Official Title: “A Randomized, Double-Blind, Placebo-Controlled Dose Escalation, Inpatient Phase I Study to Determine the Safety and Immunogenicity of a Single Oral Dose of a Combined Live, Attenuated, Enterotoxigenic Escherichia Coli (ETEC)-Cholera Vaccine (Peru-15 pCTB) in Healthy Adult Subjects”

Enterotoxigenic Escherichia (E.) coli (ETEC) are the main cause of traveler's diarrhea and are significant pathogens affecting children and elderly individuals of developing countries.

The purpose of the study is to determine the safety of the ETEC-Cholera vaccine against the E. coli responsible for the diarrhea. The study will enroll a total of 64 healthy volunteers, 18 to 45 years old at the Cincinnati Children's Hospital. The study will look at increasing doses of the vaccine or placebo given to 4 groups of 16 subjects. Subjects will remain in the inpatient unit for observation study days -1 through 9 during which stool samples will be collected. Subjects will return to the clinic on study days 10, 14, 21, and 28 for required follow up.

Subjects will be contacted by telephone months 2, 4, and 6 to assess for side effects of the study drug. All subjects will be treated with Cipro, an antibiotic, for 5 days. Subjects will participate in study related procedures for up to 8 months.

Study Type: Interventional

Study Design: Prevention, Randomized, Double Blind (Subject, Investigator), Dose Comparison, Parallel Assignment, Safety Study

Study Primary Completion Date: June 2010

Enterotoxigenic Escherichia coli (ETEC) are the principal single cause of traveler's diarrhea and are a significant pathogen affecting children and elderly individuals of developing countries. ETEC infections result in approximately 600 million total cases of diarrhea worldwide annually, with an estimated 280 million cases and over 400,000 deaths in children less than 5 years of age. The proposed study is a randomized, double-blind, placebo controlled, dose-escalation, inpatient Phase I study to determine the safety and immunogenicity of a single oral dose of a combined live, attenuated, enterotoxigenic Escherichia coli (ETEC)-cholera vaccine (Peru-15 pCTB) in healthy adult subjects. A total of 64 healthy subjects, 18 to 45 years old will be enrolled in this study. Subject participation duration is up to 8 months. The volunteers will be placed in sequential cohorts of 16 eligible subjects and will be randomized in a 3:1 ratio to receive the assigned dose of ETEC-cholera vaccine or placebo (bicarbonate buffer only), respectively. The study will be conducted at Cincinnati Children's Hospital. Subjects will remain in the inpatient unit for observation study days -1 through 9. Subjects will return to the study clinic on study days 10, 14, 21, and 28 for required evaluations. Subjects will be contacted by telephone at 2, 4, and 6 months following study drug administration to assess for any new medications, changes in concomitant medication regimens (both prescription and over the counter medications), and the occurrence of adverse events. The primary objective of this study will be to assess the safety of a combined ETEC-cholera vaccine (Peru-15-pCTB) when administered as a single oral dose over a range of doses in healthy adult subjects compared to placebo at day 28 post-vaccination.

The secondary objectives will be: to assess long-term safety follow-up from immunization through Month 6 post vaccination; to evaluate the immunogenicity of a single oral dose of ETEC-cholera vaccine over a range of doses in healthy adult subjects; and to evaluate the shedding profile of the ETEC-cholera vaccine organisms in stool for a period of 7 days. The primary endpoint of the study is the safety of ETEC-cholera vaccine as assessed by the incidence and severity of adverse events (AE) and changes in laboratory and clinical parameters through the day 28 post-vaccination visit. The secondary endpoints include immunogenicity as assessed by changes in vibriocidal antibody titer, anti-cholera toxin B-subunit antibody titer, and anti-labile toxin antibody titer.

