Trial Report Vitamin D in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome after COVID-19 or Vaccination: A Randomized Controlled Trial, 2026, Kodama et al

[John Mac]

Abstract​

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) can develop as post-vaccination syndrome (PVS) or Post-Acute Sequelae of SARS-CoV-2 infection (PASC). In our prior retrospective study, most patients with PVS who developed ME/CFS had vitamin D insufficiency or deficiency. We evaluated the efficacy of vitamin D replacement therapy guidance for ME/CFS symptom improvement in patients with vitamin D insufficiency or deficiency.

Methods: This open-label randomized controlled trial enrolled 91 participants with ME/CFS as PVS or PASC and serum 25(OH) vitamin D < 30 ng/mL across five clinical sites. Participants were randomized 1:1 to intervention (active vitamin D preparation plus vitamin D replacement therapy guidance: 25 μg daily supplementation, dietary counseling, sun exposure, and exercise) or control (active vitamin D preparation alone) for 12 weeks. The primary endpoint was the change in ME/CFS symptom count from screening to Week 12.

Results: Mean symptom change was −6.7 in the intervention group versus −1.2 in the control group (between-group difference −5.6; 95% CI: −7.2, −3.9; p < 0.001). Serum 25(OH) vitamin D improved from 18.6 to 27.1 ng/mL in the intervention group, while the control group showed a decreasing trend (between-group difference 10.2 ng/mL; 95% CI: 7.9, 12.5). Achievement of <8 symptoms (i.e., no longer meeting ME/CFS diagnostic criteria) was significantly higher in the intervention group, with 16 participants achieving this threshold compared to 1 in the control group (p < 0.001). Subgroup analyses showed consistent benefit in both PVS (n = 56) and PASC (n = 29) cohorts.

Conclusions: Vitamin D replacement therapy guidance significantly reduced ME/CFS symptoms along with improvement of serum 25(OH) vitamin D levels in patients with vitamin D insufficiency or deficiency who developed ME/CFS as PVS or PASC.

https://www.mdpi.com/2072-6643/18/3/521

 

[Clio]

Any info about the diagnostic criteria used? What would the MCID for "mean symptom change" be? Any objective measures for that or just the usual questionnaires?

"25 μg daily supplementation, dietary counseling, sun exposure, and exercise"

Going from barely below the recommended value of serum Vitamin D to barely above is equally unimpressive to me. The very wide CI of the between group difference also seems equally unimpressive.

 

[forestglip]

This protocol seems odd.

The control is alfacalcidol, some sort of vitamin D analogue, and the active group is alfacalcidol + vitamin D and guidance on ways to get vitamin D, like sun exposure and exercise:

The investigational treatment was defined as a combination of active vitamin D preparation and vitamin D replacement therapy guidance. The active vitamin D preparation was alfacalcidol (Onealpha® tablets, 1.0 μg, once daily) [Teijin Pharma Limited, Tokyo, Japan][12], and vitamin D replacement therapy guidance consisted of vitamin D supplementation, dietary guidance, sun exposure guidance, and exercise therapy as directed by the attending physician. The vitamin D supplement was NATUREMADE Super Vitamin D (25 μg, once daily) [Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan].

The control treatment was defined as a combination of active vitamin D preparation alone and general guidance. The active vitamin D preparation was alfacalcidol (Onealpha® tablets, 1.0 μg, once daily), and general guidance for ME/CFS was provided. The intervention group received investigational treatment for 24 weeks.

The control group received the control treatment for 12 weeks, followed by the investigational treatment for 12 weeks to observe the response after switching

Why is the control a vitamin D analogue if they're testing vitamin D efficacy?

Unblinded study and the intervention is many different things, so I'm not sure this can tell us much.

 

[InitialConditions]

What a bizzare trial design, which has made it harder to test whether the intervention has benefit.

 

[Utsikt]

What a bizzare trial design, which has made it harder to test whether the intervention has benefit.

It’s probably by design. They are already using the intervention based on their so-called clinical experience and this is nothing more than a charade that they believe lets them claim that what they are doing is backed by science.

 

[Mij]

The general population has vitamin D deficiencies.