Challenge Model for Assessment of Human TB Immunity

NCT01868464 | Completed Phase 1 FDA Drug

• 1 other identifier: 11-0033
• Study Type: interventional
• Target: 92
• Locations: 1 country
• Sites: 2

Brief Summary

This is a Phase I open-label, dose escalation trial to evaluate the use of Tice® BCG as a challenge for future assessment of in vivo TB immunity. Subjects will be recruited from the target population reflecting the community at 2 VTEU sites. Enrollment will occur over 14 months. Subjects who provide informed consent will be screened, and up to 120 eligible, HIV and TB uninfected subjects, 18-45 years, inclusive, will be enrolled for study interventions and sequentially assigned to 1 of 4 dose groups. Doses of Tice BCG from 2 to 16x10\^6 cfu will be delivered ID in a dose escalation format to 4 groups of 30 subjects per dose group. Primary Objectives: 1) Evaluate the safety of different doses of ID Tice BCG for use as a human challenge model for TB infection. 2) Examine shedding from ID challenge sites after administration of different doses of Tice BCG in TB naive healthy subjects. 3) Evaluate the reproducibility of BCG shedding over time with both quantitative PCR and culture.

Conditions

Tuberculosis

Keywords

challenge; Mycobacterium tuberculosis; parent protocol; TB; Tice BCG; tuberculosis

Outcome Measures

Primary Outcomes (8)

• Serious adverse events related to Tice® BCG administration

  Day 1 to Day 181

• Summary of distribution, in terms of its precision, of BCG shedding from intradermal challenge sites using subjects' peak shedding, as detected by each of 3 assays (quantitative PCR, quantitative CFU plating and quantitative MGIT BACTEC culture).

  Following Tice® BCG administration biweekly to Week 6

• Summary of distribution, terms of its central tendency (mean or GM), of BCG shedding from intradermal challenge sites at 3 time points, as detected by each of 3 assays (quantitative PCR, quantitative CFU plating and quantitative MGIT BACTEC culture).

  Following Tice® BCG administration biweekly to Week 6

• The number of subjects experiencing Grade 3 (severe) clinical safety laboratory adverse events

  Day 1 to Day 181

• The number of subjects experiencing Grade 3 (severe) injection site reactions following Tice® BCG administration.

  Day 1 to Day 15

• The number of subjects experiencing Grade 3 (severe) solicited systemic reactions following Tice® BCG administration

  Day 1 to Day 15

• The number of subjects in groups 3 and 4 experiencing Grade 3 (severe) injection site reactions.

  Between Days 16 and 99 following Tice® BCG administration

• The number of subjects spontaneously reporting Grade 3 (severe) adverse events related to Tice® BCG administration following Tice® BCG administration.

  Day 1 to Day 56

Secondary Outcomes (4)

• Summary of distribution of the area under the curve for repeated measures of shedding over time from 3 assays (quantitative PCR, quantitative CFU plating and quantitative MGIT BACTEC culture). Summarized in terms of its central tendency (mean or GM)

  8 weeks (56 days) following Tice® BCG administration

• Summary of distribution of the area under the curve, in terms of its precision, for repeated measures of shedding over time from 3 assays (quantitative PCR, quantitative CFU plating and quantitative MGIT BACTEC culture).

  8 weeks (56 days) following Tice® BCG administration

• Summary of distribution, in terms of its precision, of BCG shedding from intradermal challenge sites using subjects' peak shedding, as detected by each of 3 assays (quantitative PCR, quantitative CFU plating and quantitative MGIT BACTEC culture).

  8 weeks (56 days) following Tice® BCG administration

• Summary of distribution, terms of its central tendency (mean or GM), of BCG shedding from intradermal challenge sites at 3 time points, as detected by each of 3 assays (quantitative PCR, quantitative CFU plating and quantitative MGIT BACTEC culture).

  8 weeks (56 days) following Tice® BCG administration

Study Arms (4)

BCG 16x10^6 CFU

EXPERIMENTAL

30 subjects, one dose of Tice BCG intradermally, 16x10\^6 cfu

Biological: BCG TICE strain

BCG 2x10^6 CFU

EXPERIMENTAL

30 subjects, one dose of Tice Bacillus Calmette-Guerin vaccine (BCG) intradermally, 2x10\^6 colony forming units (cfu)

Biological: BCG TICE strain

BCG 4x10^6 CFU

EXPERIMENTAL

30 subjects, one dose of Tice BCG intradermally, 4x10\^6 cfu

Biological: BCG TICE strain

BCG 8x10^6 CFU

EXPERIMENTAL

30 subjects, one dose of Tice BCG intradermally, 8x10\^6 cfu

Biological: BCG TICE strain

Interventions

BCG TICE strain BIOLOGICAL

All doses: Tice Bacillus Calmette-Guerin (BCG) will be administered as a single 0.1 ml ID injection over the deltoid muscle of the preferred arm. Groups 1 - 4 will receive one dose of Tice BCG intradermally at 2x10\^6 cfu, 4x10\^6 cfu, 8x10\^6 cfu and 16x10\^6 cfu, respectively.

