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.

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.

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.