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

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

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

Study Overview

• Status: Recruiting
• Conditions: Tuberculosis
• Intervention / Treatment: Other: Mannitol; Dietary supplement: Nyaditum resae®

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.

• Study Type: Interventional
• Enrollment (Estimated): 48
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Charissa C Naidoo, PhD; Phone Number: 9954 (+27) 21 938 9954; Email: ccnaidoo@sun.ac.za
• Study Contact Backup: Name: Grant Theron, PhD; Phone Number: 9693 (+27) 21 938 9693; Email: gtheron@sun.ac.za

Study Locations

• South Africa
  • Western Cape
    • Cape Town, Western Cape, South Africa, 7570
      • Recruiting
      • Scottsdene Clinic
      • Contact: Charissa C Naidoo, PhD; Phone Number: 9955 (+27) 21 938 9955; Email: ccnaidoo@sun.ac.za
      • Contact: Grant Theron, PhD; Phone Number: 9693 (+27) 21 938 9693; Email: gtheron@sun.ac.za
    • Cape Town, Western Cape, South Africa, 7570
      • Recruiting
      • Wallacedene Clinic
      • Contact: Charissa C Naidoo, PhD; Phone Number: 9955 (+27) 21 938 9955; Email: ccnaidoo@sun.ac.za
      • Contact: Grant Theron, PhD; Phone Number: 9693 (+27) 21 938 9693; Email: gtheron@sun.ac.za

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Gut microbiome composition in placebo versus experimental arm	Gut microbial composition determined by next-generation sequencing of bacterial DNA in stool	Up to 18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cytokine and cluster of differentiation (CD)4+ T-cell response in placebo versus experimental arm	Cytokines responses profiled using commercial human cytokine panel, and T-cell responses characterised by flow cytometry on isolated peripheral blood mononuclear cells	Up to 18 months
Time to sputum conversion and reduction in bacillary load	Culture used to assess sputum conversion and bacillary load	Up to 6 months

Collaborators and Investigators

• Sponsor: University of Stellenbosch
• Collaborators: Fundació Institut Germans Trias i Pujol
• Investigators: Principal Investigator: Grant Theron, PHD, University of Stellenbosch

Study record dates

Study Major Dates

• Study Start (Actual): May 10, 2019
• Primary Completion (Estimated): December 31, 2024
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: February 19, 2019
• First Submitted That Met QC Criteria: February 20, 2019
• First Posted (Actual): February 22, 2019

Study Record Updates

• Last Update Posted (Actual): March 28, 2024
• Last Update Submitted That Met QC Criteria: March 27, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Microbiome
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Tuberculosis, Pulmonary; Physiological Effects of Drugs; Natriuretic Agents; Diuretics, Osmotic; Diuretics; Mannitol
• Other Study ID Numbers: N14_10_136

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No