New Challenge Pool of Norwalk Virus Inoculum

NCT00138476 | Completed Phase 1

• 3 other identifiers: 99-036BCM-IRB 10690; GCRC 2027HHSN272200800002C
• Study Type: interventional
• Target: 57
• Locations: 1 country
• Sites: 1

Brief Summary

The main objective of this study is to see the number of volunteers that get sick from a Norwalk virus (NV) inoculation with typical symptoms of nausea, vomiting, and diarrhea. If this NV preparation is shown to cause Norwalk illness, then it can be used to test new vaccines in the future. Additionally, researchers hope to determine the lowest dose of NV inoculum that can be given to volunteers and cause illness. Study participants will include 57 healthy adults, ages 18-50. Participants will either be given the NV inoculum or placebo (water without virus). Participants will be hospitalized for a maximum of 7 days and a minimum of 4 days following the NV challenge. Study procedures include physical exam, blood testing, and collection of saliva, urine, and stool samples. Participants will be involved in study related procedures for up to 180 days.

Conditions

Gastroenteritis Norovirus

Keywords

Norovirus, calicivirus, gastroenteritis, Norwalk virus, challenge

Outcome Measures

Primary Outcomes (3)

• Determine the clinical attack rate for viral gastroenteritis induced by Norwalk Virus (NV) Lot 42399.

  Up to 7 days or until clinical symptoms of diarrhea and vomiting have resolved.

• Safety and acute toxicity of a new Norwalk virus challenge pool (Lot 42399) through clinical and laboratory monitoring of subjects.

  Screening Days 30, 90, and 180

• Determine the human infectious dose 50 percent of NV Lot 42399 based on viral shedding as measured by reverse transcription polymerase chain reaction (RT-PCR), by antigen shedding or by NV seroresponse by enzyme-linked immunosorbent assay (ELISA).

  Screening, Days 2, 3, 4, 5, 6, 7, 14, 30, and 180.

Secondary Outcomes (4)

• Measure specific IgG and IgA immunoglobulin responses to NV Lot 42399 inoculation/infection by ELISA, in serum, saliva and stool.

  Screening, Days 0, 1, 2, 3, 4, 5, 6, 7, 8-13, 14, 15-21, 28, 30, 35, 42, 49, 56 and 180.

• Examine peripheral blood mononuclear cells for the presence of NV genome by RT-PCR.

  Screening, Days 2, 7, 14, 30 and 180.

• Examine a variety of serum cytokine responses including interferon alpha, interleukin-10, C-reactive protein, TNF-alpha and IL-6 to NV infection and correlate acute, convalescent, and recovery cytokine levels with illness severity.

  Screening, Days 1, 2, 3, 4, 5, 6, 7, 30, 90, and 180.

• Examine stool by immune electron microscopy for NV particles.

  Screening, Days 0, 1, 2, 3, 4, 5, 6, 7, 8-13, 14, 15-21, 28+/-3, 30, 35+/-3, 42+/-3, 49+/-3, and 56+/-3.

Study Arms (5)

Group 4: 0.48 RT-PCR units or Placebo

EXPERIMENTAL

Group 4: dosage group of 10 subjects will receive 0.48 RT-PCR units of Lot 42399 NV or placebo control (8 subjects will receive NV and 2 subjects will receive placebo control).

Drug: Placebo; Biological: Norwalk Virus

Group 3: 4.8 RT-PCR units or Placebo

EXPERIMENTAL

Group 3: dosage group of 12 subjects will receive 4.8 RT-PCR units of Lot 42399 NV or placebo control (10 subjects will receive NV and 2 subjects will receive placebo control).

Drug: Placebo; Biological: Norwalk Virus

Group 2: 48 RT-PCR units or Placebo

EXPERIMENTAL

Group 2: dosage group of 12 subjects will receive 48 RT-PCR units of Lot 42399 NV or placebo control (10 subjects will receive NV and 2 subjects will receive placebo control).

