Shigellosis
Conditions
Keywords
bacteriophage, phage, Shigella
Brief summary
The study is a first-in-human Phase 1/2a randomized, double-blind, placebo-controlled trial to assess the clinical safety and efficacy of ShigActive in healthy adults with experimental Shigella challenge.
Detailed description
The purpose of this study is to determine if ShigActive is safe and effective in healthy adults in a continuous Phase 1/2a trial. Phase 1 will asses the safety of ShigActive in healthy adults, while Phase 2a will evaluate the safety and efficacy of ShigActive in healthy adults after a challenge with Shigella. ShigActive is a collection of bacteriophages. Bacteriophages (or phages) are viruses that infect only bacteria. The phages in ShigActive infect a specific type of bacteria called Shigella, which is the causative agent of shigellosis or dysentery. ShigActive is intended to significantly reduce or eliminate Shigella levels in the human gastrointestinal tract, which in turn, is anticipated to reduce the incidence and/or severity of shigellosis.
Interventions
BIOLOGICALbacteriophage
A cocktail of lytic Shigella-specific bacteriophages orally administered with sodium bicarbonate solution
OTHERPlacebo
Placebo orally administered with sodium bicarbonate solution
Sponsors
University of Maryland, Baltimore
Intralytix, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
1. Age 18 to 50 years. 2. Access to CVD clinical site and available and willing to be followed for the planned duration of the study, including all follow-up visits. 3. Able and willing to provide informed consent. 4. Willing to participate after all aspects of trial explained. 5. Assessment of understanding: 1. Volunteer demonstrates understanding of this study; 2. Completes a questionnaire prior to first treatment with verbal demonstration of understanding of all questionnaire items answered incorrectly; 3. Receives a passing score of 70% or higher on the Comprehension Assessment Tool. 6. Agrees not to enroll in another study of an investigational research agent during the study, with the exception of potentially life-saving or COVID-19-related experimental treatments. 7. Good general health as shown by medical history, physical exam, and screening laboratory tests or clinical laboratory abnormalities per clinical judgment of the PI. 8. Agrees not to donate blood or blood products during participation in the study or for 30 days after completion of study participation. 9. Within normal/acceptable laboratory ranges during screening including: 1. Absolute neutrophil count (1,500-8,000/mm\^3; 1,200-8,000/mm\^3 for African-American subjects); 2. Bilirubin (\<1.4 mg/dL unless known Gilbert's syndrome, then \>2.0 mg/dL); 3. Serum IgA (≥70 mg/dL or below lower limit of normal range); 4. HLA-B27 negative (Phase 2a only); 5. Stool culture (No Salmonella, Shigella, Campylobacter, Yersinia; presence of normal flora; no pathogenic protozoa by microscopic examination). 10. Hemoglobin ≥11.5 g/dL for volunteers who were assigned female sex at birth, ≥13.0 g/dL for volunteers who were assigned male sex at birth. a. For transgender participants who have been on hormone therapy for more than 6 consecutive months, determine hemoglobin eligibility based on the gender with which they identify (i.e., a transgender female who has been on hormone therapy for more than 6 consecutive months should be assessed for eligibility using the hemoglobin parameters for persons assigned female sex at birth). 11. White blood cell count = 3,300 to 11,000 (2,800-11,000 for African-Americans) cells/mm\^3. 12. Total lymphocyte count ≥800 cells/mm\^3. 13. Remaining differential either within institutional normal range or with site physician approval. 14. Platelets = 125,000 to 450,000/mm\^3. 15. Chemistry panel: alanine aminotransferase (ALT) \<1.25 times the institutional upper limit of normal and creatinine ≤ institutional upper limits of normal. 16. Negative HIV-1 and -2 blood test: must have a negative FDA-approved enzyme immunoassay (EIA). 17. Negative for HBsAg. 18. Negative for HCV antibody. 