A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled, Single Dose, Dose-ranging Study to Determine the Safety and Immunogenicity of Bivalent GI.1 and GII.4 Vaccine Administered Orally to Healthy Volunteers Aged Greater Than or Equal to 18 Years and Less Than or Equal to 80 Years Old.
Overview
- Phase
- Phase 2
- Intervention
- Placebo
- Conditions
- Norovirus Infections
- Sponsor
- Vaxart
- Enrollment
- 135
- Locations
- 3
- Primary Endpoint
- Number of Participants With Solicited Symptoms of Reactogenicity (Gastrointestinal [GI] and Systemic)
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
This study is designed to evaluate the safety and immunogenicity of two monovalent Norovirus (NoV) oral tableted vaccine candidates, VXA-G1.1-NN and VXA-GII.4-NS co-administered (bivalent delivery) against a matching placebo arm. Bivalent GI.1 and GII.4 vaccines are being investigated for the prevention of noroviral gastroenteritis caused by norovirus GI.1 and GII.4.
Detailed Description
Norovirus infections are a leading cause of sporadic and epidemic gastroenteritis across all age groups worldwide. This study is designed as a standard double-blind placebo-controlled single administration, dose ranging study to evaluate the safety and immunogenicity of 2 different doses of VXA-GII.4-NS plus VXA-G1.1-NN (high and medium dose administered orally for the prevention of Norovirus infection), compared with a placebo. This study will enroll a total of 135 subjects with10 sentinel subjects in an open label period (dosing staggered to not-more-than 2 subjects per 24 hours) and randomize 125 subjects in three arms. The first 10 sentinel subjects will receive the open label high dose of active vaccine. If no dose-related toxicities are observed, and upon the recommendation of the SMC following review of safety data, subjects will be randomized in a 2:2:1 ratio to one of the 3 study arms to receive active vaccine or placebo. After vaccination on Day 1, the study will include an Active Study Period that runs through 4 weeks after administration (Day 29), and a Follow-up Period of one year for safety and duration of immune response.
Investigators
Eligibility Criteria
Inclusion Criteria
- •To be eligible for this study, subjects must meet all the following:
- •In stable and good general health, without significant medical illness, based on medical history, physical examination, and vital signs at screening based on investigator judgement.
- •Body mass index (BMI) between \>/= 17.0 and \</= 35.0 kg/m2 at screening SNG.
- •Available for all planned visits and tele-health appointment, and willing to complete all protocol-defined procedures and assessments (including ability and willingness to swallow multiple small enteric-coated tablets per study dose).
- •Female subjects must not be breastfeeding and must provide a negative pregnancy test at screening and pre-dose.
- •Female subjects must fulfill one of the following criteria:
- •i. At least 1 year post-menopausal (defined as amenorrhea for greater than or equal to 12 consecutive months prior to screening without alternative medical cause) or surgically sterile.
- •ii. Female subjects of childbearing potential must be willing to use a highly effective form of contraception for 30 days prior to initial vaccination and until 60 days after last vaccination. Acceptable forms are oral, implantable, intrauterine, transdermal, intravaginal, injectable, double barrier or abstinence (subjects using diaphragms must also use condom). The form of contraception must be approved by the investigator.
- •iii. Male subjects must agree to practice abstinence from heterosexual intercourse or to use an effective method of birth control as noted above from first vaccination to 60 days after last vaccination. Male subjects must agree to refrain from donating sperm and practice abstinence from all intercourse or to use an effective method of double barrier birth control or condom as noted above from first vaccination to 60 days after last vaccination.
- •Capable of understanding and giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in the protocol.
Exclusion Criteria
- •The subjects must be excluded from participating in the study if they meet any of the following:
- •Known clotting/bleeding issues and/or personal and family history with increased risk of bleeding or clotting.
- •Presence of significant uncontrolled medical or psychiatric illness (acute or chronic) including institution of new medical/surgical treatment or significant dose alteration for uncontrolled symptoms or drug toxicity within 3 months prior to screening and reconfirmed at baseline.
