A Phase 2b, Double-Blind, Placebo Controlled Trial to Evaluate the Efficacy of Intramuscularly Administered CssBA+dmLT Against Moderate-severe Diarrhea in a Controlled Human Infection Model With Enterotoxigenic Escherichia Coli (ETEC) Strain B7A in Healthy Adults
Overview
- Phase
- Phase 2
- Intervention
- CssBA
- Conditions
- Escherichia Infection
- Sponsor
- National Institute of Allergy and Infectious Diseases (NIAID)
- Enrollment
- 72
- Locations
- 2
- Primary Endpoint
- Number and percentage of CssBA+dmLT injected participants experiencing SAEs
- Status
- Completed
- Last Updated
- 15 days ago
Overview
Brief Summary
The study is designed to evaluate the safety, immunogenicity, and efficacy of the intramuscular administration of a CS6 based vaccine (CssBA) against ETEC co-administered with double mutant labile toxin (dmLT) in preventing moderate-severe diarrhea (MSD) following challenge with ETEC strain B7A in healthy adults. Approximately 72 adult participants, divided into 4 cohorts of 18, will be randomized 1:1 to receive vaccine (45 micrograms CssBA with 0.5 micrograms dmLT) or placebo (normal saline) on an outpatient basis. All participants will receive 3 intramuscular (IM) doses of vaccine or placebo at 3-week intervals (days 1, 22 and 43). Following vaccination, participants will be followed as outpatients for safety using a memory aid from the time of each vaccination through 7 days post each vaccination. Approximately 28 days (plus or minus 1 day) after receipt of the 3rd dose of study agent, participants meeting challenge criteria will be admitted to an inpatient unit and be administered an oral dose of 1 x 10^10 cfu (colony-forming unit) of ETEC strain B7A. Five days after challenge, participants will be treated with ciprofloxacin, except in cases of known allergy or intolerance. Participants will be discharged from the inpatient unit when they have completed their 3-day antibiotic course and are able to care for themselves. After discharge from the inpatient unit, participants will return for clinic visits and have a phone visit to provide any updates on medication, medical history and AE/SAEs. The primary objectives are: 1) Estimate CssBA+dmLT efficacy in preventing moderate-severe diarrhea (MSD) following challenge with ETEC strain B7A in healthy adults. 2) Evaluate the safety of intramuscular injection of CssBA+dmLT.
Detailed Description
The study is designed to evaluate the safety, immunogenicity, and efficacy of the intramuscular administration of a CS6 based vaccine (CssBA) against ETEC co-administered with double mutant labile toxin (dmLT) in preventing moderate-severe diarrhea (MSD) following challenge with ETEC strain B7A in healthy adults. Approximately 72 adult participants, divided into 4 cohorts of 18, will be randomized 1:1 to receive vaccine (45 micrograms CssBA with 0.5 micrograms dmLT) or placebo (normal saline) on an outpatient basis. All participants will receive 3 intramuscular (IM) doses of vaccine or placebo at 3-week intervals (days 1, 22 and 43). Following vaccination, participants will be followed as outpatients for safety using a memory aid from the time of each vaccination through 7 days post each vaccination. Approximately 28 days (plus or minus 1 day) after receipt of the 3rd dose of study agent, participants meeting challenge criteria will be admitted to an inpatient unit and be administered an oral dose of 1 x 10\^10 cfu (colony-forming unit) of ETEC strain B7A. After receipt of challenge agent, the participant will fast for 90 minutes. Participants will be monitored daily for diarrhea and other signs/symptoms of enteric illness. All stool will be collected and graded, and loose stools (grade 3-5) will be weighed. Five days after challenge (or earlier if clinically indicated), participants will be treated with ciprofloxacin, except in cases of known allergy or intolerance in which case trimethoprim-sulfamethoxazole will be used. Participants will be discharged from the inpatient unit when they have completed their 3-day antibiotic course and are able to care for themselves, including maintaining hydration status. Follow-up outpatient visits for 5 days and 4 weeks after discharge will monitor safety and immunologic parameters, and a phone visit will be conducted 6 months after last dose of study agent. The primary objectives are: 1) Estimate CssBA+dmLT efficacy in preventing moderate-severe diarrhea (MSD) following challenge with ETEC strain B7A in healthy adults. 2) Evaluate the safety of intramuscular injection of CssBA+dmLT. The secondary objectives are: 1)Determine illness severity following ETEC B7A challenge in participants who received CssBA+dmLT vs placebo using an evidence-based disease severity score (1). 2)Evaluate ETEC CS6- and LT-specific serum IgG and IgA responses following vaccination and challenge. 3)Evaluate ETEC CS6- and LT-specific IgG and IgA in Antibodies from Lymphocyte Supernatant (ALS) following vaccination and 4) Determine the prevalence and duration of fecal shedding of B7A following challenge.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Non-pregnant, non-breast-feeding adults, age 18 to 49 years (inclusive) at the time of enrollment.
