Phase I Open Label BCG Clinical Trial Assessing TB Drugs and Vaccines

A Phase I Single Site Open Label Clinical Trial for the Development of a Human BCG Challenge Model to Assess TB Drugs and Vaccines.

The purpose of the study is to develop a BCG challenge model for use in short term Phase I human trials capable of assessing the ability of TB drugs and/or vaccine-induced immune responses to impact in vivo mycobacterial replication as a method of assessing antimycobacterial agents and/or protective immunity elicited by vaccines or host-directed therapy. The trial will illuminate the nature of local and systemic immune responses to BCG and treatment response, as well as demonstrate our local capacity for newer, more innovative study designs.

Study Overview

• Status: Completed
• Conditions: Tuberculosis
• Intervention / Treatment: Drug: BCG Vaccine USP; Drug: Isoniazid; Drug: Rifampin

Detailed Description

This is phase 1, open-label, randomized clinical protocol to develop a human challenge model using the licensed and available BCG VACCINE USP (TICE® strain) with and without INH or Rifampin (RIF). Part 1 will involve 10 participants who will be screened and consented, given an intradermal injection of BCG; five of these participants will receive oral INH for 3 days. Part 2 will involve 10 participants who will be screened and consented, given an intradermal injection of BCG; five of these participants will receive oral RIF for 7 days. All participants will undergo physical exams, clinical evaluations, blood draws, urine collections, skin biopsies, and pregnancy tests. This study will measure the rate of replication by utilizing qPCR and in vitro culture, systemic innate and adaptive immune responses, including humoral and cellular assay analyses and the evaluation and PPD/IGRA status.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutchinson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• 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 device 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 ®, 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.

Exclusion Criteria:

• 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,
• Received or plan to receive inactivated or killed vaccines 2 weeks before or after Tice® BCG administration,
• Plans to enroll in another clinical trial* that could interfere with safety assessment of the investigational product at any time during the study period. Includes trials that have a study intervention such as a drug, biologic, or device.
• Received an experimental agent* within 30 days prior to Tice® BCG administration or planned receipt of an experimental agent within 90 days after Tice® BCG administration, Includes vaccine, drug, biologic, device, blood product, or medication.
• Have a history of use of a systemic antibiotic within 14 days prior to Tice® BCG administration or planned use of a systemic antibiotic for 3 months after Tice® BCG administration,
• Have any medical, psychiatric, occupational, or behavioral problems that make it unlikely for the subject to comply with the protocol as determined by the investigator,
• Are health care providers at the highest risk of acquiring MTB infection, such as pulmonologists performing bronchoscopies on TB patients,
• Are breastfeeding or plan to breastfeed at any given time throughout the study,
• Have long term use of high dose oral or parenteral glucocorticoids, or high-dose inhaled steroids. Defined as taken for 2 weeks or more in total at any time during the past 2 months. High dose defined as prednisone ≥ 20 mg total daily dose, or equivalent dose of other glucocorticoids. High dose defined as > 800 mcg/day of beclomethasone dipropionate or equivalent. If short term corticosteroids are given, then the subject should not receive Tice® BCG or have blood collected for immunogenicity studies within 1 week of steroid administration.
• Have immunosuppression or are taking systemic immunosuppressants as a result of an underlying illness or treatment,
• Use of anticancer chemotherapy or radiation therapy (cytotoxic) within 36 months prior to Tice® BCG administration,
• Any active neoplastic disease,
• Have a pulse rate less than 50 bpm or greater than 100 bpm,
• Have a systolic blood pressure less than 90 mm Hg or greater than 140 mm Hg,
• Have a diastolic blood pressure less than 50 mm Hg or greater than 90 mmHg,
• Have a WBC less than 4.0x103/uL or greater than 10.5x103/uL,
• Have hemoglobin less than 11.5x103/uL (female) or less than 12.5x103/uL (male),
• Have a platelet count less than 140x103/UL,
• Have a creatinine greater than 1.30 mg/dL,
• Have an ALT (SGPT) greater than 40 IU/L (female) or greater than 55 IU/L (male),
• Have known HIV, Hepatitis B, or Hepatitis C infection,
• Have a history of alcohol or drug abuse in the last 5 years,
• Have had a positive PPD skin test in the past or received BCG vaccine (BCG vaccination history will be determined by self-report, country of birth, and/or evidence of BCG scar),
• Have a BMI >35,
• PPD skin test within 2 months prior to Tice® BCG administration or planned receipt during the study other than from participation in this study,
• Oral temperature ≥ 100.4°F (≥ 38.0°C) or other symptoms of an acute illness within 3 days before Tice® BCG administration. (Subject may be rescheduled),
• Any medical disease or condition that, in the opinion of the investigator, is a contraindication to study participation. Includes medical disease or condition that would place the subject at an unacceptable risk of injury, render them unable to meet the requirements of the protocol, or may interfere with the evaluation of responses or their successful completion of the study.
• Have any condition that would, in the opinion of the site investigator, place the subject at an unacceptable risk of injury or render the subject unable to meet the requirements of the protocol or compromise the interpretation of data or the scientific integrity of the protocol.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: BCG Challenged-Isoniazid Treated; Will receive INH in the dose of 300 mg for three days post BCG injection.	Drug: BCG Vaccine USP; 2x10^6 cfu Tice® BCG (ID); Other Names: BCG; Drug: Isoniazid; INH in the dose of 300 mg for three days post BCG injection.; Other Names: INH
Placebo Comparator: BCG Challenged-Isoniazid Untreated; Will not receive any INH or RIF dose.	Drug: BCG Vaccine USP; 2x10^6 cfu Tice® BCG (ID); Other Names: BCG
Active Comparator: BCG Challenged-RIF Treated; Will receive RIF in the dose of 600 mg for seven days post BCG injection.	Drug: BCG Vaccine USP; 2x10^6 cfu Tice® BCG (ID); Other Names: BCG; Drug: Rifampin; RIF in the dose of 600 mg for seven days post BCG injection.; Other Names: RIF

