escalation cohorts evaluated, and dose cohorts needing to be expanded. An additional 10-24 participants will be enrolled in 1 or 2 cohorts of 10-12 participants each at tolerable dose regimen(s) selected based on the accumulated clinical data to identify the recommended phase 2 dose(s) (RP2D). In the Phase 2 randomized dose optimization portion of the study, approximately 120 subjects will be randomized to Dose A (120 mg total dose), Dose B (160 mg total dose), or matching vehicle control, with an overall assignment ratio of 1:1:1. The total number of participants in both portions of the study will be approximately 160. The study involves 8-10 site visits spread over approximately 52 weeks. Participants in an extended PK sub study will have up to 4 additional visits, to a maximum of 108 weeks post-dose. The participants will either receive the active study drug (EP-104GI) or matching vehicle control. Matching vehicle control will be used only in randomized dose optimization portion of the study. Participants randomized to receive vehicle control may receive EP-104GI (Dose A or Dose B) following the completion of Week 24 providing they meet eligibility criteria for crossover to EP-104GI. Participants randomized to receive EP-104GI on Day 0 will not receive EP-104GI or vehicle control at Week 24. The study drug or matching vehicle control will be administered by qualified personnel during an esophagogastroduodenoscopy (EGD) procedure at the Baseline/Dosing visit. Safety will be assessed throughout the study. Blood and urine samples will be collected at site visits for laboratory assessments and to measure plasma levels of EP-104GI. Participants will complete questionnaires to assess symptoms of dysphagia and odynophagia and will undergo 3-5 EGDs with esophageal biopsies at the Baseline, Week 4 (dose escalation phase only), Week 12, Week 24 (randomized dose optimization phase only), Week 26, and Week 52 (randomized dose optimization phase only).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Symptomatic EoE;
- •For women of childbearing potential, a negative pregnancy test and willing to use a highly effective method of birth control until end of study;
- •Willing and able to adhere to study-related procedures and visit schedule;
- •Willing and able to provide informed consent.
- •Criteria for crossover to EP 104GI from vehicle control (randomized dose optimization portion):
- •Has completed the randomized dose optimization portion of the trial to Week 24, inclusive
- •Without safety concerns for receiving EP 104GI ie, does not meet exclusion criteria or have other safety issue
排除标准
- •Concomitant esophageal disease, relevant GI disease, or any condition, history, or laboratory abnormality that might interfere with the study;
- •Oral or esophageal mucosal infection of any type (bacterial, viral, or fungal);
- •Oropharyngeal or dental conditions that prevents normal eating;
- •Severe esophageal motility disorders other than EoE;
- •Contraindication to or factors that substantially increase risks associated with EGD or biopsy, or narrowing of the esophagus that precludes EGD with a standard 9-10 mm endoscope, stricture requiring dilation within 8 weeks prior to Screening, or the need for dilation prior to EGD at Baseline;
- •Any condition for which the use of corticosteroids is contraindicated (Participants with well controlled non-insulin dependent diabetes are permitted);
- •Active or quiescent systemic fungal, bacterial, viral, or parasitic infections, or ocular herpes simplex. Or recent use of IV or oral antibiotics;
- •Hypersensitivity, or intolerance to corticosteroids, or to any of the ingredients in the investigational medicinal product, including carboxymethyl cellulose, and polysorbate 80, or to the ingredients in Synacthen / cosyntropin (used in the ACTH stimulation test);
- •Recent use of disallowed medications, or unwillingness to not use disallowed medications during the study;
- •Recent initiation of a elimination or elemental diet (dietary therapy must remain stable throughout the study);
- •Morning serum cortisol level ≤ 5 μg/dL (138 nmol/L);
- •Clinically significant abnormal laboratory values;
- •Recent or currently planned participation in another interventional trial ;
- •Previous participation in this study and had received study treatment;
- •Females who are pregnant, breastfeeding, or planning to become pregnant during the study;
- •Malignancies or history of malignancy within prior 5 years, except for treated or excised non-metastatic BCC, SCC of the skin, or cervical carcinoma in situ;
- •History of alcohol or drug abuse;
- •Any other reason, that, in the Investigator's opinion, unfavorably alters participant risk, confounds results, or prevents the participant from complying with study requirements.
研究组 & 干预措施
EP-104GI 4 mg
4 submucosal injections of EP-104GI administered during an EGD procedure at the Baseline/Dosing visit.
干预措施: EP-104GI (Drug)
EP-104GI 8 mg
8 submucosal injections of EP-104GI administered during an EGD procedure at the Baseline/Dosing visit.
干预措施: EP-104GI (Drug)
EP-104GI 20 mg
8 submucosal injections of EP-104GI administered during an EGD procedure at the Baseline/Dosing visit.
干预措施: EP-104GI (Drug)
EP-104GI 30 mg
12 submucosal injections of EP-104GI administered during an EGD procedure at the Baseline/Dosing visit.
干预措施: EP-104GI (Drug)
EP-104GI 48 mg
12 submucosal injections of EP-104GI administered during an EGD procedure at the Baseline/Dosing visit.
干预措施: EP-104GI (Drug)
EP-104GI 64 mg
16 submucosal injections of EP-104GI administered during an EGD procedure at the Baseline/Dosing visit.
干预措施: EP-104GI (Drug)
EP-104GI 80 mg
20 submucosal injections of EP-104GI administered during an EGD procedure at the Baseline/Dosing visit.