BCG 16x10^6 CFU; BCG 2x10^6 CFU; BCG 4x10^6 CFU; BCG 8x10^6 CFU

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Eligibility Criteria for Study Entry:
• Provide written informed consent prior to initiation of any study procedures.
• Are males or non-pregnant females between the ages of 18 and 45 years, inclusive.
• Women of childbearing potential\* in sexual relationships with men must use an acceptable method of preventing conception\*\* from 30 days prior to 3 months after Tice® BCG administration.
• \*Not sterilized via tubal ligation, bilateral oophorectomy, hysterectomy, or successful Essure placement (permanent, non-surgical, non-hormonal sterilization) with documented radiological confirmation test at least 90 days after the procedure, and still menstruating or \< 1 year of the last menses if menopausal).
• \*\*Includes, but is not limited to, sexual abstinence, monogamous relationship with vasectomized partner who has been vasectomized for 6 months or more prior to the subject receiving Tice® BCG, barrier methods such as condoms or diaphragms with spermicide or foam, effective intrauterine devices, NuvaRing®, successful Essure® placement (permanent, non-surgical, non-hormonal sterilization) with documented confirmation test at least 3 months after the procedure), and licensed hormonal methods such as implants, injectables or oral contraceptives ("the pill").
• For women of childbearing potential, negative serum pregnancy test at screening and negative urine pregnancy test within 24 hours prior to enrollment and Tice® BCG administration.
• Are in good health, as judged by the investigator and determined by vital signs (oral temperature, pulse, and blood pressure), medical history and physical examination.
• Have a negative HIV-1 ELISA test.
• Have negative serology tests for hepatitis B surface antigen and hepatitis C virus antibody.
• Have a negative QuantiFERON®-TB Gold test. --Negative is defined as Nil response \< 0.8 IU/ml and TB Antigen response minus Nil response \< 0.35 IU/mL or TB Antigen response minus Nil response \> 0.35 IU/mL and \< 25% of Nil response and Mitogen response minus Nil response \> 0.5 IU/ml.
• Have a urine dipstick for protein less than 1.
• Have a urine dipstick negative for glucose.
• Ability to understand and complete all study visits as required per protocol and be reachable by telephone.

You may not qualify if:

• Have a history of suspected, confirmed, treated or have other evidence of active tuberculosis. Symptoms may include recurrent fever, fatigue, night sweats, weight loss, oral ulcers, diarrhea, nausea, vomiting, or bleeding.
• Have any systemic symptoms\* within 72 hours before Tice® BCG administration or signs of lymphadenopathy, hepatosplenomegaly, or pulmonary disease by physical examination on day of Tice® BCG administration.
• Includes fever, chills, malaise, fatigue, headache, night sweats, weight loss, nausea, vomiting, bleeding, diarrhea, abdominal pain, rhinorrhea, cough, wheezing, or shortness of breath.
• Have history of any significant acute or chronic medical conditions\* or need for chronic medications that, in the opinion of the investigator, will interfere with immunity or affect safety.
• Includes, but is not limited to, disorders of the liver, kidney, lung, heart, or nervous system, or other metabolic or autoimmune/inflammatory conditions.
• Have any history of excessive scarring or keloid formation.
• Have household contact or occupation involving significant contact with someone who is immunocompromised\*.
• Includes persons with HIV, AIDs, or active cancer; infants (children \< 1 year); pregnant women; or persons who are immunosuppressed for approximately 6 weeks (during the time of active ID lesion drainage).
• Have a history of epilepsy. (Does not include febrile seizures as a child).
• Have a pacemaker, prosthetic valve, or implantable cardiac devices.
• Have a history of bleeding disorder.
• Have a known allergy to any Tice® BCG components (glycerin, asparagine, citric acid, potassium phosphate, magnesium sulfate, iron ammonium citrate, and lactose).
• Received blood products or immunoglobulin within 6 months prior to Tice® BCG administration.
• Received immunotherapy within one year prior to Tice® BCG administration.
• Received or plan to receive live attenuated vaccines 4 weeks before or after Tice® BCG administration.

Sponsors & Collaborators

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

Study Sites (2)

Emory Vaccine Center - The Hope Clinic

Decatur, Georgia, 30030-1705, United States

Location

Saint Louis University - Center for Vaccine Development

St Louis, Missouri, 63104-1015, United States

Location

Related Publications (1)

• Blazevic A, Edwards RL, Xia M, Eickhoff CS, Hamzabegovic F, Meza KA, Ning H, Tennant J, Mosby KJ, Ritchie JC, Girmay T, Lai L, McCullough M, Beck A, Kelley C, Edupuganti S, Kabbani S, Buchanan W, Makhene MK, Voronca D, Cherikh S, Goll JB, Rouphael NG, Mulligan MJ, Hoft DF. Phase 1 Open-Label Dose Escalation Trial for the Development of a Human Bacillus Calmette-Guerin Challenge Model for Assessment of Tuberculosis Immunity In Vivo. J Infect Dis. 2024 May 15;229(5):1498-1508. doi: 10.1093/infdis/jiad441.

  PMID: 38019956 DERIVED

MeSH Terms

Conditions

Tuberculosis

Interventions

BCG Vaccine

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

Tuberculosis Vaccines; Bacterial Vaccines; Vaccines; Biological Products; Complex Mixtures

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 30, 2013
• First Posted: June 4, 2013
• Study Start: May 28, 2014
• Primary Completion: December 18, 2017
• Study Completion: December 18, 2017
• Last Updated: January 27, 2020

Record last verified: 2017-07-19

Locations

US (2)