Phase I Study to Determine the Optimal Human Challenge Dose for a Norovirus GII.4 Challenge Stock (CIN-1)

NCT02337842 | Withdrawn Phase 1

• 2 other identifiers: 12-0033HHSN272200800006C
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

This is phase I, double blind, placebo-controlled safety and infectivity study of experimental human Norovirus genogroup GII.4 administered to healthy adults 18-49 years of age. Subjects susceptible to the human norovirus GII.4 challenge strain. The challenge study will be conducted in 2-3 cohorts of approximately 20 subjects each.Subjects will remain in the inpatient facility for at least four days following challenge and assessed daily for clinical and virologic evidence of norovirus infection. The primary objectives are to evaluate the safety and reactogenicity of the norovirus GII.4 (CIN-1; 031693) challenge stock and to determine a safe and optimal challenge dose of Norovirus GII.4 Challenge Stock norovirus to achieve illness in \> /=50% of subjects. Illness is defined as: diarrhea (\>3 loose or liquid stools or \>300 gm of loose or liquid stool /24h), and/or vomiting during the inpatient period, in a participant with evidence of infection.

Conditions

Gastroenteritis Norovirus

Keywords

NoV, CIN-1, GII4. Norovirus, challenge, FUT-2 gene, HBGA-blocking Ab

Outcome Measures

Primary Outcomes (5)

• Number of subjects experiencing any mild, moderate or severe reactogenicity outcomes.

  Day 1 to Day 180

• Proportion of subjects with Norovirus-GII.4 Challenge Stock (CIN-1; 031693) associated illness following norovirus GII.4 challenge

  Day 1 to Day 5

• Number of serious adverse events related to virus challenge reported at any point during the study

  Day 1 to Day 180

• Number of subjects experiencing Grade 3 adverse events after virus challenge throughout the study to day 30

  Day 1 to Day 30

• Determine Infectious Dose50 based on infection rate after challenge with various doses.

  Day 1 to Day 180

Secondary Outcomes (11)

• Infection rate within each dose, defined as proportion of subjects excreting challenge virus in stool 24 hours after challenge

  24 hours after challenge

• Proportion of subjects with norovirus specific IgG-ASC / 10^6 PBMC (freshly isolated PBMCs)

  Day 1 to Day 45

• Clinical Severity Score of vomiting and/or diarrhea related to the challenge strain using the Modified Vesikari Scale

  Day 1 to Day 5

• 95% confidence intervals of vomiting and/or diarrhea related to the challenge strain

  Day 1 to Day 5

• Mean duration (hours) of vomiting and/or diarrhea related to the challenge strain

  Day 1 to Day 5

Study Arms (4)

Cohort 1

EXPERIMENTAL

N= 9 subjects will receive single oral dose of GII.4 CIN-1 at 10\^3 RT-PCR units and N=1 single oral dose Placebo.

Biological: Norovirus GII.4 Challenge Pool CIN-1; Other: Placebo

Cohort 2

EXPERIMENTAL

N=9 subjects will receive single oral dose of GII.4 CIN-1 either at 10\^2 or 5x10\^3 RT-PCR units and N=1 single oral dose of Placebo.

Biological: Norovirus GII.4 Challenge Pool CIN-1; Other: Placebo

Cohort 4

EXPERIMENTAL

N=36 subjects will receive single oral dose of GII.4 CIN-1 at either 5x10\^4 or 5x10\^3 or 10\^3 or 10\^2 or 10\^4 or 5x10\^2 or 5x10\^1RT-PCR units , N=4 subjects receive a single oral dose of Placebo

Biological: Norovirus GII.4 Challenge Pool CIN-1; Other: Placebo

Cohort 3

EXPERIMENTAL

N=18 subjects will receive single oral dose of GII.4 CIN-1 at either 10\^4, 10\^3, 5x10\^2 or 5x10\^1 RT-PCR units and N=2 single oral dose of Placebo

Biological: Norovirus GII.4 Challenge Pool CIN-1; Other: Placebo

Interventions

Norovirus GII.4 Challenge Pool CIN-1 BIOLOGICAL

Norovirus Challenge GII.4 Strain 031693. Cohort 1: receive single oral dose of GII.4 CIN-1 at 10\^3 RT-PCR units. Cohort 2: single oral dose of GII.4 CIN-1 either at 10\^2 or 5x10\^3 RT-PCR units. Cohort 3: single oral dose of GII.4 CIN-1 at either 10\^4, 10\^3, 5x10\^2 or 5x10\^1 RT-PCR units. Cohort 4: single oral dose of GII.4 CIN-1 at either 5x10\^4 or 5x10\^3 or 10\^3 or 10\^2 or 10\^4 or 5x10\^2 or 5x10\^1RT-PCR units.

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 or serum 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 procent 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 secretor positive for HBGA binding.

You may not qualify if:

• 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 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) and/or provide any child day care services (in-home or non-residential facility).
• 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 degre Fahrenheit and/or diarrhea or vomiting within seven days prior to challenge.
• Have a pulse rate less than 55 bpm or greater than 100 bpm. If heart rate is \<55 beats per minute and the investigator determines that this is not clinically significant (e.g., athletes) and heart rate increases \> 55 beats per minute on moderate exercise (two flights of stairs), subject will not be excluded.
• Have a systolic blood pressure less than 90 mm Hg or greater than 140 mm Hg on two separate measurements (screening and pre-challenge).
• Have a diastolic blood pressure less than 50 mm Hg 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)

Cincinnati Children's Hospital Medical Center - Infectious Diseases

Cincinnati, Ohio, 45229-3026, United States

Location

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: January 8, 2015
• First Posted: January 14, 2015
• Study Start: September 1, 2015
• Primary Completion: January 1, 2016
• Study Completion: January 1, 2016
• Last Updated: June 3, 2016

Record last verified: 2015-08

Locations

US (1)