- •Willing and able to sign and date informed consent document prior to study procedures.
- •Stated willingness to be available for all study visits and comply with all trial procedures throughout the duration of the trial, including adherence to Lifestyle Considerations.
- •Participants of childbearing potential must have a negative pregnancy test at study enrollment.
- •For participants of childbearing potential\*: agree to use highly effective contraception with heterosexual intercourse for at least 1 month prior to the first vaccination through at least two months after receipt of the challenge agent or last dose of study product if not challenged. True abstinence is also acceptable.
- •Childbearing potential in a participant assigned female at birth is defined as not sterilized via tubal ligation, bilateral oophorectomy, salpingectomy, hysterectomy, or successful Essure(R) placement (permanent, non-surgical, non-hormonal sterilization) with documented radiological confirmation test at least 90 days after the procedure, and still menstruating or \<1 year of the last menses if menopausal.
- •Acceptable forms of highly effective contraception for participants assigned female at birth include same sex relationships, abstinence from sexual intercourse with a male partner, monogamous relationship with vasectomized partner who has been vasectomized for 180 days or more prior to the participant enrollment, barrier methods such as condoms or diaphragms with spermicide, effective intrauterine devices, NuvaRing(R), and licensed hormonal methods such as implants, injectables, or oral contraceptives ("the pill"). Periodic abstinence \[e.g., calendar, ovulation, symptothermal, post-ovulation methods\] and withdrawal are not acceptable methods of contraception.
- •Body mass index (BMI) 19 to less than 40 kg/m\^2 at screening.
- •In good health. As determined by medical history and physical examination to evaluate acute or ongoing chronic medical diagnoses/conditions that have been present for at least 90 days, which would affect the assessment of safety of participants and interpretations of the scientific aims of the trial. Chronic medical diagnoses/conditions should be stable for the last 60 days (no hospitalizations, ER, or urgent care for condition or need for supplemental oxygen). This includes no change in chronic prescription medication, dose, or frequency as a result of deterioration of the chronic medical diagnosis/condition in the 60 days before enrollment. Any prescription change that is due to change of health care provider, insurance company, etc., or done for financial reasons, and in the same class of medication, will not be considered a deviation of this inclusion criterion. Any change in prescription medication due to improvement of a disease outcome, as determined by the Principal or sub-Investigator licensed to make medical diagnosis, will not be considered a deviation of this inclusion criterion. Participants may be on chronic or as needed (prn) medications if, in the opinion of the participating site PI or appropriate sub-investigator, they pose no additional risk to participant safety or assessment of reactogenicity and immunogenicity, and do not indicate a worsening of medical diagnosis/condition. Similarly, medication changes subsequent to enrollment and trial vaccination are acceptable provided the change was not precipitated by deterioration in the chronic medical condition, and there is no anticipated additional risk to the participant or interference with the evaluation of responses to trial vaccination.
