Pilot, double-blind, randomized, placebo-controlled clinical trial of the supplement food Nyaditum resae® in adults with or without latent TB infection: Safety and immunogenicity

Abstract

BackgroundNyaditum resae® (NR) is a galenic preparation of heat-killed Mycobacterium manresensis, a new species of the fortuitum complex, that is found in drinkable water, and that has demonstrated to protect against the development of active TB in a murine experimental model that develop human-like lesions.MethodsDouble-blind, randomized, placebo-controlled Clinical Trial (51 volunteers included). Two different doses of NR and a placebo were tested, the randomization was stratified by Latent Tuberculosis Infection (LTBI)-positive (n = 21) and LTBI-negative subjects (n = 30). Each subject received 14 drinkable daily doses for 2 weeks.ResultsAll patients completed the study. The 46.3% of the overall reported adverse events (AE) were considered related to the investigational treatment. None of them were severe (94% were mild and 6% moderate). No statistical differences were found when comparing the median number of AE between the placebo group and both treatment groups. The most common AE reported were gastrointestinal events, most frequently mild abdominal pain and increase in stool frequency. Regarding the immunogenic response, both LTBI-negative and LTBI-positive volunteers treated with NR experienced a global increase on the Treg response, showed both in the population of CD25+CD39-, mainly effector Treg cells, or CD25+CD39+ memory PPD-specific Treg cells.ConclusionThis clinical trial demonstrates an excellent tolerability profile of NR linked to a significant increase in the population of specific effector and memory Tregs in the groups treated with NR in both LTBI-positive and negative subjects. NR shows a promising profile to be used to reduce the risk of active TB.

Safety of heat‐killed Mycobacterium setense manresensis as a novel food pursuant to Regulation (EU) 2015/2283

“…In addition, in a RCT performed with the NF (Montané et al., ), no statistically significant differences were found in the occurrence of adverse events between the placebo and the two treatment groups. Because of the limitations of the study (e.g.…”

“…As indicated in the publication of a human trial with this NF (Montané et al., ), the occurrence of non‐tuberculous mycobacteria including mycobacteria of the M. fortuitum complex (a group of related Mycobacterium to which also the species M. setense belongs) from tap water has been reported for different continents including also European countries (Martín Casabona and Rosselló Urgell, ; Falkinham, ; Fernandez‐Rendon et al., ; Imwidthaya et al., ; Kubalek and Mysak, ; Nasr‐Esfahani et al., ; Moghim et al., ; Primm et al., ; Scarlata et al., ).…”

“…The applicant proposed a daily intake of one 200 mg capsule of the NF containing ≤ 10 5 (≤ 125 ng) of heat‐killed M. setense manresensis in mannitol for 14 days. The applicant indicated that this limitation of 14 days is not based on a safety concern, but is proposed for precautionary reasons, considering that this duration corresponds to the duration of intake of the NF in the presented human trial (Montané et al., ). In response to an EFSA request, the applicant proposes that between two 14‐day periods of intakes, there should be a minimum of 6 months with no consumption of the NF.…”

“…M. tuberculosis ‐ specific regulatory T‐helper cells (Tregs, i.e. CD25 + CD39 ‐ , CD25 + CD39 + , CD25 − CD39 − , CD25 − CD39 + ) (Montané et al., ). According to the article, the study was conducted in compliance with the Helsinki declaration and the Good Clinical Practice guidelines of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use.…”

Pulmonary non-tuberculous mycobacterial infections: current state and future management

“…manresensis, a new species under the M. fortuitum complex, which is commonly found in drinking water, was heatkilled and used as oral vaccine to stop the progression of active TB and as adjuvant for TB treatment in a mouse model [270]. It has been developed into a galenic preparation food supplement known as Nyaditum resae® and used in clinical trials, which seemed to be effective in reducing the risk of developing active TB [271,272].…”