Clinical trial NCT04992520: Controlled Human Infection Model Challenge/Rechallenge
Official title: Controlled Human Infection Model Challenge/Rechallenge: Shigella Flexneri 2a and S. Sonnei Cross-protective Antigens Discovery in Healthy Adults in the United States
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Shigellosis
Lead sponsor: PATH
Sponsor class: OTHER
Collaborators: name: United States Department of Defense
name: Johns Hopkins University Center for Immunization Research (CIR)
First posted: 2021-08-05
Enrollment: 46
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

Brief summary: The goal of this study is to better understand Shigella immunity. The study will compare the shigellosis rate in participants previously challenged with a different Shigella serotype to the attack rate in participants not previously exposed to Shigella (naive participants).

Detailed description: This is a single-center controlled human infection model (CHIM) study designed to assess the cross-protective efficacy and markers of protection after challenge and heterologous rechallenge with Shigella strains of different serotypes in naïve healthy adult volunteers.

Eligibility criteria: Inclusion Criteria:

1. Healthy adults, male or female, aged 18 to 50 years (all inclusive) at the time of enrollment.
2. General good health, without clinically significant medical history, physical examination findings, or clinical laboratory abnormalities per judgment of Principal Investigator (PI).
3. Willingness to participate in the study after all aspects of the protocol have been explained and written informed consent obtained.
4. Completion of a training session and demonstrated comprehension of the protocol procedures and knowledge of Shigella-associated illness by passing a written examination (70% passing score).
5. Availability for the study duration, including all planned follow-up visits.
6. Female participants must have a negative pregnancy test at screening and prior to each challenge.
7. Female participants must agree to avoid pregnancy for 29 days following the last challenge dose by use of an efficacious hormonal or barrier method of birth control during the study. Abstinence is acceptable. Female participants unable to bear children must have this documented (e.g., tubal ligation or hysterectomy).
8. Willingness to refrain from participation in a study of another investigational agent for 90 days following the last challenge dose.

Exclusion Criteria:

1. Presence of a significant medical or psychiatric condition that in the opinion of the investigator precludes participation in the study. Some medical conditions that are adequately treated and stable would not preclude entry into the study.
2. Clinically significant abnormalities in screening on physical exam or screening laboratory results as determined by PI or PI in consultation with the research monitor and Sponsor.
3. Recent receipt of another investigational product (within 30 days before enrollment).
4. Positive enzyme-linked immunosorbent assay (ELISA) and confirmatory tests for human immunodeficiency virus (HIV).
5. Positive hepatitis C (HCV) ELISA and confirmatory test (e.g., HCV ribonucleic acid (RNA)).
6. Positive hepatitis B virus surface antigen (HBsAg) by ELISA.
7. Use of any medication that affects immune function (e.g., corticosteroids and others) within 30 days preceding the first challenge or planned use during the active study period (topical and ophthalmologic steroids are allowable).
8. Evidence of impaired immune function or immune compromise (known immunodeficiency syndrome; either congenital, acquired, or iatrogenic; active autoimmune disease; repeated serious infections without known cause).
9. Immunoglobulin A (IgA) deficiency (serum IgA \< 7 mg/dL or below the limit of detection of the assay).
10. Positive blood test for human leukocyte antigen (HLA)-B27.
11. Personal or family history of an inflammatory arthritis.
12. Currently pregnant or nursing.
13. Have household contacts who are \< 2 years old or \> 80 years old or infirm or immunocompromised.
14. Employment as a health care worker with direct patient care, in a daycare center (for children or the elderly), or direct food handler; includes individuals who work directly with food in commercial establishments.
15. Evidence of current alcohol or drug dependence, or history of dependence in the last 6 months.
16. Recent vaccination (including licensed vaccines) or receipt of an investigational product (within 30 days before challenge through 90 days following the last challenge dose). Annual influenza vaccine, an emergency authorized or licensed COVID-19 vaccine, or a TdaP or Travelers' diarrhea (TD) booster may be administered beyond 30 days after each challenge.
17. Treatment with immunoglobulins or blood products within 3 months of challenge.
18. Current or prior history of inflammatory bowel disease or irritable bowel syndrome or abnormal stool pattern (\> 3/day or \< 3/ week, or loose or liquid stools).
19. Chronic use of anti-diarrheal, anti-constipation, or antacid therapy; or use of these medications in the 7 days prior to challenge.
20. Use of proton pump inhibitors or H2 blockers (H2-receptor antagonists) within 48 hours prior to challenge.
21. Use of antibiotics within 7 days prior to challenge.
22. Known allergy to any 2 of the following antibiotics: ciprofloxacin, trimethoprim-sulfamethoxazole, or penicillin.
23. Symptoms of travelers' diarrhea associated with travel to countries where Shigella or other enteric infections are endemic (most of the developing world) within 3 years prior to challenge OR planned travel to endemic countries during the active study period.
24. History of shigellosis, Shigella vaccination or challenge, or a laboratory worker with known exposure to Shigella within the last 5 years.
25. Serum immunoglobulin G (IgG) titer \> 2500 to either Shigella flexneri 2a or Shigella sonnei lipopolysaccharide.
26. Any other criteria which, in the investigator's opinion, would compromise the ability of the volunteer to participate in the study, the safety of the study, or the results of the study.

Primary outcomes:
measure: Percentage of Participants With Shigellosis Following Shigella Challenge
timeFrame: 8 days after challenge administration (Days 1-8 and Days 90-97 for challenge 2)
Secondary outcomes:
measure: Maximum Volume of Loose Stools in Any 24-hour Period
timeFrame: 8 days after challenge administration (Days 1-8 and Days 90-97 for challenge 2)
measure: Percentage of Participants With Severe Diarrhea
timeFrame: 8 days after challenge administration (Days 1-8 and Days 90-97 for challenge 2)
measure: Percentage of Participants With Diarrhea of Any Severity
timeFrame: 8 days after challenge administration (Days 1-8 and Days 90-97 for challenge 2)
measure: Total Weight of Grade 3-5 Stools Per Participant After Challenge
timeFrame: 8 days after challenge administration (Days 1-8 and Days 90-97 for challenge 2)
measure: Percentage of Participants With Nausea, Vomiting, Anorexia, Abdominal Pain/Cramps Rated as Moderate to Severe
timeFrame: 8 days after challenge administration (Days 1-8 and Days 90-97 for challenge 2)
measure: Percentage of Participants With Dysentery
timeFrame: 8 days after challenge administration (Days 1-8 and Days 90-97 for challenge 2)
measure: Time to Onset of Diarrhea
timeFrame: From challenge administration to the end of the 8-day inpatient period (Days 1-8 and Days 90-97 for challenge 2)
measure: Number of Participants With More Severe Diarrhea
timeFrame: 8 days after challenge administration (Days 1-8 and Days 90-97 for challenge 2)
measure: Number of Participants With Fever After Challenge
timeFrame: 8 days after challenge administration (Days 1-8 and Days 90-97 for challenge 2)
measure: Shigella Clinical Severity Score
timeFrame: 8 days after challenge administration (Days 1-8 and Days 90-97 for challenge 2)
measure: Number of Colony Forming Units (CFUs) of the Challenge Strain Per Gram of Stool
timeFrame: 8 days after challenge administration (Days 1-8 and Days 90-97 for challenge 2)
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: Center for Immunization Research (CIR) at Johns Hopkins School of Public Health (JHSPH)
state: Maryland
Study officials:
affiliation: Johns Hopkins University
name: Kawsar Talaat, MD
role: PRINCIPAL_INVESTIGATOR
References: