A Phase 2 Bridging Study to Assess the New Formulation of ETVAX

Study Overview
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Brief Summary
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This is a phase 2,prospective double-blind, randomized, parallel-group study with the aim to demonstrate non-inferiority, in terms of immunogenicity, between the wet formulation and a newly developed partially dried formulation of selected components of ETVAX.

Detailed Description
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This is a phase 2, prospective double-blind, randomized, parallel-group study with the aim to demonstrate non-inferiority, in terms of immunogenicity, between the wet formulation and a newly developed partially dried formulation of selected components of ETVAX.. A total number of 126 subjects will be included in each arm of the study, i.e. 252 subjects in total. Assuming a 10% dropout rate the target number of subjects to be recruited per study arm is therefore 140, i.e. 280 subjects in total. Healthy volunteers between 18-50 years will be eligible for enrolment into the study. Eligible subjects will be randomized on Day 1 (Visit 2) to receive either of the two oral formulations of ETVAX (1:1) and consecutively included the study. The treatment allocation (Wet formulation/Partially dried formulation) will be double-blind. The study subjects will receive two oral doses, two weeks apart (Day 1/Visit 2 and Day 15 /Visit 3).The dosing will occur at the clinic (CTC in Gothenburg, Sweden). A follow-up visit will be performed 7 days after the last (second) dose in all study subjects The primary endpoint to be measured for each patient in the study is response (yes/no) to a vaccine. A vaccine responder will be defined by a ≥2-fold increase in IgA and/or IgG antibody levels against LTB in serum between post- compared to pre-immunization samples. The response rates (seroconversion rates) of IgA and/or IgG anti-LTB antibodies in serum will be derived and compared between the two treatment groups. The secondary endpoint to be measured for each patient in the study is the occurrence of solicited symptoms for six days after each vaccination (day of vaccination and five subsequent days). Exploratory analyses will be done to evaluate if ETVAX vaccination induces circulating antigen specific memory B- and/or T cells that can be assessed using recently established laboratory assays. For the exploratory analyses, subgroups of subjects (n=20-40, evenly distributed between the two treatment arms) will participate in additional follow-up visits 5± 1, 30± 7 and 90± 14 days after the second dose. Blood samples will be collected on all exploratory visits. The extra visits and analyses for exploratory analyses may continue after the main part of the study has been completed and the database locked.

Official Title
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A Phase 2 Immunological Bridging Study Assessing the Non-inferiority of a New Formulation of ETVAX®. A Prospective Double-blind, Randomized Study in Healthy Volunteers.

Conditions
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Healty Volunteers, Preventable Disease, Vaccine

Intervention / Treatment
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* Biological: Etvax
* Biological: Etvax


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female aged 18-50 years, inclusive at the time of signing the informed consent. Healthy constitution as established by medical history and physical examination. Willing and able to give written informed consent for participation in the study. Able to comply with study activities, as judged by the Investigator. Female Participants: Women of child-bearing potential (for definition see Section 9.3.6 in the protocol): Have to agree to use an acceptable birth control method during participation in the investigation (see Section 9.3.6). A negative pregnancy test (beta human chorionic gonadotropin dipstick test in urine) at Visit 2/Day 1 will be required. Male Participants: Have to agree to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm, as defined in Section 9.3.6 Exclusion criteria 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. Current malignancy or history of malignancy during the last five years, based on anamnesis. Gastroenteritis within two weeks prior to vaccination. Regular use of laxatives, antacids or other agents that lower stomach acidity. Any planned major surgery during the duration of the study. After 10 minutes supine rest, any vital signs outside the following ranges: Systolic BP > 160 mm Hg Diastolic BP > 100 mm Hg Heart rate < 40 or >85 beats per minute Antibiotic therapy within two weeks prior to the vaccination. Known Hepatitis A, B, C, and/or HIV infection. Concomitant intake of immunomodulating drugs during the study period or less than 3 months prior to the first immunization. Local anti-histamine treatment is however allowed. Any other significant medical conditions (e.g. poorly controlled psychiatric condition) judged by the Investigator to preclude entry. Intends to receive any other vaccine during the study period, or within two weeks prior to trial vaccination. Has previously received Dukoral or any type of ETEC or cholera vaccines. Brought up in ETEC-endemic areas (e.g., urban and rural areas of Central and South America, Caribbean, most countries in Asia, Africa, etc.). Has travelled to ETEC-endemic areas within the last 3 years OR spent > two months in ETEC endemic areas during the last 10 years. Intends to travel to ETEC endemic countries during the study period. Known or suspected history of drug, chemical or alcohol abuse, as deemed by the investigator/physician. History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as judged by the Investigator, or history of hypersensitivity to drugs with a similar chemical structure or class to ETVAX®. Participation in any other clinical study that included drug treatment with the last administration within the past 3 months prior to administration of study treatment in this study. Patients consented and screened but not dosed in previous clinical studies are not excluded. Concomitant participation in any other clinical study. Females who are pregnant as determined by urine test at inclusion and prior to each vaccination. Females who are nursing. Unable to participate in all study visits. Any condition or circumstance which would make the subject unsuitable for participation in the study in the opinion of the investigator/physician.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A randomized, placebo controlled phase 2
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: The wet formulation of ETVAX.<br>The wet formulation consists of a liquid suspension of inactivated bacteria (ETEX 21-24) and LCTBA in one vial, freeze-dried dmLT adjuvant in a second vial, and effervescent buffer granules in a separate sachet. Prior to administration, the buffer is dissolved in 150 ml tap water, followed by the addition of the content of the vaccine vial (inactivated bacteria mixed with LCTBA) and reconstituted and diluted adjuvant dmLT from the second vial. | Biological: Etvax<br>* Preparation of complete Wet formulation. The vaccine supplied as a liquid, is mixed with the 150 ml of sodium bicarbonate buffer solution on the day of preparation for use on dosing day. Just prior to administration 10 µg of dmLT is added by pipette (50 µl).<br>|
| Active Comparator: The partially dried formulation of selected components of ETVAX.<br>The partially dried formulation, dmLT and LCTBA are spray-dried and mixed with the buffer granules and stabilizing excipients in a sachet. Prior to administration, the content of the buffer sachet (buffer, dmLT, and LCTBA) is dissolved in 150 ml tap water, followed by the addition of a liquid suspension of inactivated bacteria (ETEX 21-24). | Biological: Etvax<br>* Preparation of partially dry formulation. The partially dry formulation of vaccine is prepared by adding the effervescent powder containing the dmLT and LCTBA to 150 ml of water. After mixing, the content of the vaccine vial is added to the mixture and the vaccine is administered to the volunteer within 30 minutes after adding the buffer powder to the water.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Vaccine response | The primary endpoint to be measured for each patient in the study is response (yes/no) to a vaccine. A vaccine responder will be defined by a ≥2-fold increase in IgA and/or IgG antibody levels against LTB in serum between post- compared to pre-immunization samples. The response rates (seroconversion rates) of IgA and/or IgG anti-LTB antibodies in serum will be derived and compared between the two treatment groups. | 3 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Solicited symptoms after vaccination | Occurrence of solicited symptoms for six days after each vaccination (day of vaccination and five subsequent days). | 3 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prophylaxis against diarrhea due to enterotoxigenic E. coli