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Nyaditum Resae® as a Co-adjuvant During First-line Treatment for Active Pulmonary Tuberculosis and Its Impact on the Gut Microbiota

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ClinicalTrials.gov Identifier: NCT03851159
Recruitment Status : Recruiting
First Posted : February 22, 2019
Last Update Posted : April 17, 2019
Sponsor:
Collaborator:
Fundació Institut Germans Trias i Pujol
Information provided by (Responsible Party):
Grant Theron, University of Stellenbosch

Brief Summary:
This will be the first study to evaluate the use of Nyaditum resae® as a potential agent for reducing antibiotic-associated gut dysbiosis in patients with drug-susceptible TB, and potentially improving clinical and microbiological markers of outcome

Condition or disease Intervention/treatment Phase
Tuberculosis Dietary Supplement: Nyaditum resae® Other: Mannitol Not Applicable

Detailed Description:

About one tenth of the 1.7 billion individuals infected with Mycobacterium tuberculosis (Mtb) will progress to active tuberculosis (TB). This probability increases in people with human immunodeficiency virus (HIV) and other risk co-morbidities such as malnutrition, diabetes and substance abuse. Chronic microbial colonisation with unrelated bacteria are associated with TB pathogenesis (e.g., mice colonised with Helicobacter hepaticus exhibit poor control of TB), indicating that the gut microbiota may modulate progression to active TB. Furthermore, first-line TB treatment (Isoniazid, Rifampicin, Ethambutol, Pyrazinamide; HREZ) depletes gut commensal bacteria (Ruminococcus, Coprococcus and Bifidobacterium) with immunomodulatory roles [interleukin (IL)-1, interferon (IFN)-γ and Th17 responses, respectively).

Recent work identified heat-killed Mycobacterium manresensis (hkMm), a harmless member of the fortuitum complex naturally found in drinking water, as a promising candidate for reducing the risk of active TB. Mtb-infected mice treated with hkMm had significantly reduced lung pathology (fewer and smaller lesions,) bacillary load and proinflammatory cytokines (TNF-α, IFN-γ, IL-6, and IL-17) compared to untreated control mice, and in mice receiving hkMm with HREZ, survival rates were significantly increased. Moreover, mice treated with hkMm had increased microbial diversity and an altered gut microbial composition relative to untreated mice. This could prove beneficial for TB patients during prolonged antibiotic treatment as supplementation with hkMm may help protect gut microbiota, and potentially improve clinical outcome.

In individuals with and without latent M. tuberculosis infection, two weeks of daily oral doses of Nyaditum resae® (a preparation of hkMm approved as a food supplement by Manremyc) demonstrated enhanced effector and memory specific regulatory T-cell responses. Similar clinical trials with Nyaditum resae® are currently being done in paediatrics (NCT02581579) and close contacts of active TB cases in Tbilisi, Georgia (NCT02897180; 2017-2023). The probiotic is also being registered as a food supplement in several countries.

In the proposed study, the efficacy of Nyaditum resae® in reducing antibiotic-associated gut dysbiosis and disease progression in patients with active TB will be tested. To do this, the investigators will assess changes in the microbiota during treatment (with or without Nyaditum resae® supplementation) and attempt to identify genera associated with a favourable or unfavourable treatment outcome in TB patients.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 48 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Other
Official Title: Nyaditum Resae® (a Food Supplement) as a Co-adjuvant During First-line Treatment for Active Pulmonary Tuberculosis and Its Impact on the Gut Microbiota - a Pilot Double-blind Randomised Controlled Trial
Estimated Study Start Date : April 16, 2019
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : December 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Tuberculosis
Drug Information available for: Mannitol

Arm Intervention/treatment
Placebo Comparator: No Intervention: HIV-negative
HIV-negative patients are selected to receive the placebo for the first two weeks of first-line TB treatment.
Other: Mannitol
Placebo

Experimental: Intervention: HIV-
HIV-negative patients are selected to receive the food supplement for the first two weeks of first-line TB treatment.
Dietary Supplement: Nyaditum resae®
Heat-killed Mycobacterium manresensis

Placebo Comparator: No Intervention: HIV+
HIV-positive patients are selected to receive the placebo for the first two weeks of first-line TB treatment.
Other: Mannitol
Placebo

Experimental: Intervention: HIV+:
HIV-positive patients are selected to receive the food supplement for the first two weeks of first-line TB treatment.
Dietary Supplement: Nyaditum resae®
Heat-killed Mycobacterium manresensis




Primary Outcome Measures :
  1. Gut microbiome composition in placebo versus experimental arm [ Time Frame: Up to 18 months ]
    Gut microbial composition determined by next-generation sequencing of bacterial DNA in stool


Secondary Outcome Measures :
  1. Cytokine and cluster of differentiation (CD)4+ T-cell response in placebo versus experimental arm [ Time Frame: Up to 18 months ]
  2. Time to sputum conversion and reduction in bacillary load [ Time Frame: Up to 6 months ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 18-65 years
  • New cases
  • Sputum Xpert Ultra (Xpert) positive for Mycobacterium tuberculosis
  • Have not initiated TB treatment
  • If HIV-positive, are stable on antiretroviral therapy

Exclusion Criteria:

  • Resistance to any of the first-line drugs (Xpert rifampicin-resistant)
  • Previous TB
  • Diabetes mellitus
  • Taking immunomodulatory drugs (e.g. cancer chemotherapy, tumour necrosis factor (TNF) inhibitors or other anti-inflammatory medication, phosphodiesterase inhibitors, corticosteroids within the past 6 months, and cholesterol-lowering drugs)
  • Pregnant or lactating women
  • Chronic hepatitis

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 ClinicalTrials.gov identifier (NCT number): NCT03851159


Contacts
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Contact: Grant Theron, PhD (+27) 21 938 9693 ext 9693 gtheron@sun.ac.za
Contact: Charissa C Naidoo, PhD (+27) 21 938 9954 ext 9954 ccnaidoo@sun.ac.za

Locations
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South Africa
Scottsdene Clinic Recruiting
Cape Town, Western Cape, South Africa, 7570
Contact: Grant Theron, PhD    (+27) 21 938 9693 ext 9693    gtheron@sun.ac.za   
Contact: Charissa C Naidoo, PhD    (+27) 21 938 9954 ext 9954    ccnaidoo@sun.ac.za   
Sponsors and Collaborators
University of Stellenbosch
Fundació Institut Germans Trias i Pujol

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Responsible Party: Grant Theron, Associate Professor, University of Stellenbosch
ClinicalTrials.gov Identifier: NCT03851159     History of Changes
Other Study ID Numbers: N14_10_136
First Posted: February 22, 2019    Key Record Dates
Last Update Posted: April 17, 2019
Last Verified: April 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Grant Theron, University of Stellenbosch:
Microbiome
Additional relevant MeSH terms:
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Tuberculosis
Tuberculosis, Pulmonary
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Mannitol
Diuretics, Osmotic
Diuretics
Natriuretic Agents
Physiological Effects of Drugs