High-Dose Thiamine Hydrochloride for Fatigue in Rheumatoid Arthritis: A Randomized, Double‑Blind, Placebo‑Controlled Trial

The primary objective is to evaluate the effect of High Dose Thiamine versus placebo on the change from baseline to 4 weeks in the global score of the Bristol Rheumatoid Arthritis Fatigue Multi‑Dimensional Questionnaire (BRAF‑MDQ) in patients with rheumatoid arthritis who experience fatigue, thereby addressing a key patient‑reported outcome of disease burden. Secondary objectives include:

• Assessment of treatment differences across the BRAF‑MDQ subdomains that reflect physical functioning, daily activities, cognition, and emotional well‑being.
• Investigation of the impact of the intervention on the Bristol Rheumatoid Arthritis Fatigue Numerical Rating Scales, specifically severity, effect, and coping scores.
• Evaluation of the intervention’s effect on core outcome set measures defined by OMERACT.
• Determination of the proportion of participants achieving ≥20 %, ≥50 %, and ≥70 % reductions in BRAF‑MDQ scores after 4 weeks.
• Analysis of changes from baseline to week 4 in health‑related quality of life as measured by the EQ‑5D‑5L.

The trial enrolled adult participants of both sexes who had an established diagnosis of rheumatoid arthritis and reported significant fatigue, defined by a score exceeding 50 mm on a 100 mm visual analogue fatigue scale. Inclusion required age greater than 18 years, the ability to read and understand Danish, provision of informed consent, and willingness to use effective contraception during the study period. The sponsor did not provide the total number of participants, and thus the exact sample size is unavailable. Subjects were selected on the basis of meeting the diagnostic and fatigue criteria, without additional specifications regarding diet, physical activity, or other lifestyle habits. General health status was limited to the presence of rheumatoid arthritis with fatigue, and no further health exclusions were highlighted.

The study is a randomized, double‑blind, placebo‑controlled trial evaluating high‑dose thiamine versus matching placebo in patients with Rheumatoid arthritis who experience fatigue; participants are allocated 1:1 to receive either 1800 mg thiamine hydrochloride tablets or placebo tablets daily for four weeks. The trial consists of a screening visit to confirm eligibility, a baseline visit (day 0) at which randomization and the first dose are administered, a single follow‑up visit at week 4 to assess the primary and secondary outcomes, and an end‑of‑study visit shortly thereafter for final safety assessments; the overall participant involvement spans approximately five weeks from screening to study completion. Eligibility criteria include age > 18 years, established rheumatoid arthritis, a fatigue score > 50 mm on a 100‑mm visual analogue scale, and effective contraception. Early termination may occur if a participant withdraws consent, experiences a serious adverse event, becomes pregnant, or fails to comply with protocol‑required assessments.

The investigational product, APOVIT B1 vitamin ekstra stærk, consists of oral tablets containing thiamine hydrochloride at a strength of 300 mg per tablet. Subjects receive a total daily dose of 1800 mg, administered as six tablets taken once daily with water. The medication is supplied in tablet form and is to be ingested by the oral route.

The control arm utilizes matching placebo tablets that are identical in appearance to the active tablets but contain no active pharmaceutical ingredient. Participants in the placebo group receive six tablets daily, following the same administration schedule as the active comparator.

Dosing is scheduled for a period of four weeks, with compliance monitored by tablet count at each study visit and patient diaries documenting administration times. All administrations occur under double‑blind conditions to maintain blinding of participants and investigators.

Efficacy will be evaluated primarily by comparing the difference in least squares mean changes in the BRAF‑MDQ global score from baseline to week 4 between the high‑dose thiamine and placebo groups.

Secondary efficacy assessments will include changes from baseline to week 4 in the specific domains of the BRAF‑MDQ (Physical, Living, Cognitive, and Emotional Fatigue), as well as changes in the BRAF‑NRS Severity, Effect, and Coping scales. Additional clinical parameters will be recorded at the same time points: the count of swollen and tender joints (out of 28), pain intensity measured with a 0–100 visual analogue scale (VAS), physical disability assessed by the Health Assessment Questionnaire, patient‑ and physician‑global assessments (VAS 0–100), and acute‑phase reactants quantified by C‑reactive protein. The proportion of participants achieving ≥20 %, ≥50 %, and ≥70 % reductions in the BRAF‑MDQ score will also be determined. Health‑related quality of life will be measured using the EQ‑5D‑5L questionnaire.

All patient‑reported outcomes will be collected using the respective validated questionnaires at baseline and at the week 4 visit. Joint counts and VAS assessments will be performed by study investigators during routine clinical examinations. C‑reactive protein will be measured in a central laboratory using standard immunoassay techniques. Statistical analysis will employ analysis of covariance to estimate least squares mean changes for continuous endpoints and chi‑square or Fisher’s exact tests for categorical response rates.