A Randomized, Double-blind, Placebo-controlled Trial to Assess the Efficacy of Once-daily Dosing of IMM-124E (Travelan®) in a Controlled Human Infection Model for Enterotoxigenic Escherichia Coli (ETEC)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- Immuron Ltd.
- 入组人数
- 63
- 试验地点
- 2
- 主要终点
- To measure the protective efficacy of oral administration of Travelan compared to placebo against moderate-to-severe diarrhea following with E.coli (ETEC) challenge.
研究概览
简要总结
This is a randomized, double-blind, placebo-controlled study to investigate a single daily dose of Travelan® protects healthy adult volunteers from moderate-to-severe diarrhea upon challenge with Enterotoxigenic Escherichia coli (ETEC) strain H10407.
详细描述
Sixty subjects will be randomized to receive either the Travelan® product or a placebo followed by challenge with ETEC strain H10407. Subjects will receive Travelan® or placebo tablets as a single daily dose beginning 2 days prior to experimental challenge with ETEC strain H10407. Travelan®/placebo will be administered for a total of 7 days, or until antibiotic treatment has been initiated. Antibiotic treatment will be initiated if early antibiotic treatment criteria are met or 5 days after challenge.
Early antibiotic treatment will commence when any of the following criteria are met, and a physician determines it to be warranted:
- Severe diarrhea based on volume (800 g in 24 hours)
- Diarrhea of any severity AND 2 or more of the following symptoms: severe abdominal pain, severe abdominal cramps, severe nausea, severe headache, severe myalgias, severe arthralgia), any fever (≥ 38.0°C), or any vomiting
- Any fever ≥ 39.0°C
- Subjects who experience unexpectedly severe events such as symptomatic hypotension (disproportionate to volume loss), renal dysfunction, or altered mental state at the discretion of the investigators.
- A study physician determines that early treatment is warranted for other reasons.
The placebo is a commercially sourced high-protein milk product repackaged and masked to mirror the Travelan® product.
Upon admission to the inpatient unit, clinical monitoring will consist of daily medical assessments with adverse event (AE) determination, vital signs at least three times daily, examination and weighing of all stools and safety laboratory tests. Any subject passing a loose diarrheal (grade 3-5 stool) will be encouraged to start drinking oral fluids at a rate equal to 1.5 times their stool output (or at the same rate as their emesis output as applicable). Intravenous (iv) rehydration will be provided if pre-specified criteria are met.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Consenting, eligible participants will be randomized in a 1:1 ratio to receive either the test article Travelan® or placebo. Once enrolled into the study (subject meets all eligibility criteria and is selected by the investigator for inclusion in the study), subjects will be assigned a randomization number. The subject will receive the study treatment regimen assigned to the corresponding randomization number. Subjects will receive the test article/placebo in containers bearing their assigned identification numbers. This number will be linked to the randomization code list securely maintained throughout the clinical phase of the study by the designated study staff. Investigators and participants will remain blinded to group assignments until completion of the clinical phase of the trial and validation of the clinical data.
入排标准
- 年龄范围
- 18 Years 至 50 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Male or female between 18 and 50 years of age, inclusive at time of screening visit.
- •General good health, without significant medical illness, abnormal vital signs or physical examination findings, or clinical laboratory abnormalities, as determined by the principal investigator (PI) in consultation with the Medical Monitor and Sponsor.
- •Demonstrate comprehension of the protocol procedures, requirements, and CHIM this will be evaluated by completing a multiple choice comprehension assessment (passing grade > 70%) during screening and in the consenting process.
- •Willing to participate, as evidenced by signing the informed consent document.
- •Available for all planned follow-up visits.
- •Negative serum pregnancy test at screening and negative serum and/or urine pregnancy test on the day of admittance to the inpatient unit for all female participants. All females must agree to use an efficacious hormonal or barrier method of birth control during the study. Efficacious methods of birth control include hormonal birth control methods (oral contraceptive pills, patches, vaginal rings, long-acting reversible contraception, surgical sterilization, condoms with spermicide, or abstinence from intercourse with a male partner. Female participants unable to bear children must have this documented (e.g., tubal ligation or hysterectomy).
