Phase I Norovirus Challenge Model

Study Overview
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Brief Summary
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This is a safety and infectivity study of experimental human Norovirus genogroup GII.4 administered to 48 healthy non-pregnant adults, 18-49 years of age, negative for COVID-19 by antigen testing at the time of norovirus challenge. Subjects will be admitted to the Vaccine Research Center inpatient facility and challenged with a dose of human norovirus GII.4 challenge strain. The challenge study will be conducted in 3 cohorts of approximately 16 subjects each, 15 subjects will have a functional FUT-2 gene (secretor positive) and 1 subject will have a non-functional FUT-2 gene (non-secretor). Subjects in Cohort 1 will receive 3.5x10^3 copies of norovirus, in Cohort 2 will receive 3.5x10^4 copies of norovirus and in Cohort 3 will receive 3.5x10^5 copies of norovirus. Based on the illness rate of subjects meeting the primary outcome measure in secretor - positive subjects of the initial cohort, the decision will be made with regards to dosing of the second and the third cohorts. Study duration is approximately 12-18 months with subject participation duration of 6-8 months. The primary objective of this study is to determine the optimal challenge dose of Norovirus GII.4 CIN-3 Batch No.: 01-16C3 to achieve illness in > / = 50% of subjects (illness is defined as norovirus infection determined by positive Polymerase Chain Reaction (PCR) and either: a) > / = 3 loose or liquid stools, in a 24-hour period, b) > / = 300 gm of loose or liquid stool in a 24-hour period or c) and/or any episode of vomiting), during the inpatient period.

Detailed Description
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This is a double-blind, safety and infectivity study of experimental human Norovirus genogroup GII.4 administered to 48 healthy non-pregnant adults, 18-49 years of age, negative for COVID-19 by antigen testing at the time of norovirus challenge. Subjects will be admitted to the Vaccine Research Center inpatient facility and challenged with a dose of human norovirus GII.4 challenge strain. The challenge study will be conducted in 3 cohorts of approximately 16 subjects each, 15 subjects will have a functional FUT-2 gene (secretor positive) and 1 subject will have a non-functional FUT-2 gene (non-secretor). Subjects in Cohort 1 will receive 3.5x10^3 copies of norovirus, in Cohort 2 will receive 3.5x10^4 copies of norovirus and in Cohort 3 will receive 3.5x10^5 copies of norovirus. Based on the illness rate of subjects meeting the primary outcome measure in secretor - positive subjects of the initial cohort, the decision will be made with regards to dosing of the second and the third cohorts. Subjects will remain in the inpatient facility for at least four days following the challenge and assessed daily for clinical and virologic evidence of norovirus infection. After the discharge, subjects will return to the site for evaluation on Days 6, 15, 30, 45, and 60 post challenge. A final phone call will be performed at day 180 to obtain an interim medical history. Study duration is approximately 12-18 months with subject participation duration of 6-8 months. The primary objective of this study is to determine the optimal challenge dose of Norovirus GII.4 CIN-3 Batch No.: 01-16C3 to achieve illness in > / = 50% of subjects (illness is defined as norovirus infection determined by positive Polymerase Chain Reaction (PCR) and either: a) > / = 3 loose or liquid stools, in a 24-hour period, b) > / = 300 gm of loose or liquid stool in a 24-hour period or c) and/or any episode of vomiting), during the inpatient period. The secondary objectives are: 1) To evaluate the safety of the Norovirus GII.4 CIN-3 Batch No.: 01-16C3 challenge strain; 2) To determine the rate of infection at different challenge doses by detection of norovirus GII.4 in the stool using specific qRT-PCR and Anti-norovirus GII.4 serum IgG by Enzyme-Linked Immunnosorbent Assay (ELISA) (> / = 4-fold rise from baseline through Day 30); 3) To measure the severity of acute gastroenteritis; 4) To determine the quantity and duration of virus shedding in stool by qRT-PCR.

