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Comorbidities and Coinfections in Latent TB (COMBINE-TB)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT04642755
Recruitment Status : Not yet recruiting
First Posted : November 24, 2020
Last Update Posted : November 24, 2020
National Institutes of Health (NIH)
Information provided by (Responsible Party):
Tuberculosis Research Centre, India

Brief Summary:

Approximately 2 billion people worldwide are infected with Mycobacterium tuberculosis (TB), with 90% of individuals having latent infection (LTBI). The control of TB requires clearly delineated helper T cell (Th) 1 responses and, to a lesser extent, Th17 responses, which both play important roles in the induction and maintenance of protective immune responses in mouse models of TB infection and in the prevention of active disease, as seen in LTBI. During latency, M. tuberculosis is contained in localized granulomas. Mycobacteria specific T cells mediate delayed type hypersensitivity reactions to purified protein derivative (PPD), and this reaction is generally considered to indicate an LTBI status in the absence of demonstrable active infection.

Among the various risk factors that are known to play a role in promoting active TB, HIV is the most well studied and described. However, in low-HIV-endemic countries like India, other risk factors might play a more prominent role in active TB pathogenesis. These include malnutrition, diabetes mellitus (DM), and helminth infections. LTBI individuals with these comorbidities or coinfections could be at a higher risk for developing active TB than their "healthy" LTBI counterparts without these comorbidities. Thus, it is imperative to study the pathogenesis of TB infection and disease in these "at risk" populations.

In this study, we will estimate the prevalence of severe to moderate malnutrition, uncontrolled DM, and helminth infections in LTBI-positive individuals. We will collect samples from a cohort of individuals with LTBI, those with LTBI and coexistent malnutrition, DM, or helminth coinfection, and those without any of these conditions. Individual participation may last up to 6 months. The main objective of the study is to estimate the prevalence of malnutrition, DM, and helminth infections in LTBI individuals.

Simultaneously, we will perform transcriptomic, proteomic, and metabolomic assays, including profiles in serum and urine, to determine the biosignature portfolio of these individuals. In addition, immunological assays examining cytokine/chemokine signatures as well as other immune parameters related to innate and adaptive responses will be performed to enhance the understanding of the immunological cross talk between LTBI and malnutrition, DM, and helminth infections.

Condition or disease
Latent Tuberculosis Diabete Mellitus Malnutrition Helminth Infection

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Study Type : Observational [Patient Registry]
Estimated Enrollment : 300 participants
Observational Model: Cohort
Time Perspective: Cross-Sectional
Target Follow-Up Duration: 6 Months
Official Title: A Cross-sectional Study to Estimate the Influence of Malnutrition, Diabetes Mellitus and Helminth Infections on Biosignatures in Latent Tuberculosis in a South Indian Population
Estimated Study Start Date : January 2021
Estimated Primary Completion Date : December 2025
Estimated Study Completion Date : December 2025

Group 1
LTBI+ and severe to moderate malnutrition
Group 2
LTBI+ and uncontrolled DM
Group 3
LTBI+ and helminth infection
Group 4
LTBI+ with more than one of the above conditions (severe to moderate malnutrition, DM, helminth infection)
Group 5
"Healthy" LTBI+ controls who are negative for all of the above conditions (severe to moderate malnutrition, DM, helminth infection)
Group 6
Healthy LTBI negative controls with none of the above conditions (severe to moderate malnutrition, DM, helminth infection).

Primary Outcome Measures :
  1. Prevalence of malnutrition, DM and helminth infections in LTBI individuals and their effects on biosignatures [ Time Frame: 6 months ]
    Prevalence of malnutrition, DM and helminth infections in LTBI individuals and their effects on biosignatures

Biospecimen Retention:   Samples With DNA

Tempus or PAXgene tube blood collection for DNA and RNA isolation for experimental studies and storage for future research. No human genetic testing will be performed under this protocol.

Stool samples will be collected in specialized containers and will be used for DNA extraction and storage. At screening, stool DNA for qPCR diagnostics to detect hookworms, Ascaris, Strongyloides, and Trichuris.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   14 Years to 65 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Sampling Method:   Non-Probability Sample
Study Population
The screening phase of this study will be a community-based study in South India. Participants will be recruited from villages in the Kancheepuram District, where approximately 50% of the adult population tests positive for LTBI by IGRA based on our previous study (unpublished data). We also anticipate based on our previous study that the percentage of the adult population positive for malnutrition is 35%, for DM is 20%, and for helminth infection is 20% (unpublished data).

Inclusion Criteria:

Screening Phase:

Individuals who meet the following criteria are eligible to participate in the screening phase:

  1. Aged 14 to 65 years.
  2. Willingness to provide blood, urine, and stool samples for examination.
  3. Willingness to have samples and data stored.
  4. Able to provide informed consent.

Study Phase:

Individuals are eligible for the study phase if they meet the requirements for one of the study groups, as follows:

  1. LTBI+ and severe to moderate malnutrition (BMI <17 kg/m2);
  2. LTBI+ and uncontrolled DM (HbA1c >8%);
  3. LTBI+ and helminth infection (positive stool qPCR and/or serology);
  4. LTBI+ with more than one of the conditions defined in groups 1-3;
  5. "healthy" LTBI+ controls who are negative for all of the above conditions; and
  6. healthy LTBI negative controls with none of the above conditions.

Exclusion Criteria:

Screening Phase:

  1. Pulmonary symptoms suggestive of TB (cough >2 weeks in duration and/or intermittent fever >1 week in duration and/or hemoptysis).
  2. Two IGRA tests with indeterminate results (mitogen values <10 IU).

Study Phase:

  1. Pulmonary symptoms suggestive of TB (cough >2 weeks in duration and/or intermittent fever >1 week in duration and/or hemoptysis).
  2. Pregnant or lactating women.
  3. Previous treatment for LTBI.
  4. Anemia with hemoglobin <8 g/dl (evaluated at the screening phase visit).
  5. For LTBI+ participants, clinically indicated chest X-ray positive for pulmonary TB.
  6. For malnourished participants, clinically indicated abdominal ultrasound positive for abdominal TB.
  7. Known documented cases of cancer, acquired immune deficiency syndrome, or other immunosuppressive illness.
  8. History of any other illness or condition which, in the investigator's judgment, may substantially increase the risk associated with the participant's participation in the protocol, or compromise the scientific objectives.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT04642755

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Contact: Subash Babu, MBBS, PhD 044-28369711
Contact: Pradeep Menon, MBBS,DPM,MPH 9444294262

Sponsors and Collaborators
Tuberculosis Research Centre, India
National Institutes of Health (NIH)
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Principal Investigator: Subash Babu, MBBS, PhD National Institute for Research in Tuberculosis
Principal Investigator: Thomas B Nutman, MD National Institutes of Health (NIH)
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Responsible Party: Tuberculosis Research Centre, India Identifier: NCT04642755    
Other Study ID Numbers: 2020005
AI001065-08 ( Other Grant/Funding Number: National Institutes of Health (NIH) )
First Posted: November 24, 2020    Key Record Dates
Last Update Posted: November 24, 2020
Last Verified: November 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Latent Tuberculosis
Diabetes Mellitus
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Nutrition Disorders
Parasitic Diseases
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases