A Multicenter, Double-Blind, Placebo-Controlled, Ascending-Dose, Repeat-Dose Safety and Pharmacokinetic Investigation of a Delayed-Release, Enteric-Coated Capsule Formulation of AVX 470 [Anti-TNF (Tumor Necrosis Factor) Globulin (Bovine)] in Patients With Active Ulcerative Colitis
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 33
- 试验地点
- 16
- 主要终点
- Safety and tolerability of AVX-470 over 28 days of treatment
研究概览
简要总结
The purpose of this study is to evaluate the safety and tolerability as well as the pharmacodynamic effects of multiple doses of AVX-470 administered orally in patients with active ulcerative colitis.
详细描述
There is a significant unmet medical need for effective oral pharmacologic therapies for inflammatory bowel diseases such as ulcerative colitis. Current anti-TNF therapies, including infliximab and adalimumab, are effective treatments for these conditions, but they must be administered by intravenous or subcutaneous injection. The major safety concerns associated with the use of injectable anti-TNF therapies are infection, demyelinating disease, and lymphoma, all of which are the result of systemic exposure. These uncommon but serious side effects have limited the use of systemic anti-TNF antibody therapy to patients with severe disease that have failed to respond to first-line treatments.
AVX-470 is purified immunoglobulin (Ig) from the colostrum (early milk) of cows immunized with recombinant human tumor necrosis factor (rhTNF). AVX-470 is formulated in delayed-release enteric-coated capsules designed to protect the capsule contents from gastric acids following oral administration and to provide localized delivery to sites of inflammation in the distal intestine. Prior clinical experience with bovine Ig therapies in other human diseases suggests that AVX-470 will not be absorbed to any significant extent, meaning that systemic exposure could be minimized. The development of oral anti-TNF therapy targeting local intestinal disease activity might reduce the risks associated with injectable anti-TNF therapy and allow the convenience of oral dosing.
The present study is a first-in-human, Phase 1 clinical study. It is primarily intended to evaluate the safety and tolerability of multiple doses of AVX-470 administered orally to patients with active ulcerative colitis.
Animal models of ulcerative colitis using a mouse-specific TNF antibody derived from bovine colostrum demonstrated a 50% or more reduction in tissue TNF, TNF-messenger ribonucleic acid (mRNA), interleukin (IL)-6 mRNA, and myeloperoxidase and lowering of colonic inflammatory activity. Twenty-eight-day toxicology studies demonstrated no clinical or histologic findings in exposures above the intended clinical dose range.
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
- Double (Participant, Investigator)
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 aged 18 75, inclusive
- •Established diagnosis of ulcerative colitis involving the sigmoid colon or proximal segments of bowel
- •Total Mayo score between 5-12, inclusive, with endoscopic subscore of the Mayo score ≥ 2 and > 15 cm of involvement beyond the anal verge
排除标准
- •Women with a positive pregnancy test, who are breastfeeding, or who intend to become pregnant during the course of the study
- •Diagnosis of Crohn's disease, microscopic colitis or indeterminate colitis
- •Presence of ileostomy or colostomy, or history of prior colon resection
- •Patients with planned hospitalization or surgery during the course of the study
- •Known allergy to milk proteins, red meat or cornstarch
- •Stools positive for enteric infection, including parasitic, or C. difficile toxin within 28 days of screening
- •Documented presence of Hetatitis B (HBsAg), Hepatitis C (HCV), or HIV
- •Presence of dysplasia of any grade on colonoscopic biopsies
- •Treatment for cancer (excluding non-melanomatous cancer of the skin or cervical carcinoma in situ) or lymphoproliferative disorder (including lymphoma) within 5 years
- •History of tuberculosis (TB) or Listeria infection, or known exposure to another person with active TB disease within 12 weeks of screening; or history of past or current infection with different opportunistic infections
- •History of TNF inhibitor (infliximab, adalimumab or certolizumab pegol) use with primary treatment failure. Secondary treatment failures due to intolerance, allergic reaction, or loss of response will not constitute a basis for exclusion. Oral immunosuppressives, mesalamine, and corticosteroids (up to 20mg of prednisone per day) will be permitted so long as these medications are stable for defined periods of time before study participation commences.
研究组 & 干预措施
Placebo
Placebo will be administered daily for 28 days as a comparator with AVX-470 (all dose groups)
干预措施: Placebo (Drug)
AVX 470
AVX 470 0.2 g(Cohort 1), 1.6 g (Cohort 2) and 3.5 g (Cohort 3) will be administered daily for 28 days
干预措施: AVX 470 (Drug)
结局指标
主要结局
Safety and tolerability of AVX-470 over 28 days of treatment
时间窗: 5 weeks
Assessments weekly during treatment and 1 week post treatment
次要结局
- Pharmacokinetics (serum, stool and gastrointestinal mucosal tissue levels) of AVX-470(4 weeks)
- Measure the induction of or change in a human anti-bovine immunoglobulin antibody (HABA) response to AVX 470(4 weeks)