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Prevention of Diarrheal Disease Due to Infection With Enterotoxigenic E. Coli (ETEC)

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ClinicalTrials.gov Identifier: NCT03729219
Recruitment Status : Completed
First Posted : November 2, 2018
Last Update Posted : November 8, 2019
Sponsor:
Collaborators:
Göteborg University
United Medix Laboratories Ltd.
Oy Medfiles Ltd
University of Helsinki
University of Virginia
Information provided by (Responsible Party):
Scandinavian Biopharma AB

Tracking Information
First Submitted Date  ICMJE October 16, 2017
First Posted Date  ICMJE November 2, 2018
Last Update Posted Date November 8, 2019
Actual Study Start Date  ICMJE June 12, 2017
Actual Primary Completion Date April 15, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 1, 2018)
  • Safety: Number of vaccine attributable adverse events [ Time Frame: From first vaccination until leave for Benin, approximately 13-50 days ]
    Number of vaccine attributable adverse events
  • Immunogenicity: Fold change of serum titers of IgA and IgG against LTB [ Time Frame: Change from baseline (just before first vaccination) to Visit 3 (5-6 days after second vaccination), an average of 20 days ]
    Fold change of serum titers of Immunoglobulin A (IgA) and Immunoglobulin G (IgG) against heat-labile toxin (LTB)
  • Immunogenicity: Number of subjects responding to heat-labile toxin (LTB) [ Time Frame: Change from baseline (just before first vaccination) to Visit 3 (5-6 days after second vaccination), an average of 20 days ]
    Number of subjects responding to heat-labile toxin (LTB) based on serum Immunoglobulin A (IgA) and Immunoglobulin G (IgG) (i.e. fold change at least 2)
  • Immunogenicity: Fold change of serum titers of Immunoglobulin A (IgA) and Immunoglobulin G (IgG) against O78 lipopolysaccharide (LPS) [ Time Frame: Change from baseline (just before first vaccination) to Visit 3 (5-6 days after second vaccination), an average of 20 days ]
    Fold change of serum titers of Immunoglobulin A (IgA) and Immunoglobulin G (IgG) against O78 lipopolysaccharide (LPS)
  • Immunogenicity: Number of subjects responding to O78 lipopolysaccharide (LPS) [ Time Frame: Change from baseline (just before first vaccination) to Visit 3 (5-6 days after second vaccination), an average of 20 days ]
    Number of subjects responding to O78 lipopolysaccharide (LPS) based on serum Immunoglobulin A (IgA) and Immunoglobulin G (IgG) (i.e. fold change at least 2)
  • Diagnostic Tools:To set the optimal threshold limits of the two quantitativePolymerase chain reaction (PCR ) procedures [ Time Frame: 12 days in Benin and 30 days post-travel in Finland, approximately 42 days ]
    To set the optimal threshold limits of the two quantitative Polymerase chain reaction (PCR ) procedures by setting limits for the number of amplification cycles (Cq values) which best allows (in terms of sensitivity, specificity, and positive predictive value) for identification of clinically significant ETEC TD cases, as well as cases associated with other enteric pathogens using the culture based bacterial detection method as the "Gold standard" for comparison.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 1, 2018)
  • Efficacy: The incidence of Vaccine Preventable Outcomes (VPO) [ Time Frame: 12 days in Benin and 30 days post-travel in Finland, approximately 42 days ]
    The incidence of cases with moderate or severe ETEC VPO diarrhea in the vaccinated and placebo groups of travelers.
  • Diagnostic Tools:Extent to which the non-culture based PCR assays can help resolve mixed ETEC infections [ Time Frame: 12 days in Benin and 30 days post-travel in Finland, approximately 42 days ]
    Percentage of clinically significant Traveller's Diarrhea cases with mixed infection where decision about what is the primary causative agent is concordant between Amphidial qPCR method and culture-based antigen detection method
  • Diagnostic Tools:The extent to which the TaqMan array yields results for ETEC colonization factor that are comparable to those obtained by culture based methods. [ Time Frame: 12 days in Benin and 30 days post-travel in Finland, approximately 42 days ]
    Percentage of clinically significant Traveller's Diarrhea cases with mixed infection where decision about what is the primary causative agent is concordant between TaqMan arrays qPCR method and culture-based antigen detection method
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Prevention of Diarrheal Disease Due to Infection With Enterotoxigenic E. Coli (ETEC)
Official Title  ICMJE A Randomized, Placebo-controlled Phase II b(OEV 123) Study to Evaluate Safety, Immunogenicity, Diagnostic Methodology, and Estimate Vaccine Efficacy of an Oral Enterotoxigenic Escherichia Coli(ETEC) Vaccine(ETVAX) for Prevention of Clinically Significant ETEC Diarrhea in Healthy Adult Travelers Visiting West Africa
Brief Summary This is a Phase II b, double-blind, randomized, placebo-controlled study in healthy adults (age 18-65 years) to evaluate the safety, immunogenicity, different diagnostic tools and efficacy of ETVAX. Participants will travel to Grand Popo, Africa for 12 days. Prior travelling participants will be vaccinated with two doses of vaccine or placebo. Vaccine Preventable Outcome will be identified and then characterized as to incidence, duration, severity and frequency of Moderate or Severe Travellers diarrhea. Health related information and assessments will be recorded during the travel.
Detailed Description

