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

• ClinicalTrials.gov Identifier: NCT00287469
• Recruitment Status: Completed
• First Posted: February 6, 2006
• Results First Posted: May 29, 2019
• Last Update Posted: May 29, 2019
• Sponsor: U.S. Army Medical Research and Development Command
• Collaborators: GlaxoSmithKline; National Institute of Allergy and Infectious Diseases (NIAID)
• Information provided by (Responsible Party): U.S. Army Medical Research and Development Command

Tracking Information

• First Submitted Date: February 2, 2006
• First Posted Date: February 6, 2006
• Results First Submitted Date: October 9, 2018
• Results First Posted Date: May 29, 2019
• Last Update Posted Date: May 29, 2019
• Actual Study Start Date: July 9, 2001
• Actual Primary Completion Date: January 19, 2004 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 8, 2019)

Percent of Participants of Definite Hepatitis E by Category and Immunological Markers (Anti HEV) During the Follow-up Period [ Time Frame: 14 days after dose 3 at 6 months ]

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

• Original Primary Outcome Measures (submitted: February 2, 2006): definite hepatitis E disease with onset at least two weeks after vaccine/placebo dose 3.

Current Secondary Outcome Measures (submitted: May 8, 2019)

• Percent of Participants of Definite Hepatitis E Disease by Category During the Follow-up Period [ Time Frame: 14 days after dose 2 until 14 days after dose 3 ]
  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
• Number of Suspected, Definite, Probable and Not Confirmed Hepatitis E Disease Cases [ Time Frame: before dose 1 thru 14 days after dose 3 ]
  Number of suspected, definite, probable and not confirmed hepatitis E disease cases during surveillance period

Original Secondary Outcome Measures (submitted: February 2, 2006)

• definite and probable hepatitis E disease with onset at least two weeks post vaccine/placebo dose 3
• definite hepatitis E disease with onset at least two weeks post vaccine/placebo dose and before two weeks after vaccine/placebo dose 3.
• hepatitis E disease severity.
• vaccine safety
• level of total immunoglobulin to HEV capsid

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Safety and Efficacy Study of the Hepatitis E Vaccine in Nepal.
• Official Title: A Phase II, Prospective, Randomized, Double-blind, Placebo Controlled, Field Efficacy Trial of a Candidate Hepatitis E Vaccine in Nepal.
• Brief Summary: 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

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.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Prevention
• Condition: Hepatitis

Intervention

• Biological: Hepatitis E vaccine, recombinant (Sar 56 kDa)
  20mcg or rhE Sar 56 kDa/dose of 0.5 mL, aluminium hydroxide (0.5 mg/dose) and phenoxyethanol (2.5 mg/dose)
• Other: Placebo
  PBS buffer placebo containing alum

Study Arms

• Experimental: 20mcg Recombinant HEV
  20mcg of recombinant HEV antigen administered intramuscularly in the deltoid according to a 0, 1 and 6 month schedule
  Intervention: Biological: Hepatitis E vaccine, recombinant (Sar 56 kDa)
• Placebo Comparator: Placebo
  PBS buffer placebo containing alum was administered intramuscularly in the deltoid according to a 0, 1 and 6 month schedule.
  Intervention: Other: Placebo

Publications *

• Worm HC, Schlauder GG, Brandstätter G. Hepatitis E and its emergence in non-endemic areas. Wien Klin Wochenschr. 2002 Aug 30;114(15-16):663-70. Review.
• Worm HC, van der Poel WH, Brandstätter G. Hepatitis E: an overview. Microbes Infect. 2002 May;4(6):657-66. Review.
• Emerson SU, Purcell RH. Running like water--the omnipresence of hepatitis E. N Engl J Med. 2004 Dec 2;351(23):2367-8.
• Purcell RH. Hepatitis viruses: changing patterns of human disease. Proc Natl Acad Sci U S A. 1994 Mar 29;91(7):2401-6. Review. Erratum in: Proc Natl Acad Sci U S A 1994 Sep 13;91(19):9195.
• Worm HC, Wirnsberger G. Hepatitis E vaccines: progress and prospects. Drugs. 2004;64(14):1517-31. Review.
• Shrestha MP, Scott RM, Joshi DM, Mammen MP Jr, Thapa GB, Thapa N, Myint KS, Fourneau M, Kuschner RA, Shrestha SK, David MP, Seriwatana J, Vaughn DW, Safary A, Endy TP, Innis BL. Safety and efficacy of a recombinant hepatitis E vaccine. N Engl J Med. 2007 Mar 1;356(9):895-903.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 2, 2006): 2000
• Original Enrollment: Same as current
• Actual Study Completion Date: January 2005
• Actual Primary Completion Date: January 19, 2004 (Final data collection date for primary outcome measure)

Eligibility Criteria

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).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Nepal

Administrative Information

• NCT Number: NCT00287469
• Other Study ID Numbers: WRAIR 749; HSRRB A-9117.1; GSK 304558/003 (HEV-003); IND 7815 ( Other Identifier: FDA )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Responsible Party: U.S. Army Medical Research and Development Command
• Study Sponsor: U.S. Army Medical Research and Development Command

Collaborators

• GlaxoSmithKline
• National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

• Principal Investigator: Mrigendra P Shrestha, MD; Armed Forces Research Institute of Medical Sciences, Thailand
• Principal Investigator: Robert M Scott, MD; Walter Reed Army Institute of Research (WRAIR)

• PRS Account: U.S. Army Medical Research and Development Command
• Verification Date: May 2019