Drug: Placebo; Biological: Norwalk Virus

Group 1: 4800 RT-PCR units or Placebo

EXPERIMENTAL

Group 1: dosage group of 11 subjects will receive 4800 reverse transcription polymerase chain reaction (RT-PCR) units of Lot 42399 Norwalk Virus (NV) or placebo control (9 subjects will receive NV and 2 subjects will receive placebo control).

Drug: Placebo; Biological: Norwalk Virus

Validation Group: 4.8 and 0.48 RT-PCR units

EXPERIMENTAL

Validation Group: dosage group of 12 subjects, 4 will receive 4.8 RT-PCR units and 8 will receive 0.48 RT-PCR units of Lot 42399 NV. No placebo control.

Biological: Norwalk Virus

Interventions

Placebo DRUG

120 mL of the sodium bicarbonate solution, followed by 82 mL of sterile water, United States Pharmacopeia (USP) without virus; followed by 500 mg of sodium bicarbonate aqueous solution taken 5 minutes after placebo inoculation.

Group 1: 4800 RT-PCR units or Placebo; Group 2: 48 RT-PCR units or Placebo; Group 3: 4.8 RT-PCR units or Placebo; Group 4: 0.48 RT-PCR units or Placebo

Norwalk Virus BIOLOGICAL

Prepared and packaged from liquid feces (DC544) by clarification, centrifugation, and serial dilutions; desired doses \[reverse transcription polymerase chain reaction (RT-PCR) Units\] 4800, 48, 4.8, 0.48.

Group 1: 4800 RT-PCR units or Placebo; Group 2: 48 RT-PCR units or Placebo; Group 3: 4.8 RT-PCR units or Placebo; Group 4: 0.48 RT-PCR units or Placebo; Validation Group: 4.8 and 0.48 RT-PCR units

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Subjects must be 18 to 50 years of age and in good health as determined by medical history and physical examination.
• Subjects must sign informed consent prior to study initiation.
• All screening clinical laboratory test results within the protocol-defined normal range. Subjects with a history of positive Hepatitis A antibody or vaccination and normal liver transaminases (serum) may be accepted.
• If the subject is a woman, a negative serum pregnancy test within 3 days of inoculation and negative urine or blood pregnancy test on day of inoculation.
• Subjects must be able to demonstrate a sufficient understanding of the study protocol and the ability to follow all required study procedures, including measures to prevent Norwalk Virus (NV) contamination of the environment and spread of NV infection and illness to the community. The prospective subjects must pass (\> 75 percent correct responses, or 21 of 27 questions answered correctly) a written examination before enrollment. The exam will contain 27 multiple choice or true/false questions on all aspects of the study protocol. Subjects will be re-instructed about any question they may have answered incorrectly.
• Subjects must be available to return for follow-up visits following discharge from the General Clinical Research Center (GCRC) and deliver specimens to the investigator promptly.
• Agree to storage of unused, identifiable clinical specimens for an indefinite period at Baylor College of Medicine for use in future research.
• Subject must express the H type-1 oligosaccharide (as measured by positive salivary secretor status).
• Must use acceptable form of birth control, if female. The only acceptable birth control methods are oral contraceptives, intrauterine devices (IUDs), contraceptive implants under the skin, or contraceptive injections, and condoms with foam.