Intervention(s) in this Clinical Trial

• Drug: Ciprofloxacin 500 mg
  • 500 mg will be administered orally twice daily for 5 days.
• Biological: Peru-15-pCTB
  • Live attenuated oral combined ETEC-cholera (Peru-15 pCTB) vaccine co-administered with bicarbonate buffer solution; vaccine dose levels 1 X 10^7; 1 X 10^8; 1 X 10^9; and 1 X 10^10.
• Drug: Placebo
  • Buffer solution: 2.5 g Sodium Bicarbonate powder, 1.65 g Ascorbic Acid and 25 mg Aspartame, in 100 mL water for injection.

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: Cohort 1: vaccine dosage level 1 or placebo
  • Vaccine dose level 1: 1 X 10^7 CFU or placebo, treated with Cipro on days 7-11.
• Experimental: Cohort 3: vaccine dosage level 3 or placebo
  • Vaccine dose level 3: 1 X 10^9 CFU or placebo, treated with Cipro on days 7-11.
• Experimental: Cohort 4: vaccine dosage level 4 or placebo
  • Vaccine dose level 4: 1 X 10^10 CFU or placebo, treated with Cipro on days 7-11.
• Experimental: Cohort 2: vaccine dosage level 2 or placebo
  • Vaccine dose level 2: 1 X 10^8 CFU or placebo, treated with Cipro on days 7-11.

Primary Measures

• Safety: physical examinations, interim medical history, solicited symptoms/subject memory aid, and laboratory evaluations.
  • Time Frame: Full exam: screening and Day 28, brief exam: inpatient Days; Memory Aid Days 9-14; Medical History and symptoms: screening, inpatient period, outpatient 9-14, clinic visits and Day 10 and 14; Labs: screening, Days -1, 3, 7, 14, 28, and Termination.
    Safety Issue?: Yes
• Adverse Events (AEs) will be graded according to standardized criteria.
  • Time Frame: From the time the subject receives the first application of the investigational product until exit from the study.
    Safety Issue?: Yes

Secondary Measures

• Immunogenicity will be assessed by changes in vibriocidal antibody titer, anti-CTB antibody titer, and anti-LT antibody titer.
  • Time Frame: Days -1, 7, 10, 14, and 28.
    Safety Issue?: No
• Stool shedding of the vaccine organisms will be assessed by qualitative and quantitative cultures.
  • Time Frame: Qualitative: Days 1-10, 14, 21, 28: Quantitative: Days 1-10.
    Safety Issue?: No

Inclusion Criteria:

• Male or female age 18-45, inclusive.
• Healthy as judged by the Principal Investigator (PI) and determined by medical history, physical examination, vital signs, screening laboratories, and medication history.
• Capable of understanding, consenting and complying with the entire study protocol including the inpatient period.
• Female subjects must be of non-childbearing potential, or if of childbearing potential (as determined by the investigator) must be practicing abstinence or using an effective licensed method of birth control (e.g., oral contraceptives; diaphragm or condom in combination with contraceptive jelly, cream, or foam; intrauterine contraceptive device, or Depo-Provera; skin patch; vaginal ring or cervical cap) for 30 days prior to vaccination and must agree to continue such precautions during the study and for 30 days after the Day 28 study visit.
• Male subjects must agree not to father a child during the study and for 90 days after the Day 0 study visit.
• Provide voluntary written informed consent and attained at least 70% on an examination about the study on the first attempt.
• Have normal screening laboratories for SGPT (ALT), creatinine, sodium, potassium, total white blood count (WBC), hemoglobin, neutrophils, lymphocytes, platelets, urine protein, urine glucose and urine RBCs.

