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TuberculosisPhase 1NCT01119521

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

A Phase 1 study testing BCG strain Danish and Isoniazid in people with Tuberculosis, run by National Institute of Allergy and Infectious Diseases (NIAID) at 1 site in South Africa.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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). Read more about this study

Who is it for?
Ages 18 to 40 yearsHealthy volunteers can take part
Conditions the study is for
Tuberculosis
What is being tested?
BCG strain Danish and Isoniazid
Could I receive a placebo?
No, everyone receives an active treatment
How many people
82 participants
Where
1 siteSouth Africa
Study dates
Oct 2010to Jul 2013
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 40 years
  • All sexes
  • Healthy volunteers accepted
  • Adult

Who may be able to join

  • 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.
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  • 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.

Who cannot join

  • 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.
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  • 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.
  • Live in a household where any household member has been diagnosed or treated for active TB during the previous 2 years.
  • Have received or currently be receiving chronic (more than 14 days) immunosuppressive therapy within 6 months prior to screening. This includes chronic treatment with oral prednisone 0.5 mg/kg/day (or equivalent). Inhaled and topical steroids are allowed.
  • Persons with chronic heavy ethanol intake or injection drug use. Chronic heavy ethanol intake is defined as an average continuous daily intake of more than 2 drinks, or a pattern of ethanol use, which, in the opinion of the investigator would prejudice his or her participation in the trial. Injection drug use will be defined as any non-medical injection drug use during the previous 2 years.
  • Participated in another research study that includes receiving an experimental drug within 30 days prior to study entry.
  • Receipt of live attenuated vaccines within 60 days of study entry. Note: Medically indicated inactivated vaccines are not exclusionary, but should be given at least 2 weeks away from BCG revaccination, or any immunologic sampling time point post BCG revaccination.
  • Have a history of the use of a systemic antibiotic within the 14 days prior to revaccination or planned use of a systemic antibiotic in the 3 months after revaccination.

Trial locations and contacts

1 site in 1 country.

South Africa1 site

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

    Cape Town, Western Cape, 7925

Other trials in South Africa

About this study

Official title: Phase I Study of Whether Preclearance of Latent M. Tuberculosis (MTB) Infection With Isoniazid (INH) Enhances Specific Immune Responses to MTB Following Subsequent BCG Revaccination in Healthy, HIV-Uninfected, Tuberculin Skin Test Positive Adults

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.

Read the detailed description

This study is a phase I, single-center, open label, randomized controlled clinical trial assessing the effect of pre-clearance of latent Mycobacterium tuberculosis (MTB) by Isoniazid, isonicotinic acid hydrazine (INH) treatment before Bacillus Calmette-Guérin (BCG) revaccination versus BCG revaccination alone on mycobacterial-specific immune responses in tuberculin skin test (TST) positive adults. Subjects initially assigned to observation prior to BCG revaccination will receive INH treatment of latent tuberculosis infection (LTBI) beginning six months after revaccination. Volunteers will include 82 healthy, TST positive human immunodeficiency virus (HIV)-uninfected, male and female persons aged 18-40 years. The primary objectives of the study are to: determine the effect of INH preclearance on the kinetics and characteristics of the specific immune response following BCG revaccination in adults with latent MTB infection (TST positive); and determine the safety and reactogenicity of BCG revaccination in TST positive adults. The secondary objectives of the study are to: determine the effect of INH preclearance and BCG revaccination on MTB-specific Th1 effector and central memory cell function; determine the effect of INH preclearance and BCG revaccination on MTB-specific Treg cell function; and determine the effect of INH preclearance and BCG revaccination on innate immune responses as measured by T cell mediated inhibition of intracellular mycobacterial growth and inflammatory cytokine production. All subjects are expected to be enrolled over 12 months. The duration of screening, enrollment, and follow-up for subjects is up to 22 months. Subjects will be randomly assigned to receive either: 6 months of INH treatment for LTBI (completed within no more than 7 months) followed by intradermal BCG revaccination or 7 months of observation (run in period) followed by intradermal BCG revaccination followed after 6 months of observation by 6 months of INH treatment for LTBI. Both groups will receive their BCG vaccinations during the same time period. Volunteers will be evaluated at 7 and 14 days and 1, 3, 6 and/or 12 months after BCG revaccination and each month of INH therapy and the end of study for safety, reactogenicity and immunogenicity. Blood for immunologic studies will be drawn at study enrollment for subjects, just prior to BCG revaccination, and 1, 2 weeks and 1, 3 and either 6 or 12 months (depending on which study arm) after BCG vaccination, and months 1, 3, 6 of INH therapy and the end of study for measurement of MTB specific T cell responses. Both treatment arms will be followed for safety and immunogenicity endpoints for 12 months after BCG revaccination. Immunologic outcomes have been chosen with the goal of measuring the characteristics and kinetics of human immune responses following BCG vaccination to support the ultimate aim of developing methods to determine the biological relevance of immune responses induced by BCG revaccination and their relevance to protection from tuberculosis (TB). Overall, this study may provide key information on the characteristics and kinetics of immune responses following BCG revaccination in adults and whether these are affected by preclearance with INH treatment of LTBI.

Conditions
Tuberculosis
Being tested
BCG strain Danish, Isoniazid
Keywords
South Africa,tuberculosis,vaccine
Medical subject headings
Tuberculosis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • BCG strain DanishBiological

    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.

  • IsoniazidDrug

    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)].

Study groups in NCT01119521
Study groupRoleWhat they receive
Group A: INH; BCGExperimental6 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.
Receives: Biological: BCG strain Danish; Drug: Isoniazid
Group B: observation; BCG; observation; INHExperimental7 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).
Receives: Biological: BCG strain Danish; Drug: Isoniazid

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: 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.

  2. Direct Ex-vivo gene expression signature (RNA)

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

  3. 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

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

  4. 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.

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

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

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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted7 May 2010 (estimated)
  2. Study startOct 2010
  3. Primary completionJul 2013
  4. Study completionJul 2013

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Crossover
Masking
None (open label)
Enrolment
82 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01119521
Sponsor's protocol ID
07-0083
Status last verified
Dec 2016
First submitted
29 Apr 2010
Last updated
9 Jan 2017
Results posted
No

Publications

  • 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.

    PubMed 27412415

  • 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.

    PubMed 24135768

  • 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.

    PubMed 24814553

  • 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.

    PubMed 31611259

  • 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.

    PubMed 29145483

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing BCG strain Danish and Isoniazid in people with Tuberculosis, run by National Institute of Allergy and Infectious Diseases (NIAID) at 1 site in South Africa.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 14 inclusion and 21 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 9 Jan 2017. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in South Africa. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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. (time frame: 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.). The study lists 5 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01119521, which also lists 5 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Jan 2017.

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