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assess Viable BCG Bacteria From Intradermal Challenge Site From Culture.	Through microbial culture, quantify in colony forming units (CFU) BCG bacterial burden in skin biopsies from challenge sites. Outcome measure if the mean cfu from day 15 biopsy specimens.	15 days after BCG dosing

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Rate of AE's/SAE's	Mild (grade 1): events do not require treatment and do not interfere with the patient's daily activities Moderate (grade 2): events result in a low level of inconvenience or concern with the therapeutic measures. Moderate events may cause some interference with functioning and daily activities Severe (grade 3): events interrupt a patient's usual daily activity and may require systemic drug therapy or other treatment. Severe events are usually incapacitating.	Through study completion, an average of 16 weeks.
Assess Quantitative Bacterial 16S Ribosomal DNA PCR	Assessing the number of real time BCG genomes present in skin biopsies from challenge sites.	Day 15 post BCG dosing
Quantification by AUC of IgG in the Blood After BCG Immunization and INH or RIF Dosing.	To assess the IgG immune response after INH or RIF dosing. The AUC we report is not a integration of concentration over time. Instead, AUC reported here quantifies the overall antibody binding signal across a titration series from a single time point (Day 144). In this assay, each sample from a single visit is measured at multiple dilutions, and the signal is expressed AUC in unit MFI × log₁₀(dilution). Plotting MFI as a function of dilution generates a curve that reflects how strongly and consistently the antibodies bind over the dilution range. The AUC therefore summarizes the entire binding titration curve - capturing both signal intensity and how long the signal is maintained across dilutions.	Day 144

Collaborators and Investigators

• Sponsor: Fred Hutchinson Cancer Center
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Principal Investigator: James Kublin, MD, MPH, Fred Hutchinson Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): December 6, 2022
• Primary Completion (Actual): August 23, 2023
• Study Completion (Actual): December 1, 2023

Study Registration Dates

• First Submitted: October 13, 2022
• First Submitted That Met QC Criteria: October 19, 2022
• First Posted (Actual): October 24, 2022

Study Record Updates

• Last Update Posted (Estimated): December 16, 2025
• Last Update Submitted That Met QC Criteria: December 2, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Organic Chemicals; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, Fused-Ring; Polycyclic Compounds; Heterocyclic Compounds, 4 or More Rings; Rifamycins; Lactams, Macrocyclic; Macrocyclic Compounds; Hydrazines; Isonicotinic Acids; Acids, Heterocyclic; Rifampin; Isoniazid
• Other Study ID Numbers: 10903; RG1122457 (Other Identifier: Fred Hutch)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Sharing de-identified AE's/SAE's from all individual participants with Merck & Co during the trial.
• IPD Sharing Time Frame: During the participants active study period.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No