Official Title
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Phase I Study to Determine the Optimal Human Challenge Dose for Norovirus GII.4 CIN-3 Batch No.: 01-16C3

Conditions
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Gastroenteritis Norovirus

Intervention / Treatment
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* Biological: Norovirus GII.4 Challenge Pool


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject able to provide informed consent. Male or non-pregnant females between the ages of 18 and 49 years, inclusive. Women of childbearing potential must be using an acceptable method of birth control for at least 30 days prior to enrollment through day 45 after receipt of challenge virus. A woman is considered of childbearing potential unless post-menopausal (absence of menses for > / = 1 year) or surgically sterilized (tubal ligation, bilateral oophorectomy or hysterectomy). Acceptable contraception methods for women include but are not limited to: sexual abstinence from intercourse with men, monogamous relationship with vasectomized partner who has been vasectomized for 6 months or more prior to the subject enrolling in the study, barrier methods such as condoms or diaphragms with spermicide or foam, effective devices (intrauterine devices (IUD's), NuvaRing (R)) or licensed hormonal products such as implants, injectables or oral contraceptives. For women of childbearing potential, must have a negative serum or urine pregnancy test at screening. Are in good general health*. *As determined by medical history and physical examination to evaluate acute or currently ongoing chronic medical diagnoses or conditions, defined as those that have been present for at least 90 days, which would affect the assessment of the safety of subjects. Chronic medical diagnoses or conditions should be stable for the last 60 days (no hospitalizations, Emergency Room (ER), or urgent care for condition and no adverse symptoms that need medical intervention such as medication change/supplemental oxygen). This includes no change in chronic prescription medication, dose, or frequency as a result of deterioration of the chronic medical diagnosis or condition in the 60 days prior to enrollment. Any prescription change that is due to change of health care provider, insurance company, etc., or that is done for financial reasons, as long as in the same class of medication, will not be considered a deviation of this inclusion criterion. Any change in prescription medication due to improvement of a disease outcome, as determined by the site principal investigator or appropriate sub-investigator, will not be considered a deviation of this inclusion criterion. Subjects may be on chronic or as needed (prn) medications if, in the opinion of the site principal investigator or appropriate sub-investigator, they pose no additional risk to subject safety or assessment of reactogenicity and immunogenicity and do not indicate a worsening of medical diagnosis or condition. Similarly, medication changes subsequent to enrollment and study vaccination are acceptable provided there was no deterioration in the subject's chronic medical condition that necessitated a medication change, and there is no additional risk to the subject or interference with the evaluation of responses to study vaccination. Demonstrate knowledge and comprehension of the study by scoring > / = 70% on a quiz (test of understanding) of the study protocol and policies. Willing and able to participate in all study visits, including an inpatient stay of at least 96 hours. Exclusion Criteria: Have household contact with or have daily contact with children less than 2 years of age or persons older than 70 years of age. Have expected extended social contact (> 2 hours/day) with immunocompromised individuals in the 8 weeks after challenge*. *Including persons with HIV infection or active cancer, children <2 years of age, pregnant women or persons who are immunosuppressed (e.g. history of stem cell or organ transplantation) and/or provide any child day care services (in-home or non-residential facility). Are healthcare workers with direct patient contact or any child day care services (in-home or non-residential facility) in the 8 weeks after challenge. Are positive for COVID-19 by an antigen test at the time of admission to the challenge unit. Are food service workers expected to prepare/handle food in the 8 weeks after challenge. Plan to be living in a confined communal environment (e.g. ship, camp, or dormitory) within 8 weeks after receiving the challenge strain. For females, are pregnant or plan to become pregnant at any time between the Screening Visit through 45 days after receipt of the challenge virus. Are breastfeeding or plan to breastfeed at any given time throughout the study. Have a history of acute gastroenteritis in the 4 weeks prior to challenge or any history of chronic or recurrent diarrhea or vomiting. History of significant GI condition. * *Including: malabsorption, major GI