NCT03760003已完成2 期
A Randomized, Double Blind, Placebo Controlled, Parallel Group, Multiple Dose, Induction Study to Evaluate the Safety, Tolerability and Optimal Dose of ABX464 Compared With Placebo in Patients With Moderate to Severe Ulcerative Colitis Who Have Inadequate Response, Loss of Response, or Intolerance With at Least One of the Following Agents: Immunosuppressant Treatment (i.e. Azathioprine, 6-mercaptopurine, Methotrexate), Tumor Necrosis Factor Alpha [TNF-α] Inhibitors, Vedolizumab, JAK Inhibitors and/or Corticosteroid Treatment
适应症
干预措施
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- Abivax S.A.
- 入组人数
- 355
- 试验地点
- 130
- 主要终点
- Reduction From Baseline in Modified Mayo Score (MMS) at Week 8
研究概览
简要总结
Phase 2b study to evaluate the efficacy and the safety of 3 dose-levels of ABX464, administered daily in patients with moderate to severe Ulcerative Colitis.
详细描述
This phase 2b study will evaluate the efficacy and the safety of 3 dose-levels of ABX464, administered daily in improving Modified Mayo Score (MMS) in patients with moderate to severe Ulcerative Colitis who have inadequate response, loss of response, or intolerance with at least one of the following agents: immunosuppressant treatment (i.e. azathioprine, 6-mercaptopurine, methotrexate), tumor necrosis factor alpha [TNF-α] inhibitors, vedolizumab, JAK inhibitors and/or corticosteroid treatment .
Eligible patients will be randomized into 4 parallel intervention/treatment groups: 100mg q.d of ABX464, 50mg q.d of ABX464, 25mg q.d of ABX464, or matching placebo and will be treated for 16 weeks.
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
- 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
- •Men or women age 18 - 75 years;
- •Diagnosis of moderate to severe active UC (including ulcerative proctitis if proximal extension of disease occurs beyond 10 cm) confirmed by endoscopy and histology at least 12 Weeks prior to screening visit. Moderate to severe active UC defined by Modified Mayo Score (MMS) of 5 to 9 inclusive (on a scale of 0-9). Moderate to severe active UC should be confirmed at screening visit with a centrally read endoscopy sub-score of at least 2 (on a scale of 0-3);
- •Patients having either a documented inadequate response, no response, a loss of response, or an intolerance (defined as the occurrence of at least one Adverse Reaction leading to treatment discontinuation) to either immunosuppressant treatment (i.e., azathioprine, 6-mercaptopurine, methotrexate), tumor necrosis factor [TNF] inhibitors, vedolizumab, JAK inhibitors and/or corticosteroid treatment. Inadequate response, no response, loss of response is defined as:
- •i. Active disease or relapse in spite of thiopurines or methotrexate given at an appropriate dose for at least 3 months (i.e. azathioprine 2-2.5 mg/kg/day or mercaptopurine 1-1.5 mg/kg/day in the absence of leukopenia), and/or ii. Active disease despite corticosteroids treatment (prednisolone up to 0.75 mg/kg/day) over a period of 4 Weeks, and/or iii. Active disease or relapse in spite of adequate treatment (as defined in the SmPC) with tumor necrosis factor [TNF] inhibitors or vedolizumab, and/or iv. Active disease or relapse in spite of adequate treatment with JAK inhibitors over a period of at least 6 Weeks.
