Phase 1, Randomized, Placebo-Controlled, Blinded Study in Healthy Adults Challenged With Enterotoxigenic Escherichia Coli, of the Safety, Tolerability and Anti-Diarrheal Activity of VENBETA6890, an Orally Administered, Human Monoclonal IgA
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 36
- 试验地点
- 1
- 主要终点
- Number of Participants who Experience Treatment Emergent Adverse Events
研究概览
简要总结
This is a phase 1, randomized, placebo-controlled, blinded study in up to 36 healthy adults, aged 18-45 years, challenged with Enterotoxigenic Escherichia coli, evaluating the safety, tolerability and anti-diarrheal activity of VENBETA6890, an orally administered, human monoclonal IgA.
详细描述
Part A will consist of 1 sentinel dosing group of 2 subjects randomized 1:1 to receive VENBETA6890 or placebo and will evaluate VENBETA6890 at dose levels of 15 mg/kg. On Day 1, subjects will receive 15 mg/kg in the morning and a second dose of 15 mg/kg 8 - 12 h later in the outpatient clinic. On Day 2, they will receive a third dose of 15 mg/kg at approximately 8 - 12 h after the last dose on Day 1. The occurrence of local and systemic reactogenicity (solicited AEs) over the subsequent 7-days post-dosing will be collected; non-solicited non-serious AEs will be collected through 28-days post-dosing and serious adverse events (SAEs) will be collected through 2 months. An independent Safety Monitoring Committee (SMC) will review the cumulative 7-day safety data for the sentinel group and must approve for the study to proceed to Part B.
Part B will consist of a single inpatient cohort of up to 34 subjects who will be randomized 1:1 to receive VENBETA6890 15 mg/kg, or placebo on Day -1 at approximately 12 h pre-challenge, Day 1 at approximately 1 h pre-challenge, and Day 1 at approximately 12 h post-challenge. All subjects will be challenged with wild-type ETEC strain H10407 and will be closely monitored on the inpatient unit for ETEC diarrheal illness. Subjects will receive the 3-day course of antibiotic therapy starting on Day 6 or earlier dependent on symptoms. Discharge from the inpatient unit is contingent upon the absence of ETEC diarrheal illness, including no diarrhea and no fever, plus two sequential negative stool cultures for ETEC separated by at least 12 hours.
An SMC will review the cumulative safety data after data collected during the Day 29 visit of the inpatient challenge cohort has been compiled.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Prevention
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 45 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Male or female ages 18-45 years, inclusive at screening
- •Body weight 50 to 105 kg, inclusive at screening
- •Provide written informed consent before initiation of any study procedures.
- •Willing and able to complete all study requirements, restrictions, confinement to the Research Isolation ward, visits and procedures
- •Completion of a training session and demonstration of comprehension of the protocol procedures and knowledge of ETEC-associated illness by passing a written examination (passing grade is at least 70%).
- •Healthy as judged by the Principal Investigator (PI) and determined by medical history, physical examination, medication history, and laboratory assessments.
- •At Screening: Normal to Grade 1 values14 for the following laboratory determinations:
- •Complete Blood Count: WBC, absolute neutrophil count (ANC), hemoglobin, and platelet count
- •Comprehensive Metabolic Panel: creatinine, alanine aminotransferase (ALT), and total bilirubin
- •Urine protein and urine glucose
- •Urine illicit drug (positive cannabis allowed) and serum alcohol screening
- •Willingness to comply with COVID-19 screening PCR testing prior to dosing
- •Female subjects must be of non-childbearing potential (as defined as surgically sterile or postmenopausal for more than 1 year), or if of childbearing potential must be practicing abstinence or using an effective licensed method of birth control (e.g., history of hysterectomy or tubal ligation; use hormonal or barrier birth control such as implants, injectables, combined oral contraceptives, contraceptive patches, some intrauterine devices (IUDs), cervical sponges, diaphragms, condoms with spermicidal agents; or must have a vasectomized partner) within 28-days prior to the administration of VENBETA6890 or placebo and must agree to continue such precautions for 28 days after the last dose. A woman is eligible if she is monogamous with a vasectomized male.
- •Male subjects with female sexual partner(s) of reproductive potential must fall into one of the following categories to qualify for enrollment:
- •Documented to be surgically sterilized (defined as having successfully undergone vasectomy at least 90 days prior to Screening)
- •Must agree to use a physical barrier method of contraception (e.g., a male condom) in addition to their partner's use (if partner is a WOCBP) of a birth control method from the time of Screening until 90 days after the last dose of study drug. The following methods of contraception are acceptable for use by female partners (if WOCBP) of male subjects:
- •Oral, implantable, transdermal, injectable, or intravaginal hormonal contraception taken for at least 90 days prior to Screening
- •Intrauterine device (IUD [copper or hormonal])
- •Contraceptive sponge with condom Male subjects must agree not to donate sperm from the time of Check-in through 90 days after the final dose of study drug
- •Agrees to avoid live-culture yogurt and other probiotics for at least 14 days prior to the first dose of VENBETA6890 and during the study.
- •Agrees not to participate in another clinical trial during the study period.
