A Randomized, Double-blind, Placebo-controlled Study of the Safety, Pharmacodynamics, Efficacy, and Pharmacokinetics of TIMP-GLIA in Subjects With Well-controlled Celiac Disease Undergoing Oral Gluten Challenge
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 34
- 试验地点
- 7
- 主要终点
- Change From Baseline in Interferon-Gamma Spot Forming Units (IFN-gamma SFUs) in a Gliadin-specific Enzyme-linked Immunospot (ELISpot) at Day 20
研究概览
简要总结
Subjects enrolled in this study will be evaluated for immune responses and histological changes in the small bowel following 2 doses of TIMP-GLIA or placebo and a 14-day oral gluten challenge.
详细描述
This study is a randomized, double-blind, placebo-controlled clinical trial to assess the safety, pharmacodynamics, efficacy, and PK, of TIMP-GLIA in subjects with well-controlled celiac disease (CD) following an oral gluten challenge. Subjects aged 18 to 70 years inclusive, with documented history of biopsy-proven confirmed CD, and on a gluten-free diet (GFD) for a minimum of 6 months, will be screened. Subjects who meet all inclusion and no exclusion criteria, and provide written informed consent, will be randomized within 45 days after Screening to receive 2 intravenous (IV) infusions of TIMP-GLIA, 8 mg/kg up to a maximum of 650 mg or placebo (normal saline) in a 1:1 ratio. Treatment with drug or placebo will be followed by 14 days gluten challenge.
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 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or nonpregnant female, ages 18 to 70 years inclusive, at Screening Visit.
- •Biopsy-confirmed CD (intestinal histology showing villous atrophy).
- •Positive for human leukocyte antigen (HLA)-DQ2 or HLA-DQ2/DQ8 - results will be obtained at Screening if unknown or results are not available.
- •Self-reported to be on a GFD for at least 6 months prior to Screening and agree to continue GFD throughout study, with the exception of the oral gluten challenge.
- •Normal or negative celiac serology, at screening, defined as:
- •Measurable total serum immunoglobulin A (IgA) AND
- •Negative or weak positive tissue transglutaminase (tTG) IgA titer OR
- •If IgA deficient, defined by a serum IgA level of < 3 mg/dL, negative or weak positive DGP- IgG titer.
- •Vh:Cd ≥ 1.5 on screening biopsy.
排除标准
- •Positive for only HLA-DQ
- •History of clinically confirmed immunoglobulin E (IgE)-mediated reaction and/or anaphylaxis to wheat (i.e., "wheat allergy"), barley or rye.
- •Uncontrolled CD and/or active signs/symptoms of CD, in the opinion of the investigator.
- •Untreated or active gastrointestinal disease such as peptic ulcer disease, esophagitis (Los Angeles Classification ≥ Grade C), irritable bowel syndrome, inflammatory bowel disease, or microscopic colitis.
- •Immunocompromised individuals, including those receiving immunosuppressive doses of corticosteroids (more than 20 mg of prednisone given daily or on alternative days for 2 weeks or more within 6 months prior Dose 1, any dose of corticosteroids within 30 days of Day 1, or high dose inhaled corticosteroids [> 960 µg/day of beclomethasone dipropionate or equivalent]) or other immunosuppressive agents.
- •Presence or history of celiac-associated thyroid disease or Type 1 diabetes, regardless of current treatment.
研究组 & 干预措施
TIMP-GLIA
8 mg/kg up to a maximum of 650 mg administered intravenously on days 1 and 8.
干预措施: TIMP-GLIA (Drug)
Placebo
Normal saline administered intravenously on days 1 and 8.
干预措施: Placebo (Drug)
结局指标
主要结局
Change From Baseline in Interferon-Gamma Spot Forming Units (IFN-gamma SFUs) in a Gliadin-specific Enzyme-linked Immunospot (ELISpot) at Day 20
时间窗: Baseline (Day 15/Day 1), Day 20
The spots formed by interferon-gamma-secreting T-cells were counted with an automated ELISPOT analyzer. The average spot-forming units (SFU) per antigen was calculated. A response was considered positive when the average SFU in wells with a given peptide was at least twice that of the average SFU in the no-peptide control wells. Baseline (Day 15/Day 1) was defined as Day 15 (or Day 1 if enough blood was not available on Day 15). Peripheral blood mononuclear cell is PBMC.
次要结局
- Change From Baseline in Gliadin-specific T Cell Proliferation by Enzyme-linked Immunosorbent Assay (ELISA) at Day 20(Baseline (Day 15/Day 1), Day 20)
- Change From Baseline in Gliadin-specific T Cell Cytokine Secretion by ELISA at Day 20(Baseline (Day 15/Day 1), Day 20)
- Change From Baseline in Gut-Homing CD4, CD8 and Gamma Delta T-cells by Mass Cytometry (CyTOF) at Day 20(Baseline (Day 15/Day 1), Day 20)
- Change From Baseline in Ratio of Villus Height to Crypt Depth (Vh:Cd) at Day 29(Baseline (Screening), Day 29)
- Percentage of Participants With Greater Than or Equal to (>=) 0.4 Decrease in Vh:Cd at Day 29(Day 29)
- Change From Baseline in Number of Intestinal Intraepithelial Lymphocytes (IELs) at Day 29(Baseline (Screening), Day 29)
- Number of Participants Based on Celiac Symptom Index-Modified (CSI-M) Questionnaire Results by Treatment(Days 15, 20, 29 and 35)
- Number of Participants With Clinically Significant Change From Baseline in Hematology or Serum Chemistry Laboratory Values(From the first dose of study drug up to Day 35)
- Plasma Concentrations of TIMP-GLIA(Day 8: 0 hours (pre-infusion), end of infusion, and at 2 hours post-infusion)
- Number of Participants Who Experience at Least 1 Treatment-emergent Adverse Event (TEAE) and Serious Adverse Event (SAE)(From the first dose of study drug up to Day 35)
- Number of Participants With Clinically Significant Change From Baseline in Vital Signs(From the first dose of study drug up to Day 35)
- Change From Baseline in Deamidated Gliadin Peptide Immunoglobulin G (DGP-IgG) Antibodies at Days 8, 15, 20, 29, and 35(Baseline (Screening), Days 8, 15, 20, 29, and 35)
- Change From Baseline in Serum Complement Levels of C3a and SC5B-9 at Days 2, 8, 9, and 15(Baseline (Day 1), Days 2, 8, 9, and 15)
- Change From Baseline in Serum Complement Levels of C5a at Days 2, 8, 9, and 15(Baseline (Day 1) , Days 2, 8, 9, and 15)
- Change From Baseline in Serum Complement Levels of C1q Binding at Days 15, 20, 29, and 35(Baseline (Day 1), Days 15, 20, 29, and 35)
- Change From Baseline in Serum Cytokines (IFN-γ, IL 1-β, IL-2, IL-4, IL-6, IL-8 , IL-10, IL-12p70, and TNF-Alpha) at Days 2, 8, 9, and 15(Baseline (Day 1), Days 2, 8, 9, and 15)