25March2021

Y-ECCO Literature Review: Eathar Shakweh

Eathar Shakweh

Randomised clinical trial: high‐dose oral thiamine versus placebo for chronic fatigue in patients with quiescent inflammatory bowel disease (TARIF study)

Bager P, Hvas CL, Rud CL1Dahlerup JF

Aliment Pharmacol Ther 2021;53(1):79–86.


Eathar Shakweh
© Eathar Shakweh

Introduction

Fatigue is a common yet poorly understood manifestation of Inflammatory Bowel Disease (IBD) and can occur independently of disease activity. A prospective cohort study of 326 IBD patients initiating biologic therapy (with infliximab, vedolizumab or ustekinumab) demonstrated fatigue was prevalent at baseline (63%)1. Whilst fewer patients reported fatigue with treatment (70% at week 14, 61% at week 30 and 61% at week 54), a third continued to experience fatigue despite achieving clinical remission. This is supported by other studies, where fatigue prevalence in quiescent disease was as high as 36% in Ulcerative Colitis (UC) and 41% in Crohn’s disease (CD)2.

Compared with our understanding of the pathophysiological mechanisms resulting in gastrointestinal inflammation (which forms the basis of targeted immunotherapies), there is a paucity of data to support the mechanisms underpinning fatigue in IBD. The absence of defined treatment targets may explain why it is challenging to identify effective therapies, and this has been identified as an “unmet need” in IBD [3].

Fatigue is one of the most burdensome symptoms in IBD [3], with significant implications for quality of life. There is a real need for studies in the basic sciences arena that investigate the pathogenesis of IBD-related fatigue (including neuro-humoral mechanisms and implications of the gut microbiome) as well as robust clinical trials to evaluate the efficacy of different therapeutic strategies.

Methods

This study, designated the Thiamine Against Robust IBD Fatigue (TARIF) study, was a double-blinded randomised controlled crossover trial (RCT) which investigated the effect of high-dose oral thiamine versus placebo on fatigue in patients with quiescent IBD [defined by a faecal calprotectin <200 µg/g and normal disease activity scores – Harvey-Bradshaw Index (HBI) for CD and the Simple Clinical Colitis Activity Index (SCCAI) for UC].

Exclusion criteria included: low fatigue scores at baseline (<12 in the validated IBD-F, Section 1 scale), nutritional or haematinic deficiencies and conditions associated with fatigue, e.g. pregnancy, diabetes and chronic kidney disease (CKD). The primary outcome measure was a >3-point reduction in the IBD-F (Section 1), which comprises five questions about fatigue severity, each scored 0–4 (maximum score 20) [4].

Forty participants were recruited from a single centre in Denmark. The study period was 12 weeks. Group 1 received four weeks of high-dose oral thiamine followed by a four-week washout and four weeks of placebo, whilst group 2 commenced the study with placebo, i.e. oral placebo for 4 weeks, 4 weeks of washout, 4 weeks of high-dose oral thiamine. The unpaired t-test was used for statistical analysis to compare intra-group differences in IBD-F between weeks 4 and 12. Separate intention to treat and per protocol analyses were performed.

Key findings

Both groups combined achieved the primary endpoint at 12 weeks, with a mean 4.7-point reduction in IBD-F score (95% CI 3.4–6.0; p<0.0001).

Between weeks 0 and 4, group 1 (receiving thiamine first) achieved a greater reduction in the IBD-F (3.8) relative to group 2 (2); however, this did not reach statistical significance. Between weeks 4 and 12, there was a mean increase in IBD-F of 0.8 for group 1.

There was a mean IBD-F reduction of 4.5 in group 2 between completing placebo at 4 weeks and completing high-dose oral thiamine at 12 weeks (p=0.0003).

Fifty-five percent (n=11) of group 1 and 75% (n=15) of group 2 achieved the primary outcome whilst on thiamine compared with 25% (n=5) and 35% (n=7), respectively, whilst on placebo, equating to a number needed to treat (NNT) of 2.9.

Conclusion

This placebo-controlled RCT investigated the effect of high-dose oral thiamine in managing fatigue in patients with quiescent IBD. It was based on an Italian pilot study [5] which demonstrated improved chronic fatigue syndrome scores for 13 patients with quiescent IBD after 20 days of high-dose oral thiamine. The authors hypothesised that high-dose thiamine results in enhanced cellular thiamine uptake, with harvesting of energy from macronutrients via the Krebs cycle. The anticipated increase in ATP may alleviate fatigue.