surgery, current *eating disorder, irritable bowel syndrome, or any GI disorder (deemed clinically significant by study physician) making it unsafe to participate. Have significant acute illness or an oral temperature > /= 100.4 degrees Fahrenheit within seven days prior to challenge. Have a heart rate <45 beats per minute (bpm) or >100 bpm*. *If heart rate is <45 beats per minute and the investigator determines that this is not clinically significant (e.g., athletes) and heart rate increases > 45 beats per minute on moderate exercise (two flights of stairs), subject will not be excluded. If a subject has significant abnormalities in their heart rate, they will be informed of the values and advised to seek care from their physician. Systolic blood pressure less than 90 mm Hg or greater than 150 mm Hg on two separate measurements (screening and baseline prior to challenge)*. *If a subject has significant abnormalities in their blood pressure, they will be informed of the values and advised to seek care from their physician. Diastolic blood pressure less than 50 mm Hg or greater than 90 mm Hg on two separate measurements (screening and baseline, prior to challenge). Have long-term use (> / = 2 weeks) of high-dose oral (> / = 20 mg per day prednisone or equivalent) or parenteral glucocorticoids, or high-dose inhaled steroids for greater than 7 days in the last 6 months. Have an autoimmune, inflammatory, vasculitic or rheumatic disease, including but not limited to systemic lupus erythematosus, polymyalgia rheumatica, rheumatoid arthritis or scleroderma. Have HIV, Hepatitis B, or Hepatitis C*. *Subjects will be tested for HIV, Hepatitis B surface antigen, and antibody to Hepatitis C at screening only. Any subjects having HIV, Hepatitis B, Hepatitis C infection will not be enrolled into the study. Have a seizure disorder. Have an active malignancy or history of malignancy* or current use of immunosuppressive or cytotoxic therapy. *Excluding nonmelanotic skin cancer in remission without treatment for more than 5 years. Have abnormal screening laboratory test results per laboratory reported normal values*. *For white blood cells (WBCs), hemoglobin (Hgb), platelets, absolute neutrophil count (ANC), total bilirubin, potassium, sodium, and urine protein. Serum creatinine greater than a Grade 1 adverse event on enrollment. Alanine aminotransferase (ALT), greater than Grade 1 adverse event on enrollment. Have a chronic condition that the study physician feels would pose a threat to participating subjects*. *Including, but not limited to solid organ or stem cell transplantation, diabetes, clinically significant history of immunosuppressive illness, gall bladder disease, heart disease, lung disease, pancreatic disease, renal disease or neurological disease. Have ongoing drug abuse/dependence (including alcohol), or a history of these issues within 5 years of enrollment. Have a positive urine test for opiates. Have any medical, psychiatric, occupational, or behavioral problems that make it unlikely for the subject to comply with the protocol as determined by the investigator. Are unwilling to comply with study procedures including abstaining from smoking for the duration of the inpatient portion of the study. Have participated in a previous norovirus (NoV) challenge study or NoV vaccine study. Have received experimental products within 30 days before study entry or plan to receive experimental products at any time during the study. Plans to enroll in another clinical trial that could interfere with safety assessment of the investigational product at any time during the study period*. *Including study interventions such as drugs, biologics or devices. Plan to donate blood during the course of the study. Have received a live vaccine within 30 days before study entry or plan to receive a live vaccine prior to Day 30 of the study. Have received, or plan to receive, an inactivated vaccine within 14 days of challenge to 14 days after challenge. Received parenteral immunoglobulin or blood products within 3 months of challenge, or plan to receive parenteral immunoglobulin/blood products within 3 months after challenge. Use of antibiotics within 7 days prior to entry into the inpatient facility. Use of prescription and OTC medications containing acetaminophen, aspirin, ibuprofen, and other non-steroidal anti-inflammatory drugs within 48 hours prior to NoV challenge. Regular use of laxatives or anti-motility agents. Have a history of allergy to sodium bicarbonate. Have had a recent norovirus infection or have ever had a norovirus vaccine.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 49 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: Basic Science
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>Single dose (3.5x10^3 copies) of norovirus GII.4 CIN-3 Batch No.: 01-16C3 inoculum (with 60 mL of a 2% sodium bicarbonate before and after inoculum administration) will be given orally to subjects with functional FUT-2 gene (secretor positive), n=15, and single dose (3.5x10^3 copies) of norovirus GII.4 CIN-3 Batch No.: 01-16C3 inoculum (with 60 mL of a 2% sodium bicarbonate before and after inoculum administration) will be given to subjects with a lack a non-functional FUT-2 gene (non-secretor), n=1, on Day 1 | Biological: Norovirus GII.4 Challenge Pool<br>* Subjects will be NPO (nothing by mouth) for at least 90 minutes followed by ingestion of 60 mL of a 2% sodium bicarbonate solution by mouth. 2 minutes later, subjects will be administered Norovirus GII.4 CIN-3. Five minutes following administration of the challenge dose, subjects will be administered a 60 mL volume of a 2% sodium bicarbonate solution and then remain NPO for at least the next 90 minutes. Subjects will be observed during the 60 minutes after receipt of the challenge by a study team member to detect and treat any immediate adverse reactions.<br>|
| Experimental: Cohort 2<br>Single dose (3.5x10^4 copies) of norovirus GII.4 CIN-3 Batch No.: 01-16C3 inoculum (with 60 mL of a 2% sodium bicarbonate before and after inoculum administration) will be given orally to subjects with functional FUT-2 gene (secretor positive), n=15, and single dose (3.5x10^4 copies) of norovirus GII.4 CIN-3 Batch No.: 01-16C3 inoculum (with 60 mL of a 2% sodium bicarbonate before and after inoculum administration) will be given to subjects with a lack a non-functional FUT-2 gene (non-secretor), n=1, on Day 1 | Biological: Norovirus GII.4 Challenge Pool<br>* Subjects will be NPO (nothing by mouth) for at least 90 minutes followed by ingestion of 60 mL of a 2% sodium bicarbonate solution by mouth. 2 minutes later, subjects will be administered Norovirus GII.4 CIN-3. Five minutes following administration of the challenge dose, subjects will be administered a 60 mL volume of a 2% sodium bicarbonate solution and then remain NPO for at least the next 90 minutes. Subjects will be observed during the 60 minutes after receipt of the challenge by a study team member to detect and treat any immediate adverse reactions.<br>|
| Experimental: Cohort 3<br>Single dose (3.5x10^5 copies) of norovirus GII.4 CIN-3 Batch No.: 01-16C3 inoculum (with 60 mL of a 2% sodium bicarbonate before and after inoculum administration) will be given orally to subjects with functional FUT-2 gene (secretor positive), n=15, and single dose (3.5x10^5 copies) of norovirus GII.4 CIN-3 Batch No.: 01-16C3 inoculum (with 60 mL of a 2% sodium bicarbonate before and after inoculum administration) will be given to subjects with a lack a non-functional FUT-2 gene (non-secretor), n=1, on Day 1 | Biological: Norovirus GII.4 Challenge Pool<br>* Subjects will be NPO (nothing by mouth) for at least 90 minutes followed by ingestion of 60 mL of a 2% sodium bicarbonate solution by mouth. 2 minutes later, subjects will be administered Norovirus GII.4 CIN-3. Five minutes following administration of the challenge dose, subjects will be administered a 60 mL volume of a 2% sodium bicarbonate solution and then remain NPO for at least the next 90 minutes. Subjects will be observed during the 60 minutes after receipt of the challenge by a study team member to detect and treat any immediate adverse reactions.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of norovirus-associated illness (vomiting, diarrhea, positive PCR) in secretor-positive subjects |  | Day 1 through Day 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration (hours) of vomiting and/or diarrhea |  | Day 1 through Day 5 | 
| Duration (number of days) of viral secretion as measured by qRT-PCR |  | Day 1 through Day 60 | 
| Modified Vesikari score |  | Day 1 through Day 4 | 
| Number of solicited adverse events (AE) |  | Day 1 through Day 10 | 
| Number of subjects with infection defined as > / = 4-fold rise from baseline in GII.4-specific antibody titers in serum IgG by ELISA |  | Day 1 through Day 30 | 
| Number of subjects with infection defined as detection of norovirus GII.4 in stool by qRT-PCR |  | Day 15 | 
| Number of subjects with infection defined as detection of norovirus GII.4 in stool by qRT-PCR |  | Day 2 | 
| Number of subjects with infection defined as detection of norovirus GII.4 in stool by qRT-PCR |  | Day 3 | 
| Number of subjects with infection defined as detection of norovirus GII.4 in stool by qRT-PCR |  | Day 30 | 
| Number of subjects with infection defined as detection of norovirus GII.4 in stool by qRT-PCR |  | Day 4 | 
| Number of subjects with infection defined as detection of norovirus GII.4 in stool by qRT-PCR |  | Day 5 | 
| Number of subjects with infection defined as detection of norovirus GII.4 in stool by qRT-PCR |  | Day 6 | 
| Number of unsolicited Grade 3 adverse events |  | Day 1 through Day 30 | 
| Number of unsolicited serious adverse events (SAE) |  | Day 1 through Day 180 | 
| Peak genome equivalent copies/mL of virus in stool as measured by qRT-PCR after challenge |  | Day 1 through Day 60 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Healthy Adults, Norovirus GII.4 CIN-3, Optimal Human Challenge Dose