Low-dose prednisolone eases long-COVID symptoms modestly, but B vitamins fail in phase 3 trial

A rigorous German phase 3 trial has found that a 28-day course of low-dose prednisolone produced a statistically significant reduction in overall symptom severity among patients with post-COVID-19 syndrome, while supplementation with vitamins B1, B6, and B12 showed no efficacy at all. The PreVitaCOV trial, the first randomised, double-blind, placebo-controlled factorial study to test these two widely discussed candidates, also delivered a sobering caveat: the prednisolone effect, though measurable, fell short of the threshold the investigators had prespecified as clinically meaningful, and the benefit faded after the medication was stopped.

Post-COVID-19 syndrome, also called long-COVID or post-COVID condition, is defined by symptoms that emerge during or after a SARS-CoV-2 infection and persist for more than twelve weeks. Fatigue, shortness of breath, and cognitive complaints dominate the clinical picture, and a global modelling study has estimated that roughly six percent of people with symptomatic infection experience at least one post-COVID symptom cluster three months after infection. Despite the scale of the problem, no evidence-based pharmacological treatment has been established. Randomised trials of nirmatrelvir-ritonavir and colchicine showed no significant benefit, and systematic reviews have found little robust evidence supporting most proposed drug therapies, leaving clinicians and patients with few validated options.

Before PreVitaCOV, the evidence for corticosteroids in post-COVID was confined to small, uncontrolled observational reports suggesting symptomatic improvement, particularly in fatigue and dyspnoea, and to patients with organising pneumonia or persistent inflammatory lung disease rather than the broader symptom spectrum. B vitamins had been proposed on theoretical grounds because of their neurotropic roles, but no clinical evidence supported their use. The researchers searched PubMed from January 2020 to January 2026 and found nineteen publications, none of them therapeutic randomised controlled trials in post-COVID populations. The new trial was designed to close that gap with a design capable of testing both drugs individually and in combination.

The study was conducted at the Departments of General Practice at the Universities of Würzburg, Tübingen, and Kiel as a multicentre, randomised, double-blind, placebo-controlled, parallel-group phase 3 trial with a 2 × 2 factorial design. Ambulatory adults were eligible if they had a documented SARS-CoV-2 infection at least twelve weeks before inclusion and at least one of five symptoms—fatigue, dyspnoea, cognitive impairment, anxiety, or depression—developed during or after the infection. Key exclusions included a history of intensive care treatment for COVID-19, acute COVID-19, pregnancy, breastfeeding, diabetes mellitus, and severe comorbid conditions. Participants were allocated in a 1:1:1:1 ratio by stratified block randomisation, and participants, treating physicians, outcome assessors, and data analysts all remained blinded to treatment allocation throughout the trial.

The prednisolone regimen consisted of 20 mg once daily for five days followed by 5 mg once daily for 23 days, a dosing scheme based on short-term corticosteroid bursts used in inflammatory conditions. The B-vitamin arm provided 100 mg of vitamin B1, 50 mg of vitamin B6, and 500 μg of vitamin B12 per day for 28 days. The primary outcome was the change in overall symptom severity from baseline to day 28, measured with a study-specific composite score built from PROMIS item banks covering fatigue, dyspnoea, cognitive impairment, anxiety, and depression. A difference of at least three points in the PROMIS T-score was prespecified as clinically meaningful, and the original sample size calculation targeted 340 participants to detect such a change with 80 percent power.

Between 12 January 2023 and 25 July 2024, 2,498 patients were assessed for eligibility, 326 gave informed consent, and 323 underwent randomisation: 81 to prednisolone, 80 to B vitamins, 81 to the combination, and 81 to placebo. The intention-to-treat population of 315 participants had a mean age of 44 years, 63 percent were women, and post-COVID symptoms had been present for a median of 79 weeks—indicating a chronic, long-standing cohort. Most infections occurred during the Omicron period, 97 percent were vaccinated at least once, and participants had already tried a mean of 2.8 different treatments for their condition before enrolling. Only four percent of randomised participants dropped out, an unusually low attrition rate for trials in this population.

The primary analysis showed that all four groups improved, but by different amounts. The mean change in the PROMIS T-score from baseline to day 28 was −4.3 points in the prednisolone group, −3.2 with B vitamins, −4.5 with the combination, and −2.9 with placebo, each within-group change statistically significant. Adjusted for baseline values, the mean effect of prednisolone was −1.4 points (95 percent confidence interval −2.5 to −0.4, p = 0.008), whereas the effect of B vitamins was −0.1 points (95 percent CI −1.2 to +1.0, p = 0.85), and no interaction between the two drugs was detected (p = 0.93). The prednisolone effect was therefore real in statistical terms but roughly half the size of the prespecified three-point threshold for clinical meaningfulness.

