Study of Pre-clearance of Latent Tuberculosis Infection And BCG Revaccination

NCT01119521 | Completed Phase 1

• 1 other identifier: 07-0083
• Study Type: interventional
• Target: 82
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this research is to further study the tuberculosis (TB) vaccine, Bacillus Calmette Guérin (BCG). The goal of this study is to evaluate whether the BCG vaccine is more effective in preventing TB in adults if it is given after 6 months of treatment with a widely used anti-TB drug, isoniazid (INH). Participants will include 82 healthy, tuberculin skin test positive (TST+), HIV-uninfected, male and female volunteers, aged 18-40 years. The study will be conducted in Worcester, South Africa. Subjects will be assigned by chance to 1 of 2 possible treatment groups. Group 1 will receive 6 months of oral INH treatment followed by intradermal (administered into the skin) BCG revaccination and one year of follow-up. Group 2 will be observed for 7 months which will be followed by intradermal BCG revaccination and another 6 months of follow-up. Then 6 months of INH treatment will be given. Participants will be involved in study procedures for about to 22 months.

Conditions

Tuberculosis

Keywords

South Africa,tuberculosis,vaccine

Outcome Measures

Primary Outcomes (5)

• Adverse reactions/events [and whether they meet the definition of a serious adverse event (SAE)], the severity of these reactions, and related measurements, and assessed relationship to vaccine administration.

  1, 3, 7 and 14 days and 1, 3, 6 and/or 12 months after BCG revaccination and each month of INH therapy, up to 22 months.

• Direct Ex-vivo gene expression signature (RNA)

  At baseline, day 1, 3, and week 1 following BCG vaccination

• Effector T cell function by whole blood cytokine production (WBA),flow cytometric measures of intra-cellular cytokine production (ICS) or ELISA assays to measure immune function

  Enrollment, baseline, Week 1 and 2, Months 1, 3 and 6 after BCG vaccination, and Month 1, 3 and 6 of INH therapy.

• Memory T cell function by whole blood cytokine production (WBA),flow cytometric measures of intra-cellular cytokine production (ICS) or ELISA assays to measure immune function.

  Enrollment, baseline, Week 1 and 2, Months 1, 3 and 6 after BCG vaccination, and Month 1, 3 and 6 of INH therapy.

• Precursor frequencies of mycobacterial antigen-specific T cells will be measured by ELISPOT using standard methods and SOPs

  Enrollment, baseline, Week 1 and 2, Months 1, 3 and 6 after BCG vaccination, and Month 1, 3 and 6 of INH therapy.

Study Arms (2)

Group A: INH; BCG

EXPERIMENTAL

6 months of Isoniazid (INH) treatment for latent tuberculosis infection (LTBI) (completed within no more than 7 months) followed by intradermal Bacillus Calmette-Guérin (BCG) revaccination.

Biological: BCG strain Danish; Drug: Isoniazid

Group B: observation; BCG; observation; INH

EXPERIMENTAL

7 months of observation (run in period) followed by intradermal Bacillus Calmette-Guérin (BCG) revaccination followed after 6 months of observation by 6 months of Isoniazid (INH) treatment for latent tuberculosis infection (LTBI).

Biological: BCG strain Danish; Drug: Isoniazid

Interventions

BCG strain Danish BIOLOGICAL

Intradermal Bacillus Calmette-Guerin (BCG) live-attenuated vaccine prepared using the Danish 1331 BCG substrain; adult dose contains 2 to 8 x 10\^5 colony forming units (CFU) BCG.

Group A: INH; BCG; Group B: observation; BCG; observation; INH

Isoniazid DRUG

United States Pharmacopeia 100 mg or 300 mg oral tablets \[5 mg/kilogram/day (rounded up to nearest 100 mg; maximum dose 300 mg/day)\].

Group A: INH; BCG; Group B: observation; BCG; observation; INH

Eligibility Criteria

• Age: 18 Years - 40 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Males and non-pregnant, non-lactating females aged 18 to 40 years, inclusive.
• Be available for study follow-up.
• Be in good general health as judged by a physician on the basis of reported medical history and physical examination including blood pressure (BP) and respiratory evaluation.
• Have a visible Bacillus Calmette-Guérin (BCG) scar. Subjects with medical documentation of BCG vaccination after 2 years of age will be excluded.
• Have a positive (greater than or equal to 15 mm induration at 48 to 72 hours after placement) tuberculin skin test \[TST; Mantoux method using 2 tuberculin units (TU) Purified Protein Derivative (PPD) RT-23\].
• Weigh at least 45 kg.
• Negative human immunodeficiency virus (HIV) approved test.
• Demonstrate adequate understanding of the study and its requirements for participation, as demonstrated by discussions with study staff, and be able to provide written informed consent to participate in the study.
• Females must not be pregnant, as determined by negative pregnancy test at screening, have a negative urine pregnancy test on the day of BCG revaccination, and must be non-lactating. For women of child bearing potential, use an effective contraception (licensed hormonal treatment, monogamous relationship with vasectomized partner, surgical sterilization) for 30 days prior to immunization and for the 2-year period of study follow-up.
• Serum aspartate aminotransferase (AST) or alanine transaminase (ALT) \< 1.1 x upper limit of normal (ULN) and serum total bilirubin \< 1.1 x ULN.
• Serum creatinine \< 1.5 mg/dL; urinalysis dipstick negative for glucose and 1 plus protein.
• Total white blood cell (WBC) count \> 3.5 x 10\^3/mm\^3 and \< 10.8 x 10\^3/mm\^3.
• Hemoglobin \> 12 gm/dL (female) and \> 13.5 gm/dL (male).
• Have negative serologic tests for hepatitis B surface antigen and hepatitis C antibody.

You may not qualify if:

• Known hypersensitivity to Isoniazid (INH) or to any component of Bacillus Calmette-Guérin (BCG) vaccine.
• Exposure to a case of Tuberculosis (TB) with known INH resistance.
• Current smear or culture-confirmed or clinically diagnosed active TB
• Suspected active TB (recurrent fever, fatigue, night sweats, weight loss, oral ulcers, diarrhea, nausea or vomiting, bleeding) or patients who are receiving anti-tuberculosis drugs.
• Prior TB treatment, prior treatment for latent tuberculosis infection (LTBI), a self-reported history or vaccination card or medical record documenting receipt of BCG vaccination after 2 years of age.
• Pregnant or nursing females.
• Chronic immunosuppressive disorder or a condition requiring chronic immunosuppressive treatment such as rheumatoid arthritis or severe asthma requiring chronic corticosteroid therapy. For corticosteroids, this will mean prednisone, or equivalent, 0.5 mg/kg/day or daily use of inhaled corticosteroids. Topical steroids are allowed.
• Active dermatitis such as atopic dermatitis.
• Persons with any history of scarring badly or keloid formation based on physical examination.
• Receipt of blood products or immunoglobulin within six months of BCG revaccination.
• History of chronic illness requiring close physician follow up, including known chronic liver disease or cirrhosis, or any medical, psychiatric, occupational, or substance abuse problems that make it unlikely the volunteer will comply with the protocol as determined by the local investigator.
• History of acute or chronic medical conditions including, but not limited to diabetes mellitus, chronic renal failure/dialysis, silicosis, gastrectomy, jejunoileal bypass, solid organ transplantation such as renal or cardiac transplants, carcinoma of the head and neck, and disorders of the liver, kidney, lung, heart, or nervous system, or other metabolic or autoimmune/inflammatory conditions.
• Have any systemic symptoms including fever, myalgia, fatigue, chills, night sweats, weight loss, nausea, vomiting or bleeding, diarrhea, abdominal pain, rhinorrhea, cough, wheezing, or shortness of breath within 72 hours before vaccination or signs of mucosal ulceration, lymphadenitis, gastrointestinal, or pulmonary disease by physical examination on day of vaccination. Subjects with minor self-limited illnesses such as common colds or gastroenteritis may return for re-evaluation after 3 days if their symptoms have abated for vaccination.
• Have lymphadenopathy, hepatosplenomegaly, or other abnormalities on physical examination.
• Have close contacts, with confirmed or suspected, human immunodeficiency virus (HIV) infection or other immunodeficiency state (including diabetes mellitus, chronic dermatitis/severe eczema, chronic renal failure, hematologic malignancy), or on chronic immunosuppressive therapy. A close contact is defined as a person who lives in the same home as the subject.

Sponsors & Collaborators

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

Study Sites (1)

University of Cape Town - Institute of Infectious Disease and Molecular Medicine

Cape Town, Western Cape, 7925, South Africa

Location

Related Publications (5)

• Suliman S, Geldenhuys H, Johnson JL, Hughes JE, Smit E, Murphy M, Toefy A, Lerumo L, Hopley C, Pienaar B, Chheng P, Nemes E, Hoft DF, Hanekom WA, Boom WH, Hatherill M, Scriba TJ. Bacillus Calmette-Guerin (BCG) Revaccination of Adults with Latent Mycobacterium tuberculosis Infection Induces Long-Lived BCG-Reactive NK Cell Responses. J Immunol. 2016 Aug 15;197(4):1100-1110. doi: 10.4049/jimmunol.1501996. Epub 2016 Jul 13.

  PMID: 27412415 RESULT

• Johnson JL, Geldenhuys H, Thiel BA, Toefy A, Suliman S, Pienaar B, Chheng P, Scriba T, Boom WH, Hanekom W, Hatherill M. Effect of isoniazid therapy for latent TB infection on QuantiFERON-TB gold in-tube responses in adults with positive tuberculin skin test results in a high TB incidence area: a controlled study. Chest. 2014 Mar 1;145(3):612-7. doi: 10.1378/chest.13-1232.

  PMID: 24135768 RESULT

• Hatherill M, Geldenhuys H, Pienaar B, Suliman S, Chheng P, Debanne SM, Hoft DF, Boom WH, Hanekom WA, Johnson JL. Safety and reactogenicity of BCG revaccination with isoniazid pretreatment in TST positive adults. Vaccine. 2014 Jun 30;32(31):3982-8. doi: 10.1016/j.vaccine.2014.04.084. Epub 2014 May 9.

  PMID: 24814553 RESULT

• Suliman S, Murphy M, Musvosvi M, Gela A, Meermeier EW, Geldenhuys H, Hopley C, Toefy A, Bilek N, Veldsman A, Hanekom WA, Johnson JL, Boom WH, Obermoser G, Huang H, Hatherill M, Lewinsohn DM, Nemes E, Scriba TJ. MR1-Independent Activation of Human Mucosal-Associated Invariant T Cells by Mycobacteria. J Immunol. 2019 Dec 1;203(11):2917-2927. doi: 10.4049/jimmunol.1900674. Epub 2019 Oct 14.

  PMID: 31611259 DERIVED

• Scriba TJ, Penn-Nicholson A, Shankar S, Hraha T, Thompson EG, Sterling D, Nemes E, Darboe F, Suliman S, Amon LM, Mahomed H, Erasmus M, Whatney W, Johnson JL, Boom WH, Hatherill M, Valvo J, De Groote MA, Ochsner UA, Aderem A, Hanekom WA, Zak DE; other members of the ACS cohort study team. Sequential inflammatory processes define human progression from M. tuberculosis infection to tuberculosis disease. PLoS Pathog. 2017 Nov 16;13(11):e1006687. doi: 10.1371/journal.ppat.1006687. eCollection 2017 Nov.

  PMID: 29145483 DERIVED

MeSH Terms

Conditions

Tuberculosis

Interventions

Isoniazid

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Hydrazines; Organic Chemicals; Isonicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring

Study Design

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

Study Record Dates

• First Submitted: April 29, 2010
• First Posted: May 7, 2010
• Study Start: October 1, 2010
• Primary Completion: July 1, 2013
• Study Completion: July 1, 2013
• Last Updated: January 9, 2017

Record last verified: 2016-12

Locations

ZA (1)