Phase I, Randomized, Placebo-Controlled Trial of Linaclotide to Demonstrate Colorectal Bioactivity in Healthy Volunteers
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Mayo Clinic
- 入组人数
- 24
- 试验地点
- 1
- 主要终点
- Dose of linaclotide acetate that produces a 60% response rate for cGMP levels in rectal tissue by radioimmunoassay (RIA)
研究概览
简要总结
This randomized phase I trial studies the side effects and best dose of linaclotide acetate in preventing colorectal cancer in healthy volunteers. Chemoprevention is the use of certain drugs to keep cancer from forming. The use of linaclotide acetate may prevent colorectal cancer.
详细描述
PRIMARY OBJECTIVES:
I. To assess the pharmacodynamic effect (PD) of linaclotide (linaclotide acetate) (single daily dose x 7 days, stage I cohort dose= 0.870 mg/day) on cyclic guanosine monophosphate (cGMP) levels, based on biopsy samples obtained pre- and post-intervention from the rectum, until an effect is documented.
SECONDARY OBJECTIVES:
I. To confirm the safety and tolerability of linaclotide. II. To assess the pharmacodynamic effect of linaclotide on cGMP levels, analyzed sequentially from the transverse colon to the cecum, if no cGMP effect was observed in the rectum for the primary endpoint.
III. To compare the change in the cGMP levels from baseline to day 7 between all the assigned doses of linaclotide (including placebo), analyzed sequentially from the rectum, transverse colon, and cecum.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •PRE-REGISTRATION INCLUSION CRITERIA
- •Ability to understand and willingness to sign a written informed consent document and follow study procedures
- •Willingness to abstain from grapefruit juice, alcohol, and concomitant medications during study
- •Willingness to employ adequate contraception for men and women of childbearing potential; acceptable methods include double barrier methods, intrauterine device (IUD), postmenopausal status documented by serum follicle-stimulating hormone (FSH), and/or documentation of surgical sterilization
- •Body mass index < 35 kg/m^2
- •Willingness to provide blood and tissue specimens for research purposes
- •REGISTRATION INCLUSION CRITERIA
- •Participants must have normal organ function and have normal laboratory findings without clinically significant findings
- •Satisfactory anesthesia and intestinal preparation, with no findings of advanced adenoma, chronic inflammation, or cancer
排除标准
- •PRE-REGISTRATION EXCLUSION CRITERIA
- •Previous personal history of advanced adenomas (>= 1 cm in maximal diameter, >= 3 in total number, villous morphology, or high-grade dysplasia) or colorectal cancer
- •Family history of polyposis syndrome (e.g., familial adenomatous polyposis [FAP], hereditary non-polyposis colorectal cancer [HNPCC]) or colorectal cancer (first degree relatives younger than 60 years old)
- •History of gastroparesis
- •History of surgery involving the luminal gastrointestinal (GI) tract, including bariatric surgery
- •History of celiac disease
- •Inflammatory bowel disease (Crohn's disease, ulcerative colitis)
- •Irritable bowel syndrome, chronic constipation, functional bowel disorders, or colonic motility disorder
- •Any malignancy within 3 years of baseline; participants with a history of basal cell or squamous cell skin cancer may be enrolled at the discretion of the investigator
- •Participants may not be receiving any other investigational agents
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to linaclotide
- •History of difficulty with colonoscopy or abnormal colorectal anatomy
- •Uncontrolled current illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
- •Pregnant or lactating women
- •Use of laxatives more than 3 times per week
- •Intestinal motility agents, histamine-2 inverse agonists (H-2 blockers), or proton pump inhibitors
- •Current use of >= 5 cigarettes/day
- •Current use of >= 3 alcoholic drinks/day
- •Use anti-platelet agents within two weeks of anticipated colonoscopy
- •Use of anti-coagulants within two weeks of anticipated colonoscopy
- •History of bleeding/coagulation problems
- •Prior intolerance of or contraindications for the use of sedation or anesthetic agents, which would prevent the safe use of sedation for colonoscopy; this includes allergies to eggs and soy products
- •Any medical condition judged by the investigator to constitute a risk to safe participation
- •REGISTRATION EXCLUSION CRITERIA
- •Colonoscopic finding requiring clinical intervention
- •Use of any illicit or illegal substances detected by urinary drug screen
- •Inadequate pre-intervention bowel preparation, as determined by the study physician
研究组 & 干预措施
Arm II (placebo)
Participants receive placebo PO QD on days 1-7.
干预措施: laboratory biomarker analysis (Other)
Arm I (linaclotide acetate)
Participants receive linaclotide acetate PO QD on days 1-7.
干预措施: linaclotide acetate (Drug)
Arm I (linaclotide acetate)
Participants receive linaclotide acetate PO QD on days 1-7.
干预措施: pharmacological study (Other)
Arm I (linaclotide acetate)
Participants receive linaclotide acetate PO QD on days 1-7.
干预措施: laboratory biomarker analysis (Other)
Arm II (placebo)
Participants receive placebo PO QD on days 1-7.
干预措施: placebo (Other)
Arm II (placebo)
Participants receive placebo PO QD on days 1-7.
干预措施: pharmacological study (Other)
结局指标
主要结局
Dose of linaclotide acetate that produces a 60% response rate for cGMP levels in rectal tissue by radioimmunoassay (RIA)
时间窗: Baseline to 7 days
The pharmacological effect is measured by the arithmetic difference in mean cGMP levels before and after 7 days of linaclotide acetate in biopsies from the colonoscopy. The mean cGMP value will be calculated based on 2 biopsies from the rectum assessed at each time point. The PD response is measured by the difference in mean cGMP levels after 7 days.
次要结局
- Incidence of adverse events associated with linaclotide acetate assessed using the Common Terminology Criteria for Adverse Events version 4.0(Up to 51 days)
- Change in cGMP levels between all assigned doses, analyzed sequentially from the rectum, transverse colon, and cecum(Baseline to 7 days)
- PD effect on cGMP levels (Stage II)(Up to 6 days)
- PD effect of linaclotide acetate on cGMP levels from the transverse colon to the cecum(Up to 7 days)