19. Volunteers who were assigned female sex at birth: negative serum or urine beta human chorionic gonadotropin (β-HCG) pregnancy test performed prior to enrollment and within 24 hours of initial treatment. a. Persons who are NOT of reproductive potential due to having undergone total hysterectomy or bilateral oophorectomy are not required to undergo pregnancy testing. 20. Reproductive status: A volunteer who was assigned female sex at birth must agree to use adequate contraception, defined as consistent and correct use of an FDA-recommended contraceptive method or combination of methods in accordance with the product label. For example: 1. Barrier method (such as condoms, diaphragm, or cervical cap) used in conjunction with spermicide, and another method such as prescription hormonal contraceptive; 2. Intrauterine device (IUD); 3. Prescription hormonal contraceptive taken or administered via oral (pill), transdermal (patch) subdermal, or intramuscular route used in combination with another method, such as barrier methods; 4. Total abstinence; 5. Sterilization of a female participant's monogamous male partner prior to entry into the study; 6. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation. 21. Volunteers who were assigned female sex at birth must also agree not to seek pregnancy through alternative methods, such as artificial insemination or in vitro fertilization until after the last required protocol clinic visit. 22. Phase 2a only: Available for a 12-day inpatient stay. 23. Phase 2a only: Fully vaccinated against COVID-19 for at least 30 days prior to enrollment. 24. Phase 2a only: Successful completion of inpatient acclimation period on Day -1.
Exclusion criteria
1. Blood products received within 120 days before first treatment. 2. Investigational research agents received within 30 days before first treatment. 3. Body mass index (BMI) less than 19.0 kg/m2 or greater than 36.0 kg/m2. 4. Pregnant or breastfeeding. 5. Poor venous access, as defined by inability to obtain venous blood after 3 venipuncture attempts. 6. Persons whose occupation involves the handling of ETEC, cholera, or Shigella bacteria. 7. Regular (one time per week or more) use of antidiarrheals, stool softeners, laxatives, antacids, or other agents to lower stomach acidity. 8. Use of oral or IV antimicrobials within 2 weeks of study start or planned use during active study phase. 9. Proton pump inhibitors, H2 blockers or antacids within 48 hours prior to dosing or planned use during active study phase. 10. Abnormal bowel patterns, defined by \<3 stools per week or \>2 stools per day on average over the past 6 months. 11. Taking supplemental probiotics in the form of pills or tablets within 2 weeks of enrollment or during study period. 12. Received prior vaccines, challenges or known exposure to (e.g., laboratory worker) Shigella within the past 3 years. 13. Live attenuated vaccines received within 30 days before first study treatment or scheduled within 14 days after the first study treatment (e.g., measles, mumps, and rubella \[MMR\]; oral polio vaccine \[OPV\]; varicella; yellow fever; live attenuated influenza vaccine). 14. Any vaccines that are not live attenuated vaccines and were received within 14 days prior to first treatment (e.g., COVID-19, tetanus, pneumococcal, hepatitis A or B). 15. Allergy treatment with antigen injections within 30 days before first treatment or that are scheduled within 14 days after first treatment. 16. Immunosuppression as the result of an underlying illness 17. Immunosuppressive medications received within 30 days before first treatment or planned use during study (Not exclusionary: 1) corticosteroid nasal spray; 2) inhaled corticosteroids; 3) topical corticosteroids for mild, uncomplicated dermatitis; or 4) a single course of oral/parenteral prednisone or equivalent at doses \<60 mg/day and length of therapy \<11 days with completion at least 30 days prior to enrollment). 18. Immunoglobulin received within 60 days before first treatment. 19. Autoimmune disease (Not exclusionary: mild, well-controlled psoriasis). 