Safety, Immunogenicity and Efficacy Study of Live Attenuated ETEC Vaccine ACE527 With and Without dmLT Adjuvant in Adults

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
PATH
ClinicalTrials.gov Identifier:
NCT01739231
First received: September 21, 2012
Last updated: May 13, 2014
Last verified: January 2014
  Purpose

This is a research study about an experimental (investigational) oral ETEC vaccine (ACE527). ACE527 is a live attenuated vaccine that is being made to prevent disease from enterotoxigenic Escherichia coli (ETEC), which causes watery diarrhea, largely in children living in developing countries and in travelers to those countries. This research study is also testing an investigational adjuvant called dmLT. An adjuvant is something that is added to a vaccine to make it work better. The purpose of this study is two-fold. First, Part A aims to find out if the vaccine by itself or the vaccine combined with the adjuvant is safe, tolerable, and initiates an immune response. Second, Part B aims to find out if the vaccine by itself or the vaccine combined with teh adjuvant prevents diarrheal disease when challenged with ETEC H10407. About 60 healthy adults, ages 18-50, will participate in Part A, and they will be required to stay in the research facility for several nights for the first dose, but will not be required to stay overnight for the second and third doses. Participants will be assigned to receive either the vaccine alone, the vaccine with adjuvant, or placebo by mouth. Study procedures include: stool samples, blood samples, and documentation of side effects. Participants will be involved in study related procedures for about 8 months.

Interested volunteers from Part A will along with volunteers who were never vaccinated in Part A will return to participate in Part B. These volunteers will be required to stay overnight in the research facility for several nights after challenge, after which they will be treated with antibiotics and sent home. Study procedures include stool samples, blood samples, and documentation of infection with ETEC H10407. If the vaccine with/without adjuvant is effective, the volunteers should not development diarrhea, but if the vaccine with/without adjuvant is not effective, the volunteers will have diarrhea for a few days.


Condition Intervention Phase
Diarrhea
Biological: ACE527
Biological: ACE527 + dmLT
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase 1/2b Randomized, Double-Blinded, Placebo-controlled Study to Assess the Safety, Reactogenicity, Tolerability, Immunogenicity and Efficacy of Live Attenuated ETEC ACE527 Vaccine Administered Alone or With a Double Mutant E. Coli Heat Labile Toxin (dmLT) in Healthy Adult Volunteers

Resource links provided by NLM:


Further study details as provided by PATH:

Primary Outcome Measures:
  • Number of Serious adverse events (SAEs) [ Time Frame: 6 months after the 3rd vaccination ] [ Designated as safety issue: Yes ]
  • Number of Adverse events leading to withdrawal [ Time Frame: 6 months after 3rd vaccination ] [ Designated as safety issue: Yes ]
  • Number of Grade 3 or higher adverse reactions [ Time Frame: 4 weeks after each vaccination ] [ Designated as safety issue: Yes ]
  • Number of solicited gastro-intestinal reactions [ Time Frame: 7 days after each vaccination ] [ Designated as safety issue: Yes ]
    Solicited reactogenicity is obtained via the Diary card and includes loose stools, diarrhea, nausea, vomiting, abdominal pain, urgency of defecation, malaise, headache, chill, fever, gurgling stomach, and anorexia within one week after each vaccination. To be analyzed by severity and duration.

  • Number of solicited systemic reactions [ Time Frame: 7 days after each vaccination ] [ Designated as safety issue: Yes ]
    Solicited systemic reactogenicity is obtained via the Diary card and includes fever, malaise and headache within one week after each vaccination. To be analyzed by severity and duration.

  • Number of unsolicited adverse events [ Time Frame: 4 weeks after each vaccination ] [ Designated as safety issue: Yes ]
    Obtained within four weeks after each vaccination. To be analyzed by severity, duration and relationship to vaccination.

  • Vaccine efficacy - prevention of severe diarrhea after challenge [ Time Frame: Baseline through 120 hour observation period ] [ Designated as safety issue: No ]

    The primary efficacy endpoint of the Phase 2b open challenge study is the prevention of severe diarrhea according to the following definition:

    • Severe diarrhea: >800 grams of grade 3-5 stools passed over the 120 hour observation period. Diarrhea episodes beginning at or before the first 120 hrs of observation will be followed to resolution and the total stool output weight will be considered in determining whether a volunteer meets the primary efficacy endpoint. The end of a diarrheal episode occurs when a volunteer does not pass any grade 3-5 stool within 24 hours.



Secondary Outcome Measures:
  • Immunogenicity [ Time Frame: Baseline through 84 days post-vaccination ] [ Designated as safety issue: No ]
    Antibody Lymphocyte Supernatant (ALS) assays and serology will be performed to assess the systemic and mucosal immunogenicity of the vaccine and vaccine/adjuvant combination. Microbiology will be utilized to assess the shedding pattern of ACE527. T and B cell assays will be carried out with specimens obtained within 24 hours prior to vaccination and 28 days following the last vaccination. Cytokine assays will be carried out wiht specimens obtained prior to initial vaccination and approximately 8, 24, 48 and 72 hours following each dose.


