A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled, Dose-finding Study to Evaluate the Efficacy and Safety of IMU-838 for Induction and Maintenance Therapy in Moderate-to-severe Ulcerative Colitis
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 发起方
- Immunic AG
- 入组人数
- 263
- 试验地点
- 130
- 主要终点
- Induction Phase: Symptomatic Remission and Endoscopic Healing at Week 10
研究概览
简要总结
This is a phase 2, multicenter, randomized, double-blind, placebo-controlled, dose-finding study to evaluate the efficacy and safety of IMU-838 for induction and maintenance therapy with an option for open-label treatment extension in moderate-to-severe ulcerative colitis (CALDOSE-1).
详细描述
The investigational medicinal product (IMP) IMU-838 (vidofludimus calcium) is a new compound that selectively inhibits the human enzyme dihydroorotate dehydrogenase (DHODH). Dihydroorotate dehydrogenase plays a major role in the de-novo pyrimidine synthesis and is specifically expressed at high levels in proliferating or activated lymphocytes. Resting lymphocytes satisfy their pyrimidine requirements through a DHODH-independent salvage pathway. Thus, IMU-838-mediated DHODH inhibition selectively affects activated, rapidly proliferating lymphocytes. The metabolic stress secondary to DHODH inhibition leads to a reduction of pro-inflammatory cytokine release including interleukin (IL)-17 (IL-17A and IL-17F) and interferon gamma (IFNγ), and to an increased apoptosis in activated lymphocytes.
This is a phase 2, multicenter, randomized, double-blind, and placebo-controlled trial in patients with moderate-to-severe UC with an option for open-label treatment extension. The study comprises a blinded induction phase to establish the optimal dose of IMU-838 to induce response and remission, a blinded maintenance phase to evaluate the potential of IMU-838 to maintain remission until Week 50, and an open-label treatment extension arm for all patients who discontinue the blinded phase as scheduled or prematurely, subject to certain restrictions. A subset of patients will undergo a pharmacokinetic (PK) period at the start of the open-label period to establish a full single-dose PK profile.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
10 mg IMU-838 (Induction)
Two 5 mg tablets once daily of IMU-838 for 10 to 22 weeks depending on symptomatic remission at Weeks 10 or 22.
Patients will receive only half of their assigned full dose during the first week of treatment.
干预措施: IMU-838 (Drug)
30 mg IMU-838 (Induction)
Two 15 mg tablets once daily of IMU-838 for 10 to 22 weeks depending on symptomatic remission at Weeks 10 or 22.
Patients will receive only half of their assigned full dose during the first week of treatment.
干预措施: IMU-838 (Drug)
45 mg IMU-838 (Induction)
Two 22.5 mg tablets once daily of IMU-838 for 10 to 22 weeks depending on symptomatic remission at Weeks 10 or 22.
Patients will receive only half of their assigned full dose during the first week of treatment.
干预措施: IMU-838 (Drug)
placebo (Induction)
The placebo tablets will be identical to the IMU-838 tablets in terms of appearance, constitution of inactive ingredients, and packaging.
干预措施: Placebo (Drug)
10 mg IMU-838 (Maintenance)
Two 5 mg tablets once daily of IMU-838 until Week 50 or ulcerative colitis relapse.
干预措施: IMU-838 (Drug)
30 mg IMU-838 (Maintenance)
Two 15 mg tablets once daily of IMU-838 until Week 50 or ulcerative colitis relapse.
干预措施: IMU-838 (Drug)
placebo (Maintenance)
The placebo tablets will be identical to the IMU-838 tablets in terms of appearance, constitution of inactive ingredients, and packaging. Patients who have received placebo during the induction phase will be 're-randomized' to continue to receive placebo (in a blinded fashion).