This is a Phase II b, double-blind, randomized, placebo-controlled study in healthy adults (age 18-65 years) to evaluate the safety, immunogenicity, different diagnostic tools and efficacy of two doses of ETVAX. Study participants will be recruited among students, and personnel at the University of Helsinki and Helsinki University Hospital and among those responding to recruitment advertisements. To be eligible, the participants have to commit themselves to comply with the study protocol which involves in addition to vaccination, study visits and sampling, and commitment to travel to Grand Popo, Benin and stay there for 12 days. After providing written informed consent, eligible participants will be randomized (ratio 1:1, and block randomization in groups of 6) and immunized with two doses of vaccine or placebo, given 14±7 days apart while in Finland. The last dose of vaccine will be administered at least one week before departure (and no more than 30 days prior to travel) to Benin. Eligible participants will pay four pre-travel visits (V0 + V 1-3) to Aava Travel Clinic / University of Helsinki prior to travel. They will be asked to fill in pre-travel questionnaire latest at visit 1 (Q1) and fill in an Adverse Event Form (AEF1 and AEF2) after each dose, and give blood and fecal samples and saliva before travel. The participants will go together to Benin in groups of 25-35 individuals at a time.

In Benin, the participants will be seen within 48 hours of arrival to the study site in Grand Popo. Once the participants arrive at the study site in Grand Popo, they will be provided with practical information and contact details of the study personnel. They will receive the health card (HC1) and a stool collection kit with instructions.