You may not qualify if:

• Living with or having daily contact with children age 10 years or less or a woman known to be pregnant. This includes contact at home, school, day-care, or equivalent facilities.
• Living with or having daily contact with childcare workers.
• Living with or having daily contact with elderly persons, aged 70 years or more, or the infirmed, diapered individuals, persons with disabilities or incontinent persons. This includes work or visits to nursing homes and day-care or equivalent facilities.
• Evidence of recent (within 3 months), or of current nonbacterial gastroenteritis suggestive of Norwalk Virus (NV) infection \[vomiting or unformed or watery stools (\>2 during a 24 hour period)\].
• History of chronic functional dyspepsia, chronic gastroesophageal reflux disease, peptic ulcer disease, gastrointestinal hemorrhage, gall bladder disease, inflammatory bowel disease, irritable bowel syndrome, frequent diarrhea, or diverticulitis anytime during the subject's lifetime.
• Positive serological tests for hepatitis viruses B (core and/or surface antigen serology) and/or C, human immunodeficiency virus (HIV)-1, or syphilis. Prior to HIV-1 testing, subjects will be counseled by a qualified clinical investigator as to the purpose and meaning of such testing. Any subject with a positive test will be referred to the local HIV-1 clinic or his/her private practitioner.
• Pregnant or lactating woman.
• Regular use of medication, such as, but not limited to, corticosteroids, anti-diarrhea medications, opioids, immunosuppressive agents, nonsteroidal anti-inflammatory drugs, antipyretics, and anticoagulants (e.g., warfarin or heparin or gold salts). Oral contraceptives are permitted.
• Use of antibiotics within 14 days of inoculation.
• Use of an investigational drug within 30 days prior to the start of study drug.
• Evidence of renal disease, as indicated by (any of the following) , serum sodium, or serum potassium outside normal laboratory range, or BUN or serum creatinine \>upper limit of normal range, or uric acid \>8.5 mg/dL.
• A baseline serum amylase value of 115 IU/L or greater or a baseline serum lipase value of 210 IU/L or greater.
• Evidence of cardiovascular disease, as indicated by (any of the following) blood pressure \>150/90 mm HG in two measurements on different days, hospitalization for myocardial infarction, arrhythmia, syncope, or murmur (non-functional) detected on physical examination.
• Evidence of liver or other reticuloendothelial disease as indicated by (any of the following) serum alanine aminotransferase (ALT) \> 1.25 times normal, aspartate aminotransferase (AST) \> 1.25 times normal, alkaline phosphatase \> 1.25 times normal, hepatosplenomegaly, jaundice, or lymphadenopathy on physical examination.
• Evidence of hematologic, rheumatologic, or immunologic disease, as indicated by (any of the following) white blood cell count \<3.0 thous./cu.mm, white blood cell count \>11.0 thousand/cu.mm, neutropenia (\<1500/cu.mm), hemoglobin outside laboratory normal range, history of more than 3 hospitalizations for invasive bacterial infections (pneumonia, meningitis), acute or chronic dermatitis (e.g., eczema, seborrhea, psoriasis) or collagen vascular disease \[e.g., systemic lupus erythematosus (SLE) or dermatomyositis\].

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (1)

Baylor College of Medicine - Molecular Virology and Microbiology

Houston, Texas, 77030-3411, United States

Location

Related Publications (2)

• Atmar RL, Opekun AR, Gilger MA, Estes MK, Crawford SE, Neill FH, Ramani S, Hill H, Ferreira J, Graham DY. Determination of the 50% human infectious dose for Norwalk virus. J Infect Dis. 2014 Apr 1;209(7):1016-22. doi: 10.1093/infdis/jit620. Epub 2013 Nov 18.

  PMID: 24253285 RESULT

• Reeck A, Kavanagh O, Estes MK, Opekun AR, Gilger MA, Graham DY, Atmar RL. Serological correlate of protection against norovirus-induced gastroenteritis. J Infect Dis. 2010 Oct 15;202(8):1212-8. doi: 10.1086/656364.

  PMID: 20815703 DERIVED

MeSH Terms

Conditions

Gastroenteritis

Condition Hierarchy (Ancestors)

Gastrointestinal Diseases; Digestive System Diseases

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 26, 2005
• First Posted: August 30, 2005
• Study Start: August 1, 2004
• Primary Completion: April 1, 2012
• Study Completion: September 1, 2012
• Last Updated: May 9, 2014

Record last verified: 2012-04

Locations

US (1)