A Phase 2b Double-Blinded, Randomized, Placebo-Controlled, Human Norovirus GI.1 (Norwalk Virus Inoculum) Challenge Study Following Administration of an Oral, Single-dose Norovirus Vaccine Expressing GI.1 VP1 and dsRNA Adjuvant to Protect Against Norovirus Gastroenteritis (NVG) in Healthy Adult Volunteers (G1-1 Challenge)

  • STATUS
    Recruiting
  • End date
    Dec 2, 2023
  • participants needed
    120
  • sponsor
    Vaxart
Updated on 17 October 2022
Accepts healthy volunteers

Summary

This is a Phase 2b randomized, double-blind, placebo-controlled vaccination and challenge study to assess the protective efficacy of the Vaxart Norovirus vaccine (VXA-G1.1-NN). Healthy adults will be randomized in a 1:1 ratio to receive one oral dose of vaccine or placebo.

  • Arm 1: VXA-G1.1-NN oral vaccine tablets [1x1011 IU±0.5 log]
  • Arm 2: Placebo tablets similar in appearance and number to active vaccine tablets

Approximately 28 days post-vaccination, subjects will be admitted to an isolation ward and challenged with the NV GI.1 Norwalk challenge strain. After challenge, subjects will be monitored for signs and symptoms of acute gastroenteritis (AGE) from Day 29 to discharge. At 4 days post challenge (Day 33) asymptomatic subjects will be discharged from the isolation ward and will be followed in a series of outpatient visits and telephone calls. Symptomatic subjects may be kept in the isolation ward for up to an additional 3 days.

Description

Study Population Healthy male and female adult volunteers age 18 to 49 years inclusive with blood type O or A and who are confirmed H type-1 antigen secretory positive Investigational Product

Active Vaccine:

  • Norovirus GI.1 Norwalk VP1 Vaccine (VXA-G1.1-NN), an Oral E1/E3-Deleted Replication-Defective Recombinant Adenovirus serotype 5 with double-stranded ribonucleic acid (dsRNA) Adjuvant. The vaccine vector encodes for a full-length VP1 gene from Norwalk virus (NV). The adjuvant is a short hairpin RNA, expressed as a 21 nucleotide sequence (GAAACGA TATGGGCTGAATAC) as a tandem sequence in forward and reverse orientations separated by 6 nucleotides that comprise the loop of the RNA. The final drug product (DP) is formulated into enteric-coated tablet.
  • Dose: 1x10E11 IU±0.5 log

Placebo Control:

• Oral tablets similar in appearance and number to active vaccine tablets Multiple tablets of study drug will be dispensed to allow delivery of the intended vaccine dose (1x10E11 IU). A matching number of placebo tablets will be dispensed to maintain the study blinding.

Viral Challenge Inoculum

  • Norovirus GI.1 (Norwalk Virus Inoculum Lot 001-09NV, IND 14697)
  • Dose: 1x10E6 Genomic Copies (GC). A dose which allows 50% - 65% infectivity in the healthy adult population (per NV infection rate observed in the GI.1 viral titration study

Study Hypothesis Norovirus vaccine (VXA-G1.1-NN) will protect against Norovirus Gastroenteritis (NVG) related to norovirus (NoV) infection in the challenge model

Approximately 120 subjects will be dosed in the vaccination phase to ensure at least 100 subjects (~ 50 VXA-G1.1-NN vaccine and 50 placebo) are available to participate in the challenge phase. Approximately 28 days post-vaccination, subjects will be admitted to an isolation ward and challenged with the NV GI.1 Norwalk challenge strain. After challenge, subjects will be monitored for signs and symptoms of acute gastroenteritis (AGE) from Day 29 to discharge. NV illness lasts 2-4 days and is self-limited. At 4 days post challenge (Day 33) asymptomatic subjects will be discharged from the isolation ward and will be followed in a series of outpatient visits and telephone calls. Symptomatic subjects may be kept in the isolation ward for up to an additional 3 days.

