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Randomized Controlled Trial
. 2020 Dec 18;12(1):e00287.
doi: 10.14309/ctg.0000000000000287.

A Double-Blind, Placebo-Controlled Trial to Assess Safety and Tolerability of (Thetanix) Bacteroides thetaiotaomicron in Adolescent Crohn's Disease

Richard Hansen  1 , Ian R Sanderson  2 , Rafeeq Muhammed  3 , Stephen Allen  4   5 , Christos Tzivinikos  5 , Paul Henderson  6   7 , Lisa Gervais  1 , Ian B Jeffery  8 , David P Mullins  8 , Eileen A O'Herlihy  8 , John D Weinberg  9 , Geoff Kitson  10 , Richard K Russell  6 , David C Wilson  7
Affiliations
Randomized Controlled Trial

A Double-Blind, Placebo-Controlled Trial to Assess Safety and Tolerability of (Thetanix) Bacteroides thetaiotaomicron in Adolescent Crohn's Disease

Richard Hansen et al. Clin Transl Gastroenterol. .

Abstract

Introduction: Thetanix (gastroresistant capsules containing lyophilized Bacteroides thetaiotaomicron) is a live biotherapeutic, under development for Crohn's disease, that antagonizes transcription factor nuclear factor kappa B, reducing proinflammatory cytokines, particularly tumor necrosis factor alpha. We aimed to assess safety and tolerability in adolescents with Crohn's disease in remission.

Methods: Subjects who were 16-18 years with Crohn's in remission (weighted pediatric Crohn's disease activity index <12.5) were recruited. Each active dose comprised ∼108.2±1.4 colony forming units of B. thetaiotaomicron (randomized 4:1 active:placebo). Part A was single dose. Part B involved 7.5 days twice daily dosing. Serial stools were analyzed for calprotectin, 16S rRNA sequencing, and B. thetaiotaomicron real-time polymerase chain reaction. Bloods were taken serially. Subjects reported adverse events and recorded temperature twice daily.

Results: Fifteen subjects were treated-8 in part A (75% men, median 17.1 years) and 10 in part B, including 3 from part A (80% men, median 17.1 years); all 18 completed. Seventy percent took concurrent immunosuppression. Reported compliance was >99% in part B. Two subjects reported adverse events deemed related-one in part A with eructation, flatulence, and reflux; one in part B with dizziness, abdominal pain, and headache. No serious adverse events were reported. There was no significant change in median calprotectin across part B (87.8 [4.4-447] to 50.5 [5.3-572], P = 0.44 by the Fisher exact test in the active group). No significant differences were found in microbiota profiles, but diversity seemed to increase in treated subjects.

Discussion: Thetanix, after single and multiple doses, was well tolerated. Although the numbers in this study were small, the safety profile seems good. Future studies should explore efficacy.

Trial registration: ClinicalTrials.gov NCT02704728.

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Conflict of interest statement

Guarantor of the article: Richard Hansen, PhD.

Specific author contributions: R.H., I.R.S., R.M., S.A., C.T., P.H., L.G., R.K.R., and D.C.W.: identified and recruited subjects for the study, completed follow-up visits, and populated case report forms. R.H., J.D.W., G.K., R.K.R., and D.C.W.: designed the study and agreed any required protocol changes. I.B.J., D.P.M., and E.A.O.H.: completed all laboratory experiments, laboratory data analysis, and bioinformatics. R.H.: was the principle investigator, undertook clinical statistical analyses, and wrote the first draft of the paper. All authors approved the final version of the manuscript.

Financial support: R. Hansen and R. K. Russell are supported by NHS Research Scotland Senior Researcher Fellowships. P. Henderson is supported by an NHS Research Scotland Career Research Fellowship.

Potential competing interests: 4D pharma sponsored the study and produce Thetanix. R. Hansen, R. K. Russell, and D. C. Wilson were paid consultancy fees during the design phase of the study. R. Hansen has received further consultancy fees regarding Phase II work and travel expenses for presenting this work at Digestive Disease Week. R. Muhammed has received travel expenses from 4D pharma. I. B. Jeffery, D. P. Mullins, E. A. O'Herlihy, and J. D. Weinberg are employees of 4D pharma. G. Kitson is an employee of ProPharma Partners Limited and was a paid consultant of 4D pharma.

Clinical trial registration: ClinicalTrials.gov (Ref: NCT02704728) and EduraCT (Ref: 2014-005666-29).

Figures

Figure 1.
Figure 1.
Microbiota profiles of treatment groups in the multiple-dose Thetanix study (part B) on days 0, 7, and 56 based on Bray-Curtis Dissimilarities. (a) Day 0 (n = 10), (b) day 7 (n = 10), and (c) day 56 (n = 9). G1, active treatment; G2, placebo; PCoA, principle components analysis. No significant differences were found in microbiota profiles between the groups at day 0 (P = 0.09), day 7 (P = 0.589), or day 56 (P = 0.299) in part B.
Figure 2.
Figure 2.
Effect of Thetanix on microbiota diversity in part A and part B using observed species and Shannon Metrics.
See this image and copyright information in PMC

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