干预措施: EP-104GI (Drug)
EP-104GI 96 mg
16 submucosal injections of EP-104GI administered during an EGD procedure at the Baseline/Dosing visit.
干预措施: EP-104GI (Drug)
EP-104GI 120 mg
20 submucosal injections of EP-104GI administered during an EGD procedure at the Baseline/Dosing visit.
干预措施: EP-104GI (Drug)
EP-104GI Dose A or matching vehicle control
20 submucosal injections of EP-104GI administered during an EGD procedure at the Baseline/Dosing visit.
干预措施: EP-104GI (Drug)
EP-104GI Dose A or matching vehicle control
20 submucosal injections of EP-104GI administered during an EGD procedure at the Baseline/Dosing visit.
干预措施: Matching vehicle control (Other)
EP-104GI 160 mg
20 submucosal injections of EP-104GI administered during an EGD procedure at the Baseline/Dosing visit.
干预措施: EP-104GI (Drug)
EP-104GI Dose B or matching vehicle control
20 submucosal injections of EP-104GI administered during an EGD procedure at the Baseline/Dosing visit.
干预措施: EP-104GI (Drug)
EP-104GI Dose B or matching vehicle control
20 submucosal injections of EP-104GI administered during an EGD procedure at the Baseline/Dosing visit.
干预措施: Matching vehicle control (Other)
结局指标
主要结局
Dose Escalation- Incidence of treatment emergent adverse events (TEAEs)
时间窗: 52 weeks
TEAEs will be summarized by dose/cohort
Dose Escalation- Severity of treatment emergent adverse events (TEAEs)
时间窗: 52 weeks
TEAEs will be summarized by dose/cohort and severity (mild, moderate, severe).
Dose Escalation- Change from baseline in morning serum cortisol levels
时间窗: 52 weeks
Cortisol will be will be summarized by dose/cohort and over time and compared to pre-dose values. A prolonged and clinically significant reduction in cortisol may indicate adrenal insufficiency.
Dose Escalation- Plasma concentrations of fluticasone propionate
时间窗: 108 weeks
Plasma concentrations of fluticasone propionate over time will be used to calculate PK parameters for each dose/cohort.
Dose Escalation- Change from baseline in physical examination results, BMI and weight change.
时间窗: 12 weeks
Physical examination results, BMI and weight will be summarized by dose/cohort and over time and compared to pre-dose values.
Randomised Dose Optimization- Change from baseline in EoEHSS grade and stage scored in 3 regions of the esophagus within the injection area (proximal, mid, distal)
时间窗: 24 weeks
The EoEHSS scores the stage and grade of 8 histologic items: eosinophil inflammation, basal zone hyperplasia, dilated intercellular spaces, eosinophil abscesses, surface layering, surface epithelial alteration, dyskeratotic epithelial cells and lamina propria fibrosis), on separate 4-point Likert scales. A composite EoEHSS grade and stage scores are calculated by summing the individual grade and stage items and dividing by the maximum score for evaluated items (range, 0-1). A lower score indicates improvement.
次要结局
- Randomised Dose Optimization- Change in endoscopist's global impression of severity(52 weeks)
- Randomised Dose Optimization- Change from baseline in EoE Histology Scoring System (EoEHSS) score in 3 regions of the esophagus within the injection area (proximal, mid, distal), excluding Week 24 as this is the primary endpoint(52 weeks)
- Dose Escalation- Change from baseline in the EoE Endoscopic Reference Score (EREFS)(36 weeks)
- Dose Escalation- Change from baseline in odynophagia measured on an 11 point Likert scale(52 weeks)
- Dose Escalation- Change from baseline in EoE Histology Scoring System (EoEHSS) score(36 weeks)
- Randomised Dose Optimization- Change from baseline in the Straumann Dysphagia Index (SDI) score(52 weeks)
- Randomised Dose Optimization- Change from baseline in the Dysphagia symptom questionnaire (DSQ) v4.0 and "Dysphagia days"(52 weeks)
- Randomised Dose Optimization- Change from baseline in the Eosinophilic Esophagitis Impact Questionnaire (EoE IQ)(52 weeks)
- Randomised Dose Optimization- Change from baseline in the Patient Global Impression of Change (PGIC)(52 weeks)
- Randomised Dose Optimization- Change from baseline in the Patient Global Impression of Severity (PGIS)(52 weeks)
- Randomised Dose Optimization- Change from baseline in peak eosinophil count (PEC)(52 weeks)
- Dose Escalation- Peak eosinophil count (PEC)(36 weeks)
- Dose Escalation- Change from baseline in the Straumann Dysphagia Index (SDI) score(52 weeks)
- Dose Escalation- Change from baseline in dysphagia measured on an 11 point Likert scale(52 weeks)
- Randomised Dose Optimization- Change from baseline in the EoE Endoscopic Reference Score (EREFS) in 3 regions of the esophagus within the injection area (proximal, mid, distal)(52 weeks)
- Randomised Dose Optimization- Change from baseline in morning serum cortisol levels(52 weeks)
- Randomised Dose Optimization- Change from baseline in vital signs (temperature, blood pressure, pulse, and respiratory rate) results(52 weeks)
- Randomised Dose Optimization- Change from baseline in physical examination results, BMI and weight change.(52 weeks)
- Randomised Dose Optimization- Plasma concentrations of fluticasone propionate(108 weeks)