Post-hoc analyses indicated that the overall effect was driven primarily by the fatigue subscore, which improved by 6.4 points with prednisolone (p < 0.001); fatigue was also the most commonly reported symptom in the patient-selected MYMOP measure, named by 58 percent of participants. At day 28, all prespecified secondary outcomes favoured prednisolone, including the MYMOP, quality of life on the EQ-5D-5L, depressive symptoms on the PHQ-8, the Chalder Fatigue Scale, pain ratings, the one-minute sit-to-stand test of physical fitness, and the Post-COVID Functional Status Scale, on which the odds of worse functional status were reduced with prednisolone (odds ratio 0.53, 95 percent CI 0.33–0.84). The number needed to treat for one additional patient to achieve a clinically meaningful change was 7.5, but the confidence interval ranged from 4.0 to 55.1, reflecting substantial uncertainty in the absolute benefit.

Safety findings were reassuring over the observation window. Adverse events were distributed similarly across groups, with 83 percent of participants overall reporting at least one adverse event and no excess clearly attributable to the study drugs. Seven serious adverse events were reported by day 60 while the trial drugs were pharmacologically active—three in the prednisolone group, two in the B-vitamin group, and one in each of the other groups—and all were classified as unrelated or unlikely to be related to the medication. No fatalities occurred, no participants withdrew because of a drug-related serious adverse event, and blinding was verified as successful using generalised Bang blinding indices, which ranged from −0.07 to 0.25 across arms, far from the value of 1 that would indicate unblinding.

The authors emphasise that the pronounced improvement in the placebo group—statistically significant on nearly every measure—likely reflects a combination of natural symptom fluctuation, regression to the mean after enrolment at a high-symptom point, genuine placebo responses, and the non-specific effects of trial participation, including regular attention and supportive contact. Placebo responses are typically strong in conditions defined by subjective symptoms such as fatigue, pain, and cognitive impairment, and in post-COVID trials they tend to persist only for the duration of the intervention. Consistent with that pattern, the between-group differences in PROMIS scores in this trial were no longer significant at days 60 and 180, although all groups continued to improve overall, and the benefit of prednisolone disappeared after the medication was stopped.

The trial has limitations that shape how the findings should be read. Symptom recording was largely subjective because objective measures and mechanistic correlates such as viral persistence or inflammatory markers are lacking; no established core outcome set exists for post-COVID trials; and generalisability is constrained by the exclusion of patients with diabetes, severe comorbidities, nursing care needs, or bedridden status. Long-COVID phenotypes such as orthostatic intolerance and postural orthostatic tachycardia syndrome were neither inclusion criteria nor explicitly assessed, and results from the computerised cognitive test battery will be reported separately. Eligibility amendments during recruitment may have increased heterogeneity, though the authors argue they also improved external validity.

The implications are deliberately measured. Short-term prednisolone may represent a pragmatic, inexpensive, and accessible option for patients with prominent fatigue, but any benefit must be weighed against the known risks of systemic corticosteroids, including metabolic, cardiovascular, and neuropsychiatric harms such as hyperglycaemia, hypertension, and mood changes, and against the absence of long-term safety data. The authors suggest that future trials should consider a fatigue-focused primary endpoint, confirm the findings in larger and more diverse populations, determine optimal dosing and treatment duration, and use biomarker profiling to identify likely responders. For B vitamins, the verdict is clearer: despite their popularity, this trial found no evidence that vitamins B1, B6, and B12 relieve post-COVID symptoms, with the observed improvement in that arm best explained by placebo effects rather than the vitamins themselves.

Subject of Research: A phase 3 factorial randomised trial of low-dose prednisolone and B vitamins for post-COVID-19 syndrome

Article Title: Low-dose prednisolone and B vitamins for post-COVID-19 syndrome in Germany: the PreVitaCOV randomised clinical trial

Article References: Gágyor, I., Klug, A., Schwager, A., Gelbrich, G., Joos, S., Fießler, C., Haeusler, K. G., Lunden, L., Escales, C., Döhring, J., Kutterer, C., Kaußner, Y., Maetzler, W., Zolk, O., Förster, C., & Kaduszkiewicz, H. (2026). Low-dose prednisolone and B vitamins for post-COVID-19 syndrome in Germany: the PreVitaCOV randomised clinical trial. eClinicalMedicine, 101, Article 104264. https://doi.org/10.1016/j.eclinm.2026.104264

Image Credits: AI Generated

DOI: 10.1016/j.eclinm.2026.104264

Keywords: long COVID, post-COVID-19 syndrome, prednisolone, B vitamins, randomised controlled trial, phase 3 trial, fatigue, PROMIS, placebo effect, corticosteroids, clinical trial, Germany