This study has a number of strengths. Firstly, it is one of the few RCTs to investigate the benefit of a drug in managing IBD-related fatigue. A recent Cochrane review that investigated the efficacy and safety of non-pharmacological and pharmacological therapies for fatigue in IBD identified only four RCTs evaluating fatigue as the primary outcome measure [6]. The conclusions that could be drawn from these studies, investigating electro-acupuncture, cognitive behavioural therapy, exercise advice and alternate week adalimumab, were limited, largely due to small sample sizes.

A further advantage of this study was the choice of therapeutic agent. Thiamine (at conventional doses) is safe, has a tolerable side effect profile and is cheap. It could therefore easily be introduced as a treatment for IBD-related fatigue.

Whilst the TARIF study demonstrated a reduction in IBD-F scores in both groups in response to thiamine, this reduction reached statistical significance only in group 2. It is possible that the study may not have been sufficiently powered to detect the desired treatment effect. Furthermore, the results may have been confounded by the different numbers of participants with rheumatoid arthritis (RA) in the two groups at baseline (three in group 1 and zero in group 2). Further limitations of this study include the single centre design in a Danish cohort and the exclusion criteria. The authors excluded patients with CKD without defining a cut-off eGFR; however, patients with RA were included. Furthermore, a wider spectrum of psychiatric and rheumatological conditions (which can cause fatigue and confound the results) should have been accounted for in the baseline characteristics.

This study suggests high-dose thiamine may be beneficial in IBD-related fatigue; however, larger studies in international cohorts, over an extended study period, are required to inform clinicians on its efficacy and safety. One consideration is that thiamine has a half-life of 10–20 days and, due to limited storage capacity, needs to be taken continuously to achieve a consistent effect [7]. In a predominantly young patient cohort, it is unclear how prescribing an additional drug may affect overall IBD medication compliance.

Avenues for further research include investigating whether achieving deeper remission (endoscopic and/or histological) results in less IBD-related fatigue. In view of fatigue’s multifaceted nature, it would also be interesting to assess the effectiveness of multi-disciplinary interventions, including the involvement of gastro-psychologists, in this patient cohort.

References

  1. Borren NZ, Tan W, Colizzo FP, et al. Longitudinal trajectory of fatigue with initiation of biologic therapy in inflammatory bowel diseases: A prospective cohort study. J Crohns Colitis. 2020;14(3):309–15.
  2. Czuber-Dochan W, Ream E, Norton C. Review article: Description and management of fatigue in inflammatory bowel disease. Aliment Pharmacol Ther 2013;37(5):505–16.
  3. Keefer L, Schneider B, Zambrano J, Charabaty A. Unmet needs of patients with IBD: Patient perspectives on the impact of disease on quality of life. Am J Gastroenterol 2020;115:S425.
  4. Czuber-Dochan W, Norton C, Bassett P, et al. Development and psychometric testing of inflammatory bowel disease fatigue (IBD-F) patient self-assessment scale. J Crohns Colitis. 2014;8:1398–406.
  5. Costantini A, Pala MI. Thiamine and fatigue in inflammatory bowel diseases: An open-label pilot study. J Altern Complement Med 2013;19(8):704–8.
  6. Farrell D, Savage E, Norton C, Jelsness-Jørgensen L, Czuber-Dochan W, Artom M. Interventions for managing fatigue in inflammatory bowel disease: A Cochrane systematic review. J Crohns Colitis. 2019;13:S558.
  7. Ariaey-Nejad M, Balaghi M, Baker EM, Sauberlich HE. Thiamin metabolism in man. Am J Clin Nutr 1970;23(6):764–78.

 

Eathar Shakweh – Short biography

Eathar is an ST3 Gastroenterology Registrar at Chelsea & Westminster Hospital, with an interest in Inflammatory Bowel Disease. She is currently enrolled in the NIHR Associate PI Scheme for the IASO trial (investigating the use of anakinra in Acute Severe Ulcerative Colitis) and is Vice Chair for the Gastro London Investigative Network for Trainees (GLINT). She aspires to pursue a PhD after her ST5 year.

Posted in ECCO News, Y-ECCO Literature Reviews, Committee News, Volume 16, Issue 1, Y-ECCO