- •Patients receiving oral corticosteroids must have been on a stable dose of prednisone or prednisone equivalent (≤20 mg/day) or on beclomethasone diproprionate (≤5mg/day) or on budesonide MMX (≤9 mg/day) for at least 2 Weeks prior to the screening visit;
- •Topical corticosteroids and topical 5-aminosalicylic acid preparations must have been withdrawn at least 2 Weeks prior to the screening visit;
- •Patients who are on oral 5-aminosalicylic acid must have been on a stable dose for at least 4 Weeks prior to the screening visit;
- •Patients who are receiving immunosuppressants in the form of azathioprine, 6-mercaptopurine, or methotrexate needed to be on a stable dose for at least 4 Weeks prior to screening visit. Patients taking methotrexate also are advised to take folic acid 1 mg/day (or equivalent) supplementation if there is no contraindication;
- •Patients on probiotics (e.g., Culturelle® [Lactobacillus GG, i-Health, Inc.], Saccharomyces boulardii) must be on stable doses for at least 2 Weeks prior to the screening visit;
- •Patients on antidiarrheals (e.g., loperamide, diphenoxylate with atropine) must be on stable doses for at least 2 Weeks prior to the screening visit;
- •Patients who have received tumor necrosis factor [TNF] inhibitors, vedolizumab or other biologics must have discontinued therapy at least 8 Weeks prior to the screening visit due to lack or insufficient efficacy or intolerance;
- •Patients previously treated with cyclosporine, tacrolimus or JAK inhibitors must have discontinued therapy at least 4 Weeks prior to the screening visit due to lack or insufficient efficacy or intolerance;
- •Patients previously treated with tube feeding, defined formula diets, or parenteral alimentation/nutrition must have discontinued treatment 3 Weeks before the screening visit and must be able to take, orally, appropriate amount of food (calories) and liquids to maintain body weight;
- •Patients with surveillance colonoscopy defined as per ECCO guidelines;
- •Patients with the following hematological and biochemical laboratory parameters obtained at screening:
- •i. Hemoglobin > 9.0 g dL-1; ii. Absolute neutrophil count ≥ 750 mm-3; iii. Platelets ≥ 100,000 mm-3; iv. Total serum creatinine ≤ 1.3 x ULN (upper limit of normal); v. Creatinine clearance > 90 mL min-1 by the Cockcroft-Gault equation within 60 days prior to baseline; vi. Total serum bilirubin < 1.5 x ULN; vii. Alkaline phosphatase, AST (SGOT) and ALT (SGPT) < 2 x ULN;
- •Patients are able and willing to comply with study visits and procedures as per protocol;
- •Patients should understand, sign and date the written voluntary informed consent form at the screening visit prior to any protocol-specific procedures are performed;
- •Patients should be affiliated to a social security regimen (for French sites only);
- •Females and males receiving the study treatment (potentially in combination with immunosuppressant) and their partners must agree to use a highly effective contraceptive method during the study and for 6 months after end of study or early termination. Contraception should be in place at least 2 Weeks prior to study participation. Women must be surgically sterile or if of childbearing potential must use a highly effective contraceptive method. Women of childbearing potential (WOCBP) will enter the study after confirmed menstrual period and a negative pregnancy test. Highly effective methods of contraception include true abstinence, intrauterine device (IUD) or hormonal contraception aiming at inhibition of ovulation, intrauterine hormone releasing system, bilateral tubal ligation, vasectomized partner. True abstinence is defined when this is in line with the preferred and usual lifestyle of the patient. In each case of delayed menstrual period (over one month between menstruations) confirmation of absence of pregnancy is required. This recommendation also applies to WOCBP with an infrequent or irregular menstrual cycle. Female and male patients must not be planning pregnancy during the trial and for 6 months post completion of their participation in the trial. In addition, male participants should use condoms and not donate sperm as long as contraception is required.
排除标准
- •Patients with Crohn's Disease (CD) or presence or history of fistula, indeterminate colitis (IC), infectious/ischemic colitis or microscopic colitis (lymphocytic and collagenous colitis);
- •History of toxic megacolon, abdominal abscess, symptomatic colonic stricture or stoma; history or imminent colectomy, colonic malignancy;
- •History or current evidence of colonic dysplasia or adenomatous colonic polyps. Patient with severe gastrointestinal complications; e.g., short bowel syndromes, recent or planned bowel surgery, Ileostomy and/or colostomy, recent bowel perforation;
- •History of more than one episode of herpes zoster or a history (single episode) of disseminated zoster;
- •Patients with active infections at screening such as infected abdominal abscess, Clostridium difficile (stool antigen and toxin required), CMV (positive IgM), TB and recent infectious hospitalization;
- •Patients previously treated with ABX464;
- •Acute, chronic or history of clinically relevant pulmonary, cardiovascular, hepatic, pancreatic or renal functional abnormality, encephalopathy, neuropathy or unstable CNS pathology such as seizure disorder, angina or cardiac arrhythmias, active malignancy or any other clinically significant medical problems as determined by physical examination and/or laboratory screening tests and/or medical history;
- •Acute, chronic or history of immunodeficiency or autoimmune disease;
- •History of malignancy excluding patients considered cured (5 years disease free survivors);
- •Serious illness requiring systemic treatment and/or hospitalization within 3 Weeks prior to baseline;
- •Pregnant or breast-feeding women;
- •Illicit drug or alcohol abuse or dependence;
- •Patients who received live vaccine 30 days or fewer before first dose of study treatment and/or who's planning to receive such a vaccine during the study duration;
- •Use of any investigational or non-registered product within 3 months or within 5 half-lives preceding baseline, whichever is longer and during the study;
- •Any condition, which in the opinion of the investigator, could compromise the patient's safety or adherence to the study protocol.
研究组 & 干预措施
Matching Placebo
Placebo Comparator
Matching placebo was administered orally (capsules) once daily for 16 weeks
干预措施: Placebo (Drug)
ABX464 100 mg
Experimental
ABX464 100 mg was administered orally (capsules) once daily for 16 weeks
干预措施: ABX464 100 mg (Drug)
ABX464 50 mg
Experimental
ABX464 50 mg was administered orally (capsules) once daily for 16 weeks
干预措施: ABX464 50 mg (Drug)
ABX464 25 mg
Experimental
ABX464 25 mg was administered orally (capsules) once daily for 16 weeks
干预措施: ABX464 25 mg (Drug)
结局指标
主要结局
Reduction From Baseline in Modified Mayo Score (MMS) at Week 8
时间窗: Week 8
Reduction from baseline in Modified Mayo Score (MMS) MMS is a composite score of UC disease activity based on the following 3 subscores: 1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal). 2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed). 3. Endoscopic subscore, scored from 0 (normal or inactive disease) to 3 (severe disease, spontaneous bleeding, ulceration). The overall MMS ranges from 0 to 9 where higher scores represent more severe disease.
次要结局
- Reduction From Baseline in MMS at Week 16(Week 16)
- Number of Participants in Clinical Remission Per MMS at Week 8(Week 8)
- Number of Participants in Clinical Remission Per MMS at Week 16(Week 16)
- Number of Participants With Clinical Response at Week 8(Week 8)
- Number of Participants With Clinical Response at Week 16(Week 16)
- Number of Participants With Endoscopic Improvement at Week 8(Week 8)
- Number of Participants With Endoscopic Improvement at Week 16(Week 16)
- Number of Participants With Mucosal Healing at Week 8(Week 8)
- Number of Participants With Mucosal Healing at Week 16(Week 16)
- Number of Participants With Reduction of Stool Frequency Relative to Baseline (Day 1)(Day 8, Day 29, Day 57, Day 85, Day 113, and Day 120 (End of Study))
- Number of Participants With Reduction of Rectal Bleeding Frequency Relative to Baseline(Day 8, Day 29, Day 57, Day 85, Day 113, and Day 120 (End of Study))
- Partial Modified Mayo Score Change From Baseline(Day 8, Day 29, Day 57, Day 85, Day 113, and Day 120 (End of Study))
- Number of Participants With Reduction Relative to Baseline in Fecal Calprotectin at Weeks 8 and 16(Week 8 and Week 16)
- Number of Participants With Reduction Relative to Baseline in C Reactive Protein at Weeks 8 and 16(Week 8 and Week 16)
- miRNA-124 Expression (Copy Number) in Whole Blood at Week 8 and Week 16(Week 8 and Week 16)
- IL-6 Serum Concentrations(Day 8, Day 29, Day 57, and Day 113)
- Number of Participants With Endoscopic Remission at Week 8(Week 8)
- Number of Participants With Endoscopic Remission at Week 16(Week 16)
- IL-10 Serum Concentrations(Day 8, Day 29, Week 8 and Week 16)
- IL-1B Serum Concentrations(Day 8, Day 29, Day 57 and Day 113)
- TNFα Serum Concentrations(Day 8, Day 29, Day 57 and Day 113)
- Change From Baseline in Infiltrate/Histopathology Using Robarts Histopathology Index (RHI) at Week 8 and Week 16(Week 8 and Week 16)
- Change From Baseline in Infiltrate/Histopathology - Geboes Score at Week 8 and Week 16(Week 8 and Week 16)
研究者
研究点 (130)
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