排除标准
- •Positive pregnancy test at Screening or within 24 h prior to VENBETA6890 or placebo dosing
- •Breastfeeding
- •Poor venous access, as defined by inability to obtain venous blood, for screening labs, after 3 venipuncture attempts
- •Abnormal vital signs, defined as:
- •Systolic BP >150 mmHg or Diastolic BP >90 mmHg
- •Resting heart rate >100 bpm
- •Temperature ≥38.0°C
- •Abnormal electrocardiogram (ECG) parameters, defined as:
- •PR>220 msec
- •QRS>120 msec
- •QTcF>450 msec for males or >460 msec for females
- •IgA deficiency
- •Evidence of current or past infection with testing for human immunodeficiency virus (HIV), hepatitis C virus (HCV) antibody, or Hepatitis B triple screening panel (Hepatitis B surface antigen, Hepatitis B surface antibody, Hepatitis B total core antibody) with confirmatory testing as indicated.
- •Having received prior vaccines for or have had prior infection with ETEC, Heat-Labile Toxin (LT), cholera, Campylobacter, or Shigella, within the past 3 years
- •History of diarrhea during travel to a developing country within the past 3 years
- •History of chronic gastrointestinal illness, including severe dyspepsia, lactose intolerance, or another significant gastrointestinal tract disease (e.g., irritable bowel syndrome, inflammatory bowel syndrome, gastric ulcer disease)
- •Regular use (≥ once weekly) of laxatives, anti-diarrheal agents, anti-constipation agents, or antacid therapies
- •History of major gastrointestinal surgery (uncomplicated laparoscopic appendectomy or cholecystectomy >1-year prior is permitted)
- •Abnormal bowel habits, as defined by <3 stools per week or >2 stools per day in the past 6 months
- •Use of systemic antibiotics within the past 2 weeks prior to Day 1
- •Use of topical (skin), otic, or ophthalmic antibiotics is acceptable, if those doses are not expected to result in significant systemic absorption levels
- •Use of oral, parenteral or high-dose inhaled steroids within 30 days. High-dose oral or parenteral steroids is defined as ≥20 mg total daily dose, or equivalent dose of other glucocorticoids; high-dose inhaled steroids is defined as >800 μg/day of beclomethasone dipropionate or equivalent.
- •Use of any medication which might affect immune function* within 30 days
- •*Examples include anti-cancer drugs, immunomodulating monoclonal antibody therapeutics, and rheumatologic therapies
- •Diagnosis of schizophrenia or other major psychiatric disease
- •Alcohol or drug abuse within last 5 years; current smokers or use of nicotine in any form within 6 months prior to screening and until after end of study.
- •Presence of immunosuppression, which could be due to active neoplastic disease or a history of any hematologic malignancy (excluding resolved non-melanoma skin cancers), radiation therapy, or primary or secondary immunodeficiencies
- •History of allergy to quinolone (e.g., ciprofloxacin) or sulfa drugs (e.g., trimethoprim-sulfamethoxazole)
- •Known history of seizure disorder (remote history of a childhood seizure disorder which has completely resolved is acceptable)
- •Has consumed any nutrients or drugs with known strong cytochrome P450 3A4/5 (CYP3A4/5) inhibitors or inducers or P-glycoprotein inhibitors or inducers, starting from 14 days prior to Day 1 until the completion of study procedures at the end of study
- •Another investigational medication within 60 days or 5 half-lives, whichever is longer prior to Day 1
- •Participation in an investigational device study within 60 days prior to Day 1
- •Consumption of prescription and over-the-counter medication (including topical medications), traditional Chinese medicine, or herbal medicine, vitamin, mineral, plant, and other dietary supplements within 14 days or 5 half-lives, whichever is longer, prior to Day 1 and throughout the study
- •Consumption of liquids or foods containing grapefruit or cranberry from 7 days prior to Day 1 (Part A) or Check-in (Part B) and throughout the study
- •Consumption of any food containing poppy seeds from 48 h prior to Day 1 (Part A) or Check-in (Part B) and throughout the study
- •Donation of bone marrow or peripheral stem cells within 90 days prior to Day 1 or blood or plasma within 60 days prior to Day 1
- •Participation in strenuous exercise within 72 h prior to Day 1 (Part A) or Check-in (Part B)
- •Consumption of caffeine-containing substances within 72 h prior to Day 1 (Part A) or Check-in (Part B)
- •Occupation involving the handling of ETEC, cholera, or Shigella bacteria
- •Occupation in food handling industry or care of: very young children (<2 years old), elderly (≥70 years) or immunocompromised
- •Any other criteria which, in the investigator's opinion, would compromise the safety of the study, the ability of a subject to participate, or the results of the study
研究组 & 干预措施
Part A arm 1 Investigational Product
Arm 1 Investigational product - Venbeta
干预措施: VENBETA6890 (Drug)
Part A Arm 2
Part A Arm 2 Placebo
干预措施: Placebo (Drug)
Part B Arm 2
Part B Arm 2 Particpants receive placebo.
干预措施: Placebo (Drug)
Part B Arm 1
Part B Arm 1 Participants receive Investigational Product
干预措施: VENBETA6890 (Drug)
结局指标
主要结局
Number of Participants who Experience Treatment Emergent Adverse Events
时间窗: up to day 60
The number of participants who experience treatment emergent adverse events. Severity of Treatment Emergent Adverse Events (TEAEs) are determined by changes in vital signs (VS), Physical examination (PE), and routine clinical laboratory tests.
Proportion of Participants who experience treatment emergent adverse events.
时间窗: up to 60 days
Severity of Treatment Emergent Adverse Events (TEAEs) are determined by changes in vital signs (VS), Physical examination (PE), and routine clinical laboratory tests.
次要结局
- Number of participants experiencing diarrhea after enterotoxigenic E.coli (ETEC) challenge(120 hours post challenge)
- Proportion of participants experiencing diarrhea after ETEC challenge(120 hours post challenge)
研究者
Mark Klempner
Professor of Medicine
University of Massachusetts, Worcester