Enrollment: 57
Study Start Date: September 2012
Study Completion Date: January 2014
Primary Completion Date: October 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cohort 1
Three oral doses of ~10^10 cfu ACE527 (12 participants) or ~10^10 cfu ACE527 + 25 ug dmLT (12 participants) or placebo (6 participants)
Biological: ACE527
~10^10 cfu ACE527 administered on Days 0, 28, and 56
Biological: ACE527 + dmLT
~10^10 cfu ACE527 + 25 ug dmLT administered on Days 0, 28, and 56
Experimental: Cohort 2
Three oral doses of ~10^10 cfu ACE527 (12 participants) or ~10^10 cfu ACE527 + 25 ug dmLT (12 participants) or placebo (6 participants)
Biological: ACE527
~10^10 cfu ACE527 administered on Days 0, 28, and 56
Biological: ACE527 + dmLT
~10^10 cfu ACE527 + 25 ug dmLT administered on Days 0, 28, and 56

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years to 50 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Male and female healthy adults between 18 and 50 years of age at the time of enrollment.
  2. General good health, without clinically significant medical history, physical examination findings or clinical laboratory abnormalities per clinical judgment of PI.
  3. Negative pregnancy test at screening and before the first (V0), second (V28), and third vaccinations (V56) for female volunteers of childbearing potential. Females of childbearing potential must agree to use an efficacious hormonal or barrier method of birth control during the study. Abstinence is acceptable. Female volunteers unable to bear children must have this documented (e.g. tubal ligation or hysterectomy) or must have negative pregnancy tests.
  4. Willingness to participate in the study after all aspects of the protocol have been explained and written informed consent obtained.
  5. Completion of a training session and demonstrated comprehension of the protocol procedures and knowledge of ETEC associated illness by passing a written examination (70% pass score).
  6. Availability for the study duration, including all planned follow-up visits.
  7. Received at least 2 doses of ACE527 vaccine alone or in combination with 25 ug dmLT 4-6 months prior to challenge (Part B only)

Exclusion Criteria:

  1. Presence of a significant medical or psychiatric condition which in the opinion of the investigator precludes participation in the study. Some medical conditions which are adequately treated and stable would not preclude entry into the study. These conditions might include stable asthma controlled with inhalers or mild hypertension stably controlled with a single agent.
  2. Significant abnormalities in screening hematology, or serum chemistry as determined by PI or PI in consultation with the Medical Officer and sponsor.
  3. Presence in the serum of HIV antibody, HBsAg, or HCV antibody.
  4. Evidence of IgA deficiency (serum IgA < 7 mg/dl or limit of detection of assay).
  5. Evidence of current excessive alcohol consumption or drug dependence.
  6. Volunteers whose Body Mass Index (BMI) is less than 19.0 or greater than 34.0 (kg/m2)
  7. Recent vaccination or receipt of an investigational product (within 30 days before vaccination).
  8. Intention to donate blood or blood products within one month following the completion of study participation (note: The Red Cross will not allow blood donations for 1 year following participation in an investigational research study).
  9. 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
  10. Working as a food handler, in child-care or as a healthcare worker with direct patient contact.
  11. Have household contacts who are <2 years old or >80 years old or infirm or immunocompromised (for reasons including corticosteroid therapy, HIV infection, cancer chemotherapy, or other chronic debilitating disease).
  12. Abnormal stool pattern (fewer than 3 per week or more than 3 per day).
  13. Regular (≥ weekly) use of laxatives, antacids, or other agents to lower stomach acidity.
  14. Use of any medication known to affect the immune function (e.g., corticosteroids and others) within 30 days preceding the first vaccination or planned use during the active study period.
  15. Symptoms consistent with Traveler's Diarrhea concurrent with travel to countries where ETEC infection is endemic (most of the developing world) within two years prior to dosing, OR planned travel to endemic countries during the length of the study.
  16. Vaccination for or ingestion of ETEC, cholera, or LT toxin within 3 years prior to dosing.
  17. Use of antibiotics during the 7 days before dosing or proton pump inhibitors, H2 blockers or antacids within 48hours prior to dosing.
  18. History of diarrhea in the 7 days prior to vaccination (outpatient diarrhea is defined as ≥ 3 unformed (grade 3 or greater) loose stools in 24 hours).
  19. Known allergy to two of the three following antibiotics: Ciprofloxacin, amoxicillin, and/or trimethoprim/sulfamethoxazole
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01739231

Locations
United States, Maryland
Center for Immunization Research (CIR) at Johns Hopkins School of Public Health (JHSPH)
Baltimore, Maryland, United States, 21224
Sponsors and Collaborators
PATH
Investigators
Principal Investigator: Clayton D Harro, MD, ScM Johns Hopkins Bloomberg School of Public Health
  More Information

Additional Information:
No publications provided

Responsible Party: PATH
ClinicalTrials.gov Identifier: NCT01739231     History of Changes
Other Study ID Numbers: VAC 006
Study First Received: September 21, 2012
Last Updated: May 13, 2014
Health Authority: United States: Food and Drug Administration

ClinicalTrials.gov processed this record on September 22, 2014