Exclusion Criteria:

• Women who are pregnant or lactating or have a positive serum pregnancy test at screening or upon admission to inpatient facility.
• Subjects who are immunocompromised or immunodeficient, or have had a prior malignancy (exception: a history of basal cell or squamous cell carcinoma in remission without treatment for more than 5 years prior to study entry).
• History of clinically significant chronic illness or other condition requiring chronic medication therapy.
• History of malabsorption or maldigestion disorder (e.g., celiac sprue), major gastrointestinal (GI) surgery, or any other chronic GI disorders that would interfere with the study or the investigational product.
• Any current or past use of immunosuppressive medications including inhaled steroids (e.g., for asthma) within 6 months of screening.
• Recent (e.g., within 5 years) history of travel to a cholera or ETEC endemic area, raised in a cholera or ETEC endemic area or a history of raising a child from an endemic area for cholera or ETEC. Individuals who may work with V. cholerae or ETEC in the laboratory are also excluded.
• Vaccination against or infection with cholera or E. coli, or participation in a clinical trial using cholera or ETEC vaccine or organisms at any time.
• History of drug or alcohol abuse any time in the last 6 months.
• Presence of HIV antibody, hepatitis C antibody, or positive hepatitis B surface antigen.
• Clinically abnormal screening electrocardiogram (ECG) defined as pathologic Q waves and significant ST-T wave changes; criteria for left ventricular hypertrophy; and any non-sinus rhythm excluding isolated premature atrial contractions.
• Presence of bacterial or parasitic pathogens in stool culture in a screening stool examination.
• IgA deficiency.
• A change in subject's normal stool pattern within 3 months of screening visit. A normal stool pattern is defined as 3 to 21 stools per week.
• Any known allergy or sensitivity to Ciprofloxacin.
• Have any known allergy to components of the vaccine [M9 minimal salts, glycerin, dextrose anhydrous, sodium chloride, peptone (vegetable) acid hydrolysate, magnesium sulfate heptahydrate, and aspartame] or placebo/bicarbonate buffer (water, sodium bicarbonate, ascorbic acid, and aspartame).
• Any medical illness requiring a new prescription medication or hospitalization during the screening period or having a temperature greater than or equal to 38.0 degrees C during the 2 weeks prior to investigational product administration (Day 0).
• Administration of any vaccine, licensed or investigational, or any investigational product within 30 days of investigational product administration (Day 0) or any plan for participation in another investigational trial during this study.
• Use of antibiotics within 7 days of investigational product administration (Day 0).
• Use of laxatives for hard or infrequent stools one or more times in a month in any of the 3 months prior to enrollment.
• Use of any H2 receptor antagonists (e.g., Tagamet®, Zantac®, and Pepcid®), proton pump inhibitors (e.g., Prilosec® OTC, Protonix®, and Prevacid®), or prescription acid suppression medication or over-the-counter (OTC) antacids within 72 hours of investigational product administration.
• Use of prescription and OTC medications that contain acetaminophen, aspirin, ibuprofen, and other nonsteroidal anti-inflammatory drugs within 48 hours prior to investigational product administration.
• Employment as a commercial food handler, day care worker, or health care worker involved in direct patient contact. Subjects with children less than 2 years old at home or with household contacts who are immunocompromised, pregnant or breast-feeding.
• Any other condition or responsibility, such as a medical, psychiatric, or social condition or occupational responsibility that, in the judgment of the investigator, would interfere with or serve as a contraindication to the subject's participation in the protocol or assessment of the investigational product.
• Subjects who are unwilling or unable to cease smoking for the duration of the inpatient stay.
• Subjects who are unable to pass a test that describes cholera and ETEC diarrhea and explains the requirements of the clinical trial. Subjects must score a minimum of 70% upon the first attempt.
• Subjects will be excluded if their screening laboratory test results fall outside of the laboratory normal; however, transaminase levels (ALT) and creatinine levels (Cr) below the lower limit of "normal" will not be an exclusion criterion.
• Subjects with Phenylketonuria (PKU) will be excluded because the investigational product (vaccine) bicarbonate buffer contains aspartame.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 45 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: Accepts Healthy Volunteers

Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Overall Clinical Trial Officials and Contacts

Overall Contact: Mitchell Cohen (513) 636-3008 

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00654108

Study ID Number: 07-0052

ClinicalTrials.gov Identifier: NCT00654108

Health Authority: United States: Institutional Review Board