- •A negative Covid-19 PCR test is required on the day of admission to the unit to comply with Pharmaron's Covid-19 policy (subjects reporting to admission for Cohort 1 who test positive for COVID-19 may rescreen for Cohort 2)
- •Acceptable hematology and blood chemistry levels as assessed by the PI. i.e., Serum creatinine <1.3 mg/dL. AST, GGT, amylase, lipase, alkaline phosphatase not to exceed 1.5x upper limit of normal (ULN)
- •Vital signs will be assessed in the supine position and must be within the following ranges:
- •Oral body temperature between 35-37oC inclusive
- •Systolic blood pressure between 90-140 mmHg inclusive
- •Diastolic blood pressure between 55-90 mmHg inclusive
- •Pulse rate between 45-90 bpm inclusive
排除标准
- •Presence of a significant medical condition (e.g., psychiatric conditions such as significant anxiety, depression, or somatization disorder; gastrointestinal disease, such as peptic ulcer, symptoms or evidence of active gastritis/dyspepsia, gastroesophageal reflux disease, inflammatory bowel disease, or irritable bowel syndrome (as suggested by medical history or medical diagnosis); history of major gastrointestinal surgery; or laboratory abnormalities that in the opinion of the investigator preclude participation in the study. Significant medical conditions include HIV, active Hepatitis B or C infection, ongoing immunosuppression for any reason, autoimmune disease, any underlying cardiac, pulmonary, endocrine, or renal conditions, any gastrointestinal illness (chronic reflux, inflammatory bowel disease, ulcer), any diabetes mellitus, and other such illnesses that can put a volunteer at increased risk. Exclusionary laboratory abnormalities include any abnormality that is grade 2 or above, or any two grade 1 laboratory abnormalities.
- •Immunosuppressive illness or evidence of IgA deficiency (serum IgA levels outside the normal range). This includes any disease that requires immunosuppressive medication such corticosteroids, monoclonal antibodies that target key aspects of the immune system (e.g. rituximab or TNF-blockers, or any autoimmune disease).
- •Positive serology results for HIV, HBsAg, or HCV antibodies, and confirmatory tests if appropriate.
- •Positive urine drug screen (positive for the presence of amphetamines, barbiturates, opiates, phencyclidine, cocaine, benzodiazepines, methadone, and propoxyphene at screening and at the discretion of the study physician, with the exception of stable persons with a diagnosis of ADHD that is well-controlled with a prescribed amphetamine.
- •History of alcohol abuse in the past 3 months or drug abuse in the past year
- •Significant abnormalities in screening laboratory hematology, serum chemistry or electrocardiogram, as determined by the PI or PI in consultation with the Medical Monitor and Sponsor. Significant ECG abnormalities include the following:
- •PR > 220 msec
- •QRS complex > 120 msec
- •QTcF > 450 msec (male) or >460 msec (female)
- •Serum bilirubin exceeds upper limit of normal
- •Use of any medication known to affect immune function (e.g., corticosteroids and others) within 30 days preceding receipt of the investigational products or planned to be used during the active study period. Any regular systemic corticosteroid will be exclusionary, while topical, intranasal, and inhaled steroids will be permitted.
- •Nursing or lactating on the day of admittance to the inpatient unit.
- •Inability to tolerate 150 ml of sodium bicarbonate buffer.
- •Recent vaccination (including licensed vaccines) or receipt of an investigational product (within 30 days before challenge through 30 days following the challenge dose).
- •History of diarrhea (> 3 unformed or liquid stools over a 24-hour period) in the 2 weeks prior to the planned inpatient phase.
- •Fewer than 3 stools per week or more than 3 stools per day as the usual frequency, or loose or liquid stools other than on an occasional basis.
- •Regular use of laxatives or any agent that increases gastric pH (regular defined as at least weekly).
- •Use of proton pump inhibitors, H2 blockers, or antacids within 48 hours of dosing.
- •A fever (≥38.0°C) in the 2 weeks prior to time of challenge.
