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

Stellenbosch University (SU)

Status: Active, not recruiting

Conditions: Tuberculosis

Treatments: Dietary Supplement: Nyaditum resae®; Other: Mannitol

Study type: Interventional

Funder types: Other

Identifiers

NCT03851159

N14_10_136

Details and patient eligibility

About

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

Full 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.

Enrollment: 48 patients

Sex: All

Ages: 18 to 65 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Other

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

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48 participants in 4 patient groups, including a placebo group

No Intervention: HIV-negative

Placebo Comparator group

Description:

HIV-negative patients are selected to receive the placebo for the first two weeks of first-line TB treatment.

Treatment:

Other: Mannitol

Intervention: HIV-

Experimental group

Description:

HIV-negative patients are selected to receive the food supplement for the first two weeks of first-line TB treatment.

Treatment:

Dietary Supplement: Nyaditum resae®

No Intervention: HIV+

Placebo Comparator group

Description:

HIV-positive patients are selected to receive the placebo for the first two weeks of first-line TB treatment.

Treatment:

Other: Mannitol

Intervention: HIV+:

Experimental group

Description:

HIV-positive patients are selected to receive the food supplement for the first two weeks of first-line TB treatment.

Treatment:

Dietary Supplement: Nyaditum resae®