- •Oral temperature is less than 100.4 degrees Fahrenheit (38 degrees Celsius) at the time of enrollment.
Exclusion Criteria
- •Abnormal stool pattern (fewer than 3 stools per week or more than 3 stools per day) on a regular basis; loose or liquid stools on other than an occasional basis.
- •History of microbiologically confirmed ETEC or cholera infection in the last 3 years.
- •Symptoms consistent with MSD concurrent with travel to countries where ETEC infection is endemic (refer to MOP section for a list of endemic countries) within 3 years prior to enrollment.
- •Vaccination for, ingestion of or occupational handling of ETEC, cholera, or E. coli heat labile toxin within 3 years prior to enrollment.
- •Any condition that, in the judgment of the investigator, precludes participation because it could affect participant safety or endpoint evaluation.
- •Unable to understand spoken and written English.
- •Venous access deemed inadequate for phlebotomy/cannulation needs of the study.
- •Have any disease or medical condition that, in the opinion of the Principal or sub-Investigator licensed to make medical diagnosis, is a contraindication to study participation. These include:
- •History within the past 12 months of inflammatory bowel disease (IBD) (including ulcerative colitis, Crohn's disease, indeterminate colitis, or celiac disease), irritable bowel syndrome (IBS), or any active uncontrolled gastrointestinal disorders or diseases as assessed by the investigator.
- •Within the past 12 months have symptoms or evidence of active gastritis or severe gastroesophageal reflux disease not well controlled on medication, gastric surgery, or gastric acid hyper-secretory disorders (e.g., Zollinger-Ellison syndrome), gastrointestinal obstruction, ileus, gastric retention, bowel perforation, toxic colitis, persistent infectious gastroenteritis, persistent or chronic diarrhea of unknown etiology, Clostridium difficile infection.
Arms & Interventions
Cohort 2A
Participants will receive 45 mcg CssBA with 0.5 mcg dmLT vaccine intramuscular injection on Days 1, 22 and 43, outpatient. Participants who meet the challenge criteria will orally receive 1x10\^10 cfu of ETEC strain B7A, inpatient, approximately 28 days after the third dose of study agent. N= 18.
Intervention: CssBA
Cohort 1A
Participants will receive 45 mcg CssBA with 0.5 mcg dmLT vaccine intramuscular injection on Days 1, 22 and 43, outpatient. Participants who meet challenge criteria will orally receive 1x10\^10 cfu of ETEC strain B7A, inpatient, approximately 28 days after the third dose of study agent. N= 18.
Intervention: B7A (ETEC challenge strain)
Cohort 1A
Participants will receive 45 mcg CssBA with 0.5 mcg dmLT vaccine intramuscular injection on Days 1, 22 and 43, outpatient. Participants who meet challenge criteria will orally receive 1x10\^10 cfu of ETEC strain B7A, inpatient, approximately 28 days after the third dose of study agent. N= 18.
Intervention: CssBA
Cohort 1A
Participants will receive 45 mcg CssBA with 0.5 mcg dmLT vaccine intramuscular injection on Days 1, 22 and 43, outpatient. Participants who meet challenge criteria will orally receive 1x10\^10 cfu of ETEC strain B7A, inpatient, approximately 28 days after the third dose of study agent. N= 18.
Intervention: dmLT
Cohort 1B
Participants will receive 0.6 mL of 0.9% normal saline intramuscular injection on Days 1, 22 and 43, outpatient. Participants who meet challenge criteria will orally receive 1x10\^10 cfu of ETEC strain B7A, inpatient, approximately 28 days after the third dose of study agent . N= 18.
Intervention: B7A (ETEC challenge strain)
Cohort 1B
Participants will receive 0.6 mL of 0.9% normal saline intramuscular injection on Days 1, 22 and 43, outpatient. Participants who meet challenge criteria will orally receive 1x10\^10 cfu of ETEC strain B7A, inpatient, approximately 28 days after the third dose of study agent . N= 18.