- •Cancer, or treatment for cancer or any procedure or preventive medication for cancer or to prevent recurrence, within past 3 years (excluding fully treated and resolved basal cell carcinoma or squamous cell carcinoma)
- •Presence of immunosuppression or medical condition possibly associated with impaired immune responsiveness, including diabetes mellitus- type 1 and 2
- •History of irritable bowel disease or other 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:
- •a. Any history of: i. GI malignancy ii. malabsorption iii. pancreatobiliary disorders iv. inflammatory bowel disease v. irritable bowel disease vi. hiatal hernia vii. surgical resection b. History of diagnosis or treatment in past 5 years of: i. esophageal or gastric motility disorder ii. gastro esophageal reflux disorder iii. peptic ulcer iv. cholecystectomy
- •History of any form of angioedema
- •History of serious reactions to vaccination such as anaphylaxis, respiratory problems, hives or abdominal pain
- •Diagnosed bleeding disorder or significant bruising or bleeding difficulties that could make blood draws problematic.
Arms & Interventions
Placebo Arm
Placebo tablets (N= 25)
Intervention: Placebo
Open Label Sentinel
Bivalent GII.4/GI.1 vaccine Bivalent GII.4/GI.1 high dose vaccine (VXA-GII.4-NS plus VXA-G1.1-NN) 1×10 to the power 11 tablets total dose is 2×10 to the power 11 IU/dose (sentinel n=10)
Intervention: Open label Bivalent GII.4/GI.1 high dose vaccine 2×10 to the power 11 IU/dose
Medium Dose Arm
Bivalent GII.4/GI.1 vaccine Bivalent GII.4/GI.1 medium dose vaccine (VXA-GII.4-NS plus VXA-G1.1-NN) 5×10 to the power 10 tablets total dose is 1×10 to the power 11 IU/dose (N=50)
Intervention: Bivalent GII.4/GI.1 medium dose vaccine 1×10 to the power 11 IU/dose
High Dose Arm
Bivalent GII.4/GI.1 vaccine Bivalent GII.4/GI.1 high dose vaccine (VXA-GII.4-NS plus VXA-G1.1-NN) 1×10 to the power 11 tablets total dose is 2×10 to the power 11 IU/dose (N=50)
Intervention: Bivalent GII.4/GI.1 high dose vaccine 2×10 to the power 11 IU/dose
Outcomes
Primary Outcomes
Number of Participants With Solicited Symptoms of Reactogenicity (Gastrointestinal [GI] and Systemic)
Time Frame: Up to Day 8
Solicited adverse events (AEs) are predefined signs and symptoms of reactogenicity for which the participants were specifically questioned, and which were noted by the participant in their Solicited Symptom Diary for 7 days after drug administration, including: * fever (any temperature 100.4°F or higher) * headache * myalgia (muscle pain) * abdominal pain * anorexia (defined as not eating) * nausea * vomiting * diarrhoea * malaise/fatigue. The severity of each solicited symptoms of reactogenicity was graded by the participant as mild, moderate, severe or life-threatening. Participants with multiple Solicited AEs were only counted once in summarizing overall percentages of Solicited AEs, the highest severity of which was used.
Number of Participants With Unsolicited AEs
Time Frame: Up to Day 29
Treatment emergent AEs (TEAEs) are defined as AEs that occurred following the first administration of study medication. An unsolicited AE is an observed AE that did not fulfill the conditions prelisted in terms of diagnosis and/or onset window post-vaccination. The severity of each AE was graded by the participant as mild, moderate or severe/ life-threatening.
Serum - Anti-Vaccine Protein 1 (VP1) GI.1 Immunoglobulin A (IgA) Levels by Meso Scale Discovery (MSD) Assay
Time Frame: Day 1 and Day 29
Serum levels of Anti-VP1 GI.1 IgA were evaluated using cellular and humoral immune (HI) function assays from blood and mucosal (saliva and nasal swab) samples. 95% confidence intervals were estimated by Clopper-Pearson exact method. Assay is measured in AU/mL.
Fold Rise in Serum - Anti-VP1 GI.1 IgA Levels by MSD Assay
Time Frame: Day 1 and Day 29
Serum levels of Anti-VP1 GI.1 IgA were evaluated using cellular and HI function assays from blood and mucosal (saliva and nasal swab) samples. The fold rise was calculated per participant by dividing the antibody concentration (original scale) on Day 29 with antibody concentration at baseline (Day 1). 95% confidence intervals were estimated by Clopper-Pearson exact method.
