A Safety and Efficacy Study of the Hepatitis E Vaccine in Nepal.

Study Overview
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Brief Summary
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The purpose of this study is to determine if a hepatitis E vaccine is safe and able to prevent symptomatic liver disease due to the hepatitis E virus.

Detailed Description
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This is a prospective, randomized, double-blind, placebo-controlled with 2 study groups (vaccine and placebo). Three doses of the study vaccine are given according to a 0, 1, 6 month schedule. Vaccine efficacy will be assessed by maintaining active surveillance for clinical hepatitis every 2 weeks and hospital based surveillance for the full duration of the trial. Total planned study population is 2000 eligible subjects (1000 in the vaccine group and 1000 in the placebo group). Total vaccinated cohort for the analysis of reactogenicity is 200 (100 in the vaccine group and 100 in the placebo group). Volunteers who enroll will be followed for evidence of symptomatic liver disease for approximately 2 years, and those who become ill will be admitted to hospital for care. To evaluate safety, a randomly designated subset will be monitored for 7 days after each vaccination to solicit specific symptoms at the injection site and generally. Additionally, all adverse events will be collected for 30 days after each vaccine dose and all serious adverse events will be collected throughout the trial.

Official Title
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A Phase II, Prospective, Randomized, Double-blind, Placebo Controlled, Field Efficacy Trial of a Candidate Hepatitis E Vaccine in Nepal.

Conditions
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Hepatitis

Intervention / Treatment
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* Biological: Hepatitis E vaccine, recombinant (Sar 56 kDa)
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A male or female 18 years of age or older at the time of the first vaccination. Written or oral witnessed (if the subject was illiterate) informed consent obtained from the subject Free of obvious health problems as established by medical history before entering into the study If the subject was female, she must have a negative serum pregnancy test within 48 hours prior to each vaccination and must agree to avoid becoming pregnant during the course of vaccination and until 30 days after the last dose of vaccine. Exclusion Criteria: Use of any investigational or non-registered drug or vaccine other than the study vaccine(s) within 30 days preceding the first dose of study vaccine, or planned use during the study period. Administration of chronic (defined as more than 14 days) immunosuppressants or other immune modifying drugs within six months of vaccination. For corticosteroids, this will mean prednisone, or equivalent, * 0.5 mg/kg/day. Inhaled and topical steroids are allowed. Any chronic drug therapy to be continued during the study period with the exception of contraceptive agents, homeopathic remedies, vitamins, minerals and any other dietary supplements or other drug therapy at the discretion of the investigator. Planned administration/administration of a vaccine not foreseen by the study protocol within 30 days of the first dose of study vaccine, excluding tetanus toxoid or rabies vaccine. Any confirmed or suspected immunosuppressive or immunodeficient condition, including human immunodeficiency virus (HIV) infection, as reported by the volunteer (testing for HIV will not be performed). History of allergic disease or reactions likely to be exacerbated by any component of the vaccine. Major congenital defects or serious chronic illness. History of any neurologic disorders or seizures. Acute disease at the time of enrollment. Acute disease was defined as the presence of a moderate or severe illness with or without fever. All vaccines could be administered to persons with a minor illness such as diarrhea, mild upper respiratory infection with or without low-grade febrile illness, i.e., oral temperature < 38.0°C (100.4°F). Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic or renal functional abnormality, as determined by history. Administration of immunoglobulins and/or any blood products within the three months preceding the first dose of study vaccine or planned administration during the study period. Pregnant female. History of chronic alcohol consumption (defined as the consumption of the equivalent of 4 or more 12 ounce beers 4 or more times a week) and/or intravenous drug abuse. Antibodies to rHEV (* 20 WR U/mL).

Ages Eligible for Study
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Minimum Age: 18 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
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 20mcg Recombinant HEV<br>20mcg of recombinant HEV antigen administered intramuscularly in the deltoid according to a 0, 1 and 6 month schedule | Biological: Hepatitis E vaccine, recombinant (Sar 56 kDa)<br>* 20mcg or rhE Sar 56 kDa/dose of 0.5 mL, aluminium hydroxide (0.5 mg/dose) and phenoxyethanol (2.5 mg/dose)<br>|
| Placebo Comparator: Placebo<br>PBS buffer placebo containing alum was administered intramuscularly in the deltoid according to a 0, 1 and 6 month schedule. | Other: Placebo<br>* PBS buffer placebo containing alum<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of Participants of Definite Hepatitis E by Category and Immunological Markers (Anti HEV) During the Follow-up Period | Percent of participants of definite hepatitis E by category and immunological markers (anti HEV) during the follow-up period. Illness for at least 3 days comprised of at least 3 of the following symptoms: fatigue, loss of appetite, abdominal discomfort, right upper quadrant pain, nausea, vomiting Peak of Alanine Aminotransferase (ALT) greater then 2.5 times the upper limit of normal (2.5 x 42 =105) Percent of Participants = n x 100 / N | 14 days after dose 3 at 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of Participants of Definite Hepatitis E Disease by Category During the Follow-up Period | Percent of participants of definite hepatitis E and vaccine efficacy by category during the follow-up period Illness for at least 3 days comprised of at least 3 of the following symptoms: fatigue, loss of appetite, abdominal discomfort, right upper quadrant pain, nausea, vomiting Peak of Alanine Aminotransferase (ALT) greater then 2.5 times the upper limit of normal (2.5 x 42 =105) Percent of participants = n x 100 / N | 14 days after dose 2 until 14 days after dose 3 | 
| Number of Suspected, Definite, Probable and Not Confirmed Hepatitis E Disease Cases | Number of suspected, definite, probable and not confirmed hepatitis E disease cases during surveillance period | before dose 1 thru 14 days after dose 3 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatitis E, clinical hepatitis, vaccine, efficacy, Nepal