The following study visits and remote contacts will be conducted during the study

Vaccination Phase:

  • Pre-Screening Period (Days -90 to Screening) may be utilized for purposes of ascertaining subjects' H type-1 antigen secretory status and blood type
  • Screening Period (Days -45 to -1)
  • Day 1 Visit (Baseline assessments; day of randomization and vaccination)
  • Day 8 Visit (safety and evaluation of immune response)
  • Day 28 (evaluation of immune response; 1 day prior to challenge, start inpatient stay)

Challenge Phase:

  • Day 29 (viral challenge, sequestration)
  • Days 30 to 33 (sequestration - discharge; +3 days)
  • Day 36 Visit (evaluation of immune response and safety assessment)
  • Day 57 Visit (end of active period)

Safety Follow-Up:

  • Day 120, Day 180, Day 240 and Day 300 (follow-up contact)
  • Day 365 (follow-up phone call): Study completion

An independent Safety Monitoring Committee (SMC) will convene at pre-defined intervals during the norovirus challenge period, and also ad hoc as needed during the vaccination and challenge periods, to oversee the safety of the study.

Details
Condition Norovirus Infections
Treatment Placebo Tablets, VXA-G1.1-NN, Norovirus GI.1 Norwalk Virus Inoculum
Clinical Study IdentifierNCT05212168
SponsorVaxart
Last Modified on17 October 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

Male or female between the ages of 18 - 49 years, inclusive
Able to give written informed consent
Healthy, as determined by the principal investigator (PI) or PI in consultation with the research monitor and Sponsor Healthy = No clinically significant health concerns or medical illness, as determined by medical history, physical examination, vital signs, electrocardiogram (ECG), and clinical laboratories (complete blood count (CBC), chemistry and urinalysis)
Comprehension of the study requirements with ability and willingness to complete all assessments and comply with confinement period post viral challenge, and all scheduled visits and contacts
Confirmed blood type (A or O)
Demonstrated to be H type-1 antigen secretor positive (by saliva test)
Body mass index between 17 and 35 kg/m2, inclusive, at Screening
Female participants must have a negative pregnancy test at pre-vaccination and pre-challenge and fulfill one of the following Criteria
At least one year post-menopausal
Surgically sterile
Use of oral, implantable, transdermal or injectable contraceptives for 30 days prior to immunization and until 60 days after challenge
A reliable form of contraception must be approved by the Investigator (eg, double barrier method, Depo-Provera, intrauterine device, Norplant, oral contraceptives, contraceptive patches) d. Not be sexually active (abstinent) or in a same sex relationship (must be discussed with site staff and documented)
Male subjects must agree not to father a child or donate sperm, as well as to use
contraception/barrier (a male condom) or be abstinent from heterosexual
intercourse, from vaccination through the active period (Day 57)

Exclusion Criteria

Administration/use of any investigational drug or device 30 days prior to vaccination through the active period (Day 57)
Administration of any licensed vaccine within 30 days prior to vaccination or planned use of the above stated during the active period (through Day 57)
Presence of a significant medical condition, which, in the opinion of the investigator, precludes participation in the study. Significant medical condition = for example, psychiatric conditions, or gastrointestinal disease, such as peptic ulcer, symptoms or evidence of active gastritis or gastroesophageal reflux disease, inflammatory bowel disease, alcohol or illicit drug abuse/dependency, or other laboratory abnormalities
Laboratory values outside the range of normal for platelet counts and the following coagulation tests: prothromibin time test (PT/INR), activated partial thromboplastine time test (aPTT) and fibrinogen
Any of the following history or conditions that may lead to higher risk of clotting events and/or thrombocytopenia
Family or personal history of bleeding or thrombosis
History of heparin-related thrombotic events, and/or receiving heparin treatments
History of autoimmune or inflammatory disease
Presence of any of the following conditions known to increase risk of thrombosis within 6 months prior to screening
Recent surgery other than removal/biopsy of cutaneous lesions
Immobility (confined to bed or wheelchair for 3 or more successive days)
Head trauma with loss of consciousness or documented brain injury
Receipt of anticoagulants for prophylaxis of thrombosis
Recent clinically significant infection
Any one of the following ECG findings within 45 days prior to vaccination
Exclusionary ECG findings
QTc F (interval duration > 450 msec (male) or > 470 msec (female)
QRS interval greater than 120 msec
PR interval greater than 220 msec
Clinically significant ST-T wave changes or pathologic Q waves
History of cancer or cancer treatment within past 3 years (excluding basal cell or
squamous cell carcinomas)
Presence of immunosuppression or medical condition possibly associated with impaired immune responsiveness, including diabetes mellitus or angioedema
Donation or use of blood or blood products within 30 days prior to vaccination through the active period (Day 57)
Diagnosed bleeding disorder or significant bruising or bleeding difficulties that could make blood draws problematic
Any condition that resulted in the absence or removal of the spleen
Evidence of confirmed infection with human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) with confirmatory assays
Abnormal stool pattern (fewer than 3 bowel movements per week or more than 3 per day)
History of irritable bowel disease or inflammatory digestive or gastrointestinal condition that could affect the distribution / safety evaluation of an orally administered vaccine targeting the mucosa of the small intestine
Such conditions may include but are not limited to
Esophageal Motility Disorder
Malignancy
Malabsorption (e.g. Celiac disease, gluten intolerance)
Pancreaticobiliary disorders
Irritable bowel syndrome
Inflammatory Bowel Disease
Surgical Resection with the exception of appendectomy or a minor resection that is deemed acceptable by investigator and sponsor
Gastroesophageal reflux disease (GERD)
Hiatal Hernia
Peptic Ulcer (History of cholecystectomy is not exclusionary)
Use of proton pump inhibitors, H2 blockers or antacids within 7 days prior to
vaccination through the active period (Day 57)
Use of antibiotics within 30 days prior to vaccination through the active period (Day
Note: use of a brief (≤ 10 days) course of oral or topical antibiotic for minor upper respiratory infection (URI), urinary tract infection (UTI), dental work, or skin infection allowed within the screening period, but must be completed 7 days prior to first vaccination
Use of medication known to affect the immune function (e.g. systemic corticosteroids and others) within 14 days prior to vaccination through the active period (Day 57)
Regular use of nonsteroidal anti-inflammatory drugs within 7 days prior to vaccination through the active period (Day 57)
Use of over-the-counter probiotics or antidiarrheals within 7 days prior to vaccination through the active period (Day 57)
Evidence of recent (within 2 months of vaccination) or of current nonbacterial gastroenteritis suggestive of NV infection [vomiting or unformed or watery stools (> 2 during a 24-hour period)]
Any gastroenteritis within the past 2 weeks prior to vaccination
Acute disease within 72 hours prior to vaccination, defined as the presence of a moderate or severe illness with or without fever (as determined by the Investigator through medical history and physical examination). (Assessment may be repeated during screening period)
Presence of a fever ≥ 38ºC measured orally at baseline
History if hematochezia (blood in stool) or melena (black stool)
Any significant hospitalization within the last year which in the opinion of the investigator or sponsor could interfere with study participation
History of serious reactions to any vaccination such as anaphylaxis, respiratory problems, Guillain-Barre syndrome, hives or abdominal pain
History of a hypersensitivity or allergic reaction to any component of the investigational vaccine or placebo, including but not limited to fish gelatin. Subjects with known fish allergies should be excluded
History of drug, alcohol or chemical abuse within 1 year prior to vaccination
Positive test for drugs of abuse or alcohol at screening, vaccination baseline and pre-challenge (except for previous marijuana use; concurrent or ongoing use of marijuana during the active study period)
Consistent/habitual smoking within 2 months prior to vaccination (defined as smoking ≥ 1 pack of cigarettes a day). Smoking is not permitted during the inpatient stay
Other conditions, in the clinical judgment of the investigator, that would jeopardize the safety or rights of a subject or interfere with the evaluation of the study
Social/Occupational
Living with or having daily contact with children < 5 years old or women known to be pregnant or nursing; this includes significant contact at home, school, day-care, or equivalent facilities
Living with or having daily contact with elderly persons > 70 years of age or infirmed, diapered individuals, persons with disabilities or incontinence; this includes at work or visits to nursing homes and day-care or equivalent facilities
Employment in the food service industry such as restaurant or cafeteria facilities; specifically, this includes persons whose employment requires food handling and processing in the 4 weeks following viral challenge
Health-care workers with patient contact expected in the 4 weeks following viral challenge
Expected contact, via employment or at home, with immunocompromised persons in the 4 weeks following viral challenge. Immunocompromised persons = HIV-positive, receiving immunosuppressive medications such as oral steroids, anti-neoplastic agents
Presence of household members who have received the Ad4 or Ad7 vaccines within 2 months prior to vaccination
Employment as an airline flight attendant or cruise ship crew, scheduled to work in the 4 weeks following challenge
Persons planning to live in a confined environment (eg, a cruise, camp, etc.) in the 4 weeks following viral challenge
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