Intervention: Placebo
Cohort 2A
Participants will receive 45 mcg CssBA with 0.5 mcg dmLT vaccine intramuscular injection on Days 1, 22 and 43, outpatient. Participants who meet the challenge criteria will orally receive 1x10\^10 cfu of ETEC strain B7A, inpatient, approximately 28 days after the third dose of study agent. N= 18.
Intervention: B7A (ETEC challenge strain)
Cohort 2A
Participants will receive 45 mcg CssBA with 0.5 mcg dmLT vaccine intramuscular injection on Days 1, 22 and 43, outpatient. Participants who meet the challenge criteria will orally receive 1x10\^10 cfu of ETEC strain B7A, inpatient, approximately 28 days after the third dose of study agent. N= 18.
Intervention: dmLT
Cohort 2B
Participants will receive 0.6 mL of 0.9% normal saline intramuscular injection on Days 1, 22 and 43, outpatient. Participants who meet the challenge criteria will orally receive 1x10\^10 cfu of ETEC strain B7A, inpatient, approximately 28 days after the third dose of study agent. N= 18.
Intervention: B7A (ETEC challenge strain)
Cohort 2B
Participants will receive 0.6 mL of 0.9% normal saline intramuscular injection on Days 1, 22 and 43, outpatient. Participants who meet the challenge criteria will orally receive 1x10\^10 cfu of ETEC strain B7A, inpatient, approximately 28 days after the third dose of study agent. N= 18.
Intervention: Placebo
Outcomes
Primary Outcomes
Number and percentage of CssBA+dmLT injected participants experiencing SAEs
Time Frame: Through 6 months after last vaccination
Number and percentage of CssBA+dmLT injected participants experiencing local solicited AEs
Time Frame: Through 7 days after vaccination
Number and percentage of CssBA+dmLT injected participants experiencing MAAEs
Time Frame: Through 6 months after last vaccination
Number and percentage of CssBA+dmLT injected participants experiencing systemic solicited AEs
Time Frame: Through 7 days after vaccination
Number and percentage of CssBA+dmLT injected participants experiencing unsolicited AEs
Time Frame: Through Day 71
Number and percentage of participants experiencing moderate-severe diarrhea (MSD) with Enterotoxigenic Escherichia coli (ETEC)
Time Frame: Day 70-79
MSD is defined as experiencing \>/=4 loose/liquid stools or \>/= 400 g of loose/liquid stools in any 24-hour period during inpatient stay.
Secondary Outcomes
- GMT summarizing maximum observed antigen-specific dmLT IgA antibody titer by ALS(Day 8 -Day 99)
- GMT summarizing the maximum observed antigen-specific CS6 IgA antibody titers by ALS(Day 8 - Day 99)
- Geometric Mean Titer (GMT) summarizing the maximum observed antigen-specific CS6 IgG antibody titers by Antibodies from Lymphocyte Supernatant (ALS)(Day 8 - Day 99)
- GMT of summarizing maximum observed antigen-specific dmLT IgG antibody titer by ALS(Day 8 -Day 99)
- Mean severity of ETEC B7A-associated diarrhea(Day 70 - Day 79)
- Median number of days with a positive stool culture for B7A following challenge(Day 70 - Day 79)
- Number and percentage of participants with >/= 4-fold rise from baseline in antigen-specific CS6 antibody titer to IgA in serum(Through Day 99)
- Number and percentage of participants with >/= 4-fold rise from baseline in antigen-specific CS6 antibody titer to IgG in serum(Through Day 99)
- Number and percentage of participants with >/= 4-fold rise from baseline in antigen-specific dmLT antibody titer to IgA in serum(Through Day 99)
- Number and percentage of participants with >/= 4-fold rise from baseline in antigen-specific dmLT antibody titer to IgG in serum(Through Day 99)
- Number and percentage of participants with a positive stool culture for B7A(Day 71 - Day 79)