20. History of myocarditis, pericarditis, cardiomyopathy, congestive heart failure with permanent sequelae, clinically significant arrhythmia (including any arrhythmia requiring medication, treatment, or clinical follow-up.) 21. Clinically significant medical condition, physical examination findings, clinically significant abnormal laboratory results, or past medical history with clinically significant implications for current health. A clinically significant condition or process includes but is not limited to: 1. A process that would affect the immune response; 2. A process that would require medication that affects the immune response; 3. Any contraindication to repeated injections or blood draws; 4. A condition that requires active medical intervention or monitoring to avert grave danger to the volunteer's health or well-being during the study period; 5. A condition or process for which signs or symptoms could be confused with reactions to treatment or challenge; 6. Any condition specifically listed among the
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1: Number and Severity of Solicited and Unsolicited Adverse Reactions | Up to Day 90 | Number of subjects reporting solicited and unsolicited AEs, laboratory measures of safety, and adverse (up to Day 29) and serious adverse events (up to Day 90) following treatment with ShigActive or placebo |
| Phase 2a: Number of Solicited and Unsolicited Adverse Reactions | Up to Day 90 | Number of subjects reporting solicited and unsolicited AEs, laboratory measures of safety, and adverse (up to Day 29) and serious adverse events (up to Day 90) following treatment with ShigActive or placebo |
| Phase 2a: Onset of Clinical Shigellosis Post-Challenge | Day 2 to Day 7 (Post-Challenge) | Clinical shigellosis with onset during Day 2 to Day 7 post-challenge, defined as fever, diarrhea, and/or dysentery |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 2a: Onset of Moderate-to-Severe Shigellosis Post-Challenge | Day 2 to Day 7 (Post-Challenge) | Moderate-to-severe shigellosis with onset during Day 2 to Day 7 post-challenge, defined using graded disease severity scoring methods (Grade 3 \[mild\] to Grade 5 \[severe\]) defined by number of loose stools, fever, dysentery, and abdominal cramping |
| Phase 2a: Severity of Shigellosis Symptoms | Day 2 to Day 7 (Post-Challenge) | Severity of shigellosis symptoms (e.g., diarrhea, dysentery, fever) using graded severity scoring methods (Grade 1 \[mild\] to Grade 3 \[severe\]) |
| Phase 2a: Number of Shigella Organisms Secreted in Stool | Up to Day 15 | Qualitative and quantitative (mean, median and geometric mean colony forming units \[CFUs\]) assessment of Shigella challenge strain shedding in stool samples following treatment with ShigActive or placebo, and challenge with Shigella |
Other
| Measure | Time frame | Description |
|---|---|---|
| Phase 2a: Number of Shigella-specific Bacteriophage Shed in Stool | Up to Day 15 | Quantitation (mean, median and geometric mean PFUs) of bacteriophage shedding in stool samples following treatment with ShigActive or placebo |
| Phase 1: Number of Shigella-specific Bacteriophage Shed in Stool | Up to Day 29 | Quantitation (mean, median and geometric mean plaque forming units \[PFUs\]) of bacteriophage shedding in stool samples following treatment with ShigActive or placebo |
| Phase 2a: Geometric Mean Anti-Shigella Antibody Titers | Up to Day 90 | Magnitude of response (geometric mean titer \[GMT\] and geometric mean peak titer) of fecal and serum IgA and IgG antibodies to LPS and Ipas following treatment with ShigActive or placebo and challenge with Shigella |
| Phase 2a: Geometric Mean anti-LPS Antibody Secreting Cell (ASC) Responses | Up to Day 8 | Quantitation (point estimate, 95% confidence interval \[CI\], mean, median and geometric mean) of IgG anti-LPS ASC responses in circulating peripheral blood mononuclear cells (PBMCs) following treatment with ShigActive or placebo, and challenge with Shigella |
| Phase 1: Effect on Gut Microbiome Community States | Up to Day 29 | Assess the effect of oral phage administration on the gut microbiome in stool samples following treatment with ShigActive or placebo using next generation sequencing |
Countries
United States
Outcome results
None listed