- •Use of antibiotics during the 30 days before bacterial dosing or receipt of more than 3 courses of antibiotics over the two months prior to dosing.
- •Blood or plasma donation of one pint or more within 30 days preceding the receipt of the investigational products.
- •Lactose intolerance or allergy to milk or milk products.
- •Employment as a health care worker, food handler, childcare worker, or caregivers for elderly or immunocompromised individuals.
- •Allergy to fluoroquinolones, trimethoprim-sulfamethoxazole, doxycycline, or ampicillin/penicillin (excluded if allergic to two of four).
- •History of microbiologically confirmed ETEC infection in the last 3 years.
- •Occupation involving handling of ETEC currently, or in the past 3 years.
- •Symptoms consistent with travelers' diarrhea defined as >3 unformed or liquid stools over a 24 hour period concurrent with travel to countries where ETEC infection is endemic (most of the developing world) within 3 years prior to dosing, OR planned travel to endemic countries during the length of the study. ETEC endemic countries include all countries in Asia (except for Japan and South Korea) the Middle East, Africa, Mexico, Central and South America.
- •Vaccination for or ingestion of ETEC, cholera, Shigella, or E. coli heat-labile toxin within 5 years prior to dosing.
- •Any prior experimental infection with ETEC strain H10407, or prior experimental infection with other ETEC strains or other bacterial enteric pathogens (Salmonella, Shigella, and Campylobacter) within the past 5 years.
研究组 & 干预措施
Travelan
IMM-124E (Travelan) is the investigational product. Travelan 1200mg will be taken orally for 7 days.
干预措施: Travelan (Biological)
Placebo
ProMilk 85 milk powder is the placebo. Placebo has been manufactured into tablets using the same manufacturing process as Travelan. The same dosing schedule of 1200mg will be taken orally once-daily for 7 days.
干预措施: Placebo (Other)
结局指标
主要结局
To measure the protective efficacy of oral administration of Travelan compared to placebo against moderate-to-severe diarrhea following with E.coli (ETEC) challenge.
时间窗: Monitoring for the Inpatient Study Phase, Study Days -3 to Day 8 or day of dismissal from the clinical trial facility
The number of subjects who encounter moderate to severe diarrhea (defined as ≥4 Grade 3-5 stools in any 24-hour period post-challenge or ≥401 grams of Grade 3-5 stools in any 24-hour period post-challenge) will be recorded for the Travelan group and the placebo group. All stool samples will be collected, weighed and graded. Stool grading scale: Grade 1 = Fully formed (normal) Grade 2 = Soft (normal) Grade 3 = Thick liquid (diarrheal) Grade 4 = Opaque watery (diarrheal) Grade 5 = Rice-water (diarrheal). Diarrhea (Grade 3-5 stools) severity in a 24 hour period (1g = 1ml): 1-mild (2-3 loose/liquid stool totaling \<400 g), 2-moderate (4 to 5 loose/liquid stools or \>401 to 800 g), 3-severe (6 or more loose/liquid stools totaling \>800 g).
次要结局
- Subjects requiring oral rehydration solution and/or intravenous fluids post ETEC challenge for the Travelan group and the placebo group(Monitoring post challenge on Study Days 1-8 or Day of dismissal from the clinical trial facility.)
- Density of ETEC organisms in post-challenge stool samples at 48 hours post ETEC challenge for the Travelan group and the placebo group(Monitoring on Study Day 3 or 48 hours post challenge)
- Safety and tolerability of oral doses of Travelan compared to placebo. Measurement ofthe number of AEs graded as moderate-to-severe (Grade 2-4) for Diarrhea, fever, vomiting and other listed AEs as assessed using the CTCAE v5.0 criteria for AEs.(Monitoring for the inpatient study phase: Study Days -3 to Day 8 or day of dismissal from the clinical trial facility.])
- Percent of subjects with severe diarrhea post ETEC challenge for the Travelan group and the placebo group(Monitoring post challenge on Study Days 1-8 or Day of dismissal from the clinical trial facility.)