Serum - Anti-VP1 GII.4 IgGA Levels by MSD Assay
Time Frame: Day 1 and Day 29
Serum levels of Anti-VP1 GII.4 IgA were evaluated using cellular and HI function assays from blood and mucosal (saliva and nasal swab) samples. 95% confidence intervals were estimated by Clopper-Pearson exact method. Assay is measured in AU/mL.
Fold Rise in Serum - Anti-VP1 GII.4 IgA Levels by MSD Assay
Time Frame: Day 1 and Day 29
Serum levels of Anti-VP1 GII.4 IgA were evaluated using cellular and HI function assays from blood and mucosal (saliva and nasal swab) samples. The fold rise was calculated per participant by dividing the antibody concentration (original scale) on Day 29 with antibody concentration at baseline (Day 1). 95% confidence intervals were estimated by Clopper-Pearson exact method.
Serum - Anti-VP1 GI.1 Immunoglobulin G (IgG) Levels by MSD Assay
Time Frame: Day 1 and Day 29
Serum levels of Anti-VP1 GI.1 IgG were evaluated using cellular and HI function assays from blood and mucosal (saliva and nasal swab) samples. 95% confidence intervals were estimated by Clopper-Pearson exact method. Assay is measured in AU/mL.
Fold Rise in Serum - Anti-VP1 GI.1 IgG Levels by MSD Assay
Time Frame: Day 1 and Day 29
Serum levels of Anti-VP1 GI.1 IgG were evaluated using cellular and HI function assays from blood and mucosal (saliva and nasal swab) samples. The fold rise was calculated per participant by dividing the antibody concentration (original scale) on Day 29 with antibody concentration at baseline (Day 1). 95% confidence intervals were estimated by Clopper-Pearson exact method.
Serum - Anti-VP1 GII.4 IgG Levels by MSD Assay
Time Frame: Day 1 and Day 29
Serum levels of Anti-VP1 GII.4 IgG were evaluated using cellular and HI function assays from blood and mucosal (saliva and nasal swab) samples. 95% confidence intervals were estimated by Clopper-Pearson exact method. Assay is measured in AU/mL.
Fold Rise in Serum - Anti-VP1 GII.4 IgG Levels by MSD Assay
Time Frame: Day 1 and Day 29
Serum levels of Anti-VP1 GII.4 IgG were evaluated using cellular and HI function assays from blood and mucosal (saliva and nasal swab) samples. The fold rise was calculated per participant by dividing the antibody concentration (original scale) on Day 29 with antibody concentration at baseline (Day 1). 95% confidence intervals were estimated by Clopper-Pearson exact method.
Serum - Anti-VP1 GI.1 Blocking Antibodies (BT50) Titers by MSD Assay
Time Frame: Day 1 and Day 29
Serum levels of Anti-VP1 GI.1 BT50 were evaluated using cellular and HI function assays from blood and mucosal (saliva and nasal swab) samples. 95% confidence intervals were estimated by Clopper-Pearson exact method.
Fold Rise in Serum - Anti-VP1 GI.1 BT50 Titers by MSD Assay
Time Frame: Day 1 and Day 29
Serum levels of Anti-VP1 GI.1 BT50 were evaluated using cellular and HI function assays from blood and mucosal (saliva and nasal swab) samples. The fold rise was calculated per participant by dividing the antibody concentration (original scale) on Day 29 with antibody concentration at baseline (Day 1).
Serum - Anti-VP1 GII.4 BT50 Titers by MSD Assay
Time Frame: Day 1 and Day 29
Serum levels of Anti-VP1 GII.4 BT50 were evaluated using cellular and HI function assays from blood and mucosal (saliva and nasal swab) samples. 95% confidence intervals were estimated by Clopper-Pearson exact method.
Fold Rise in Serum - Anti-VP1 GII.4 BT50 Titers by MSD Assay
Time Frame: Day 1 and Day 29
Serum levels of Anti-VP1 GII.4 BT50 were evaluated using cellular and HI function assays from blood and mucosal (saliva and nasal swab) samples. The fold rise was calculated per participant by dividing the antibody concentration (original scale) on Day 29 with antibody concentration at baseline (Day 1). 95% confidence intervals were estimated by Clopper-Pearson exact method.