干预措施: Placebo (Drug)
30 mg IMU-838 (Open-label)
Two 15 mg tablets once daily of IMU-838 or one 30 mg tablet IMU-838 once daily for up to 10 years and up to 3 years in UK sites
干预措施: IMU-838 (Drug)
结局指标
主要结局
Induction Phase: Symptomatic Remission and Endoscopic Healing at Week 10
时间窗: 10 weeks
Composite endpoint: Proportion of patients with both, symptomatic remission (Mayo rectal bleeding subscore = 0, and Mayo stool frequency subscore of 0 or 1) and endoscopic healing (Modified Mayo endoscopy subscore of 0 or 1) at Week 10. All patients who were randomized to 30 mg/day and 45 mg/day were used for the assessment of the primary efficacy endpoint
次要结局
- Induction Phase: Symptomatic Remission and Endoscopic Healing at Different Doses at Week 10(10 weeks)
- Induction Phase: Symptomatic Remission(22 weeks)
- Induction Phase: Time to Achieving Symptomatic Remission(22 weeks)
- Induction Phase: Proportion of Patients With Clinical Response(10 weeks)
- Induction Phase: Proportion of Patients With Endoscopic Healing(10 weeks)
- Induction Phase: Proportion of Patients With Symptomatic Response(22 weeks)
- Induction Phase: Full Mayo Score(10 weeks)
- Induction Phase: Partial Mayo Score(22 weeks)
- Induction Phase: Patient Reported Outcome (PRO)-2 Mayo Score(22 weeks)
- Induction Phase: Fecal Calprotectin (fCP)(22 weeks)
- Induction Phase: C-reactive Protein (CRP)(22 weeks)
- Safety: Adverse Events(50 weeks)
- Safety: Number of Participants With Clinically Significant Findings During Physical Examination(50 weeks)
- Safety: Body Weight(50 weeks)
- Safety: Blood Pressure(50 weeks)
- Safety: Heart Rate(50 weeks)
- Safety: 12-lead Electrocardiogram (ECG)(50 weeks)
- Safety: Hematology(up to Week 50)
- Safety: Blood Chemistry(50 weeks)
- Safety: Coagulation(10 weeks)
- Safety: Urinalysis(50 weeks)
- Safety: Micro Ribonucleic Acid-122 Expression(24 hours)
- PK: IMU-838 Plasma Level(2 weeks)
- PK: Time to Cmax (Tmax)(pre-dose, 1, 2, 3, 4, 5, 6 hours post PK dose; 24 hours post PK dose; 48 hours post PK dose; 72 hours post PK dose)
- Pharmacodynamics (PK): IMU-838 Trough Level(Day 0, Day 1, Day 7, Week 2 and Week 10)
- PK: Area Under the Drug Concentration-time Curve (AUC) From Time Zero to 24 Hours (AUC0-24h)(pre-dose, 1, 2, 3, 4, 5, 6 hours post PK dose; 24 hours post PK dose; 48 hours post PK dose; 72 hours post PK dose)
- PK: AUC Time Zero to Infinity (AUC0-inf)(pre-dose, 1, 2, 3, 4, 5, 6 hours post PK dose; 24 hours post PK dose; 48 hours post PK dose; 72 hours post PK dose)
- PK: AUC Time Zero to Last Measurable Concentration (AUC0-t)(pre-dose, 1, 2, 3, 4, 5, 6 hours post PK dose; 24 hours post PK dose; 48 hours post PK dose; 72 hours post PK dose)
- PK: Maximum Plasma Concentration (Cmax)(pre-dose, 1, 2, 3, 4, 5, 6 hours post PK dose; 24 hours post PK dose; 48 hours post PK dose; 72 hours post PK dose)
- Maintenance Phase: Proportion of Patients in Symptomatic Remission(Week 14, Week 30, Week 50)
- Maintenance Phase: Time to Relapse(50 weeks)
- Maintenance Phase: Proportion of Patients Without Relapse(50 weeks)
- Maintenance Phase: fCP(50 weeks)
- Maintenance Phase: CRP(50 weeks)
- Maintenance Phase: Proportion of Patients With Endoscopic Healing(50 weeks)
- Maintenance Phase: Proportion of Patients With Microscopic Healing(50 weeks)
- Maintenance Phase: Corticosteroid-free Remission(50 weeks)
- Open-label Phase: Symptom Control(up to 4 years)
- Open-label Phase: fCP(Baseline, Week 4 OLE, Week 8 OLE, EoT up to 4 years (variable))
- Open-label Phase: CRP(Baseline, Week 4 OLE, Week 8 OLE, Week 10 OLE, Week 12 OLE, Week 16 OLE, Week 20 OLE, Week 24 OLE, Week 28 OLE, Week 32 or 38 OLE (depending if entry was after extended induction phase), EoT up to 4 years (variable))
- Maintenance Phase: Mayo PRO-2 Score(50 weeks)