Diarrhea reporting, stool collection, and stool submission procedures will be reviewed with the study participants. One routine visit at day 4 is planned for review of the participant's health status and collection of a routine stool sample. Other visits will take place when and if the participant gets Travelers Diarrhea (TD) episodes for collection of study specific stool samples and health related information and assessments. If more than one diarrhea episode occurs, 48 diarrhea and symptom (TD defined symptoms) free hours must have passed between the episodes for the new episode to be counted as a separate one. One or two days prior to departure from the Grand Popo site, all participants will have a final review of their HC1s. Health Card ( HC2) will be given. After 1-6 days back in Finland the participant has to give blood and a routine stool sample and they fill in Questionnaire 2 (Q2), HC2 will be reviewed. Approx. 30 days after return to Finland the last stool and blood sample will be collected and the post-travel questionnaire (Q3) filled and HC2 reviewed. Participants who get urinary tract infection will fill in Urinary questionnaire 4 (QU4) form at the time of infection. This follow-up is valid until V5.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
A randomized, placebo-controlled phase IIb
Masking: Triple (Participant, Care Provider, Investigator)
Masking Description:
Other parts will be blinded except unblinded person who prepares the doses.
Primary Purpose: Prevention
Condition  ICMJE Diarrhea
Intervention  ICMJE
  • Biological: E. coli ETVAX
    Oral suspension Sterile water is added to dmLT . Vaccine is poured to the effervescent solution and needed amount of dmLT is added.
  • Other: Placebo
    Oral suspension
Study Arms  ICMJE
  • Experimental: ETVAX
    Contains inactivated Tetravalent ETEC vaccine, 10 ug Double-mutant heat-labile toxin (dmLT) and effervescent power for oral solution administered twice 14 (plus minus 7) days intervals.
    Intervention: Biological: E. coli ETVAX
  • Placebo Comparator: Placebo
    Effervescent power for oral solution administered wice 14 (plus-minus 7) days intervals
    Intervention: Other: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 18, 2019)
749
Original Estimated Enrollment  ICMJE
 (submitted: November 1, 2018)
800
Actual Study Completion Date  ICMJE April 15, 2019
Actual Primary Completion Date April 15, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion criteria:

  1. Male or female age ≥18 and ≤ 65 years
  2. General good health at the time of first vaccination
  3. Female participants of childbearing potential must not be pregnant
  4. Females of childbearing potential must agree to use an efficacious hormonal or barrier method of birth control during the study
  5. Willingness to participate in the study after all aspects of the protocol have been explained and written informed consent obtained
  6. Availability for the study duration, including all planned follow-up visits
  7. Intake of atovaquone + proguanil (Malarone) as anti-malaria prophylax according to prescription guidelines mandatory before, during and after travel to Benin

Exclusion Criteria:

  1. Presence of a significant medical or psychiatric condition, which in the opinion of the investigator precludes participation in the study
  2. Known or suspected history of drug, chemical or alcohol abuse, as deemed by the investigator/physician; AUDIT > 13 points
  3. Known recent history of impaired immune function which, according to the judgement of the investigator could influence the immune response
  4. Intends to receive any other investigational vaccine during the study period, or within two weeks prior to study vaccination
  5. Intends to donate blood at any time during the study.
  6. An acute or chronic medical condition that, in the opinion of the investigator/physician, would render ingestion of the investigational products unsafe or would interfere with the evaluation of responses. This includes, but is not limited to gastrointestinal diseases and autoimmune diseases requiring treatment
  7. Any history of psychosis or bipolar disorder or on-going significant mental disorder
  8. Regular (daily) use of laxatives or agents which lower stomach acidity (antacids, proton pump inhibitors) less than one week before visit V1
  9. Use of any oral or parenteral 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
  10. Traveled to ETEC-endemic areas within the last year or visit for > two months in ETEC endemic areas during the last 10 years
  11. Receipt of Dukoral or other ETEC or cholera vaccines within 3 years or planned receipt of such vaccine except ETVAX during the study
  12. Antibiotic therapy within two weeks prior to the vaccination
  13. History of diarrhea in the 7 days prior to vaccination (defined as ≥ 3 unformed loose stools in 24 hours)
  14. Any other criteria which, in the investigator's opinion, would compromise the ability of the traveler to participate in the study, the safety of the study, or the results of the study
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Finland
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03729219
Other Study ID Numbers  ICMJE OEV 123
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Scandinavian Biopharma AB
Study Sponsor  ICMJE Scandinavian Biopharma AB
Collaborators  ICMJE
  • Göteborg University
  • United Medix Laboratories Ltd.
  • Oy Medfiles Ltd
  • University of Helsinki
  • University of Virginia
Investigators  ICMJE
Principal Investigator: Anu Kantele University of Helsinki, Dept. of Infectious Diseases
PRS Account Scandinavian Biopharma AB
Verification Date November 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP