Optimal Human Dose for GII.2 Norovirus (Snow Mountain) Challenge Studies

NCT02473224 | Completed Phase 1 FDA Drug

• 1 other identifier: 12-0034
• Study Type: interventional
• Target: 44
• Locations: 1 country
• Sites: 1

Brief Summary

This is a phase I, randomized, double blind, as well as partially blinded (for Cohort 4), placebo-controlled safety, illness, and infection study of a new experimental human challenge stock of the Norovirus genogroup II, genotype 2 (GII.2) isolate designated Snow Mountain virus (SMV). The study duration is 24 - 36 months. The primary objectives are to: 1) evaluate the safety and reactogenicity of the GII.2 Snow Mountain norovirus challenge stock and 2) determine a safe and optimal challenge dose of GII.2 Snow Mountain norovirus to achieve illness in a high proportion (= / \> 75%) of subjects.

Conditions

Gastroenteritis Norovirus

Keywords

challenge; GII.2; HID50; Norovirus; Snow Mountain filtrate

Outcome Measures

Primary Outcomes (7)

• Infectious Dose-50 based on infection rate after challenge with various doses

  Day 2 to Day 5

• Number of serious adverse events related to virus challenge

  Day 1 to Day 180

• Number of subjects experiencing any mild reactogenicity outcomes

  Day 1 to Day 10

• Number of subjects experiencing any moderate reactogenicity outcomes

  Day 1 to Day 10

• Number of subjects experiencing any severe reactogenicity outcomes

  Day 1 to Day 10

• Number of subjects experiencing Grade 3 adverse events

  Day 1 to Day 30

• Proportion of subjects with GII.2 Snow Mountain norovirus-associated illness following GII.2 challenge

  Day 1 to Day 5

Secondary Outcomes (18)

• Duration of diarrhea related to the challenge strain

  Day 1 to Day 5

• Duration of virus shedding in PCR-positive stool for each challenge dose

  Day -60 to Day 75

• Duration of vomiting related to the challenge strain

  Day 1 to Day 5

• Levels of pre-existing serum blockage IgG prior to challenge

  Inpatient Admission

• Levels of pre-existing serum IgA prior to challenge

  Inpatient Admission

Study Arms (4)

Cohort 1

EXPERIMENTAL

9 secretor-positive subjects will receive 1.2x10\^4 Genome Equivalent Copies (GEC) oral dose on Day 1; and 2 secretor-positive subjects will receive the placebo, n=11

Biological: Norovirus GII.2 Challenge; Other: Placebo

Cohort 2

EXPERIMENTAL

9 secretor-positive subjects will receive either 1.2 x 10\^2GEC, or 1.2 x10\^6 GEC oral dose on Day 1, depending on the percentage of subjects with illness from Cohort 1; 2 secretor-positive subjects will receive the placebo, n=11

Biological: Norovirus GII.2 Challenge; Other: Placebo

Cohort 3

EXPERIMENTAL

9 secretor-positive subjects will receive either 1GEC, 1.2 x 10\^1 GEC, 1.2 x 10\^2 GEC, 1.2 x 10\^3 GEC, 1.2 x 10\^5 GEC, 1.2 x 10\^6 GEC, or 1.2 x 10\^7 oral dose on Day 1, depending on the percentage of subjects with illness from Cohorts 1 and 2; 2 secretor-positive subjects will receive the placebo, n=11

Biological: Norovirus GII.2 Challenge; Other: Placebo

Cohort 4

EXPERIMENTAL

8 secretor-negative and 3 secretor-positive subjects will receive 1.2 x 10\^7 GEC oral dose on Day 1, n=11

Biological: Norovirus GII.2 Challenge; Other: Placebo

Interventions

Norovirus GII.2 Challenge BIOLOGICAL

GII.2 Snow Mountain Norovirus Filtrate. Cohort 1: 1.2x10\^4 Genome Equivalent Copies (GEC) oral dose on Day 1. Cohort 2: either 1.2 x 10\^2 GEC or 1.2 x10\^6 GEC oral dose on Day 1, depending on the results of prior Cohort 1. Cohort 3: either 1GEC, 1.2 x 10\^1 GEC, 1.2 x 10\^2 GEC, 1.2 x 10\^3 GEC, 1.2 x 10\^5 GEC, or 1.2 x 10\^6 GEC, or 1.2 GEC x 10\^7 oral dose on Day 1, depending on the percentage of subjects with illness from Cohorts 1 and 2. Cohort 4: optimal dose of GEC as determined by the results of cohorts 1-3

Cohort 1; Cohort 2; Cohort 3; Cohort 4

Placebo OTHER

Placebo: 80 ml of sterile water for oral administration

Cohort 1; Cohort 2; Cohort 3; Cohort 4

Eligibility Criteria

• Age: 18 Years - 49 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Subject able to provide written informed consent
• Male or non-pregnant females between the ages of 18 and 49 years, inclusive
• Women of childbearing potential must be practicing abstinence or using an acceptable method of birth control for at least 30 days prior to enrollment through day 45 after receipt of the challenge virus. Male subjects must agree not to father a child prior to day 45 after receipt of the 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 (IUDs, NuvaRing) 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 and negative urine pregnancy test within 24 hours prior to challenge
• Are in good general health, as determined by the study investigator within 60 days of challenge
• Demonstrate knowledge and comprehension of the study by scoring \>/= 70 percent on a quiz of the study protocol and policies
• Willing and able to participate in all study visits, including an inpatient stay of at least 96 hours
• Demonstrated to be H type I secretor positive for HBGA binding by assay of saliva (this applies to all cohorts except the SN cohort, which will include secretor negative subjects only)

You may not qualify if:

• Have household contact with or have daily contact with children under 2 years of age or persons older than 70 years of age
• Have expected occupational or social contact 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). Individuals who provide any child day care services (in-home or non-residential facility) are also excluded
• Are healthcare workers with patient contact in the 8 weeks after challenge
• Are food service workers expected to prepare/handle food in the 8 weeks after challenge
• Plan to be living in a confined 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 gastroenteritis in the 4 weeks prior to challenge or any history of chronic or recurrent diarrhea or vomiting
• Have a history of malabsorption or maldigestion disorder (e.g. celiac sprue), major gastrointestinal (GI) surgery, irritable bowel syndrome or any other chronic GI disorders that would interfere with the study, including chronic constipation or increased stool frequency
• Have moderate or severe illness and/or an oral temperature \>/=100.4 degrees F and/or diarrhea or vomiting within seven days prior to challenge
• Have a pulse rate less than 55 beats per minute (bpm) or greater than 100 bpm. If heart rate is \<55 bpm and the investigator determines that this is not clinically significant (e.g., athletes) and heart rate increases \> 55 bpm on moderate exercise (two flights of stairs), subject will not be excluded
• Have a systolic blood pressure less than 90 mmHg or greater than 140 mmHg on two separate measurements (screening and pre-challenge)
• Have a diastolic blood pressure less than 50 mmHg or greater than 90 mmHg on two separate measurements (screening and pre-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 rheumatic, rheumatoid arthritis or scleroderma

Sponsors & Collaborators

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

Study Sites (1)

Emory Vaccine Center - The Hope Clinic

Decatur, Georgia, 30030-1705, United States

Location

Related Publications (1)

• Rouphael N, Beck A, Kirby AE, Liu P, Natrajan MS, Lai L, Phadke V, Winston J, Raabe V, Collins MH, Girmay T, Alvarez A, Beydoun N, Karmali V, Altieri-Rivera J, Lindesmith LC, Anderson EJ, Wang Y, El-Khorazaty J, Petrie C, Baric RS, Baqar S, Moe CL, Mulligan MJ. Dose-Response of a Norovirus GII.2 Controlled Human Challenge Model Inoculum. J Infect Dis. 2022 Nov 11;226(10):1771-1780. doi: 10.1093/infdis/jiac045.

  PMID: 35137154 DERIVED

Study Design

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

Study Record Dates

• First Submitted: June 4, 2015
• First Posted: June 16, 2015
• Study Start: October 28, 2015
• Primary Completion: November 27, 2018
• Study Completion: November 27, 2018
• Last Updated: December 7, 2018

Record last verified: 2018-06-15

Locations

US (1)