Pallet Baker, Lars Bossen, Rasmus Gantzel, Henning Grønbaek
Abstract
Background & aims
Fatigue has high negative impact on many patients with primary biliary cholangitis (PBC) and treatment options are limited. Recently we showed favorable effects of four weeks of high-dose thiamine treatment on fatigue in patients with inflammatory bowel disease. We aimed to investigate the effect and safety of high-dose (600–1800 mg daily) oral thiamine treatment on chronic fatigue in patients with PBC.
Methods
Randomized, double-blinded, placebo-controlled crossover trial including patients with severe PBC-related fatigue. Participants were allocated 1:1 to either group 1) 4 weeks of high-dose thiamine, 4 weeks of washout, and 4 weeks of placebo; or group 2) 4 weeks of placebo, washout, and high-dose thiamine, respectively. Fatigue severity was quantified using the fatigue subscale of the PBC-40 questionnaire. The primary outcome was a fatigue reduction of ≥ 5 points after 4 weeks of high-dose thiamine treatment.
Introduction
Primary biliary cholangitis (PBC) is a chronic, inflammatory immune-mediated liver disease ultimately leading to liver fibrosis, cirrhosis and end-stage liver disease [1–3]. PBC is a rare disease [4] with approximately 90% being women aged between 30 to 65 years at the time of diagnosis [3]. More than 50% of patients with PBC suffer from chronic fatigue, and 20% suffer from severe fatigue with a significant negative impact on their quality of life [5–7]. However, treatment options are limited [5, 8] with liver transplantation as the only documented treatment to reduce fatigue in patients with PBC [9].
PBC-related fatigue is usually measured on a subscale of the disease-specific PBC-40 questionnaire, which includes a fatigue domain of 11 questions. All answers are scored from 1–5, providing a total fatigue score between 11 and 55 [10]. In 2013, the mean total fatigue score was 20 in the general population, and a clinical cut-off for significant PBC-related fatigue was set at a score above 32 [11].
Materials and methods
Study design
We conducted a randomized, double-blinded, placebo-controlled, crossover trial. Enrollment occurred between May 2021 and May 2022 at the Department of Hepatology and Gastroenterology at Aarhus University Hospital, Denmark. Patients were allocated 1:1 to group 1 (high-dose oral thiamine for 4 weeks in period 1, followed by 4 weeks of washout, followed by 4 weeks of oral placebo in period 2) or group 2 (oral placebo for 4 weeks in period 1, followed by 4 weeks of washout, followed by 4 weeks of high-dose oral thiamine in period 2). Individual variation in the responses was expected and minimized with the crossover design. To avoid the risk of a carryover effect, we added a 4-week washout period between period 1 and period 2. This duration was chosen as the high-dose thiamine half-life is < 5 hours and the thiamine storage time in the liver is less than 3 weeks [16, 17].
Participants
Patients with PBC for more than 3 months, age ≥ 18 years, a total fatigue score on the PBC-40 questionnaire > 32 and a fatigue duration > 6 months were eligible for study inclusion [10, 11]. The cut-off point for fatigue was equivalent to the clinical cut-off point for significant fatigue in the background population (mean + 2 standard deviations) [11]. We excluded pregnant women, patients with fatigue-causing co-morbidities (i.e. uncontrolled diabetes mellitus, dysregulated thyroid disease, anemia, and vitamin D deficiency), patients with impaired kidney function (glomerular filtration rate < 60 ml/min/1.73m2), patients who appeared to have low compliance, and patients who had planned surgery during the study period.
Results
Thirty-six of 74 patients with PBC and chronic fatigue were assessed for eligibility, enrolled and randomly assigned to the treatment sequences (Fig 1). In brief, the fourteen patients who were excluded due to fatigue-causing comorbidity included: fibromyalgia, dysregulated diabetes, cancer, apoplexia, anemia, Sjögren’s Syndrome, vitamin D deficiency, and combinations hereof.
Discussion
There is an unmet need for new and better treatments of fatigue in PBC patients. To our knowledge, this is the first trial to investigate the safety and efficacy of high-dose oral thiamine on chronic fatigue in patients with PBC. In this study four weeks of high-dose oral thiamine was well tolerated and safe in patients with PBC. However, we could not demonstrate any significant effect of high-dose thiamine on chronic fatigue compared to placebo. These results diverge from the recent study in patients with IBD where four weeks of high-dose oral thiamine was superior to placebo in reducing chronic fatigue [15].
The mechanisms behind the effect of thiamine on fatigue are still unsettled [23–25]. Thus, etiology of chronic fatigue in patients with PBC may differ from that of chronic fatigue in patients with IBD. We observed no differences in the effect when stratifying for self-reported cognitive symptoms, as suggested to be a factor for fatigue in patients with PBC [26]. Neither did we reveal any predictors for effect from high-dose thiamine.
Acknowledgments
We thank the GCP unit at Aarhus and Aalborg University Hospital, Denmark, for advice and rigorous monitoring. The study was partly funded by donations from Helsefonden.
Citation: Bager P, Bossen L, Gantzel R, Grønbæk H (2024) High-dose oral thiamine versus placebo for chronic fatigue in patients with primary biliary cholangitis: A crossover randomized clinical trial. PLoS ONE 19(3): e0301354. https://doi.org/10.1371/journal.pone.0301354
Editor: Wan-Long Chuang, Kaohsiung Medical University, TAIWAN
Received: December 11, 2023; Accepted: March 10, 2024; Published: March 29, 2024
Copyright: © 2024 Bager et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the manuscript and its Supporting Information files.
Funding: Helsefonden The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: None of the authors declare competing interests regarding the present study. Henning Gronbaek received research funding from Intercept, Abbvie, NOVO Nordisk Foundation, ARLA Food for Health, and ADS AIPHIA Development Services. Consultant AstraZeneca, NOVO Nordisk, Ipsen, and data monitoring committee at CAMURUS.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0301354#abstract0
