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

Background Post-COVID-19 syndrome is burdensome and not yet adequately treatable, with persistent symptoms including fatigue, dyspnoea, and cognitive impairment. The Pan American Health Organisation recommends rigorous evaluation of potentially beneficial interventions. We investigated the efficacy and safety of prednisolone and vitamins B1, B6, and B12 in patients with post-COVID-19. Methods This randomised, double-blind, placebo-controlled phase 3 trial (2 × 2 factorial design) was conducted in adults with post-COVID-19 at three university sites in Germany. Adult patients with persistent symptoms after a documented SARS-CoV-2 infection ≥12 weeks ago and without acute COVID-19, major comorbidities, pregnancy or breastfeeding, prior intensive care treatment for COVID-19, recent use of trial drugs, or potentially interacting concomitant medications were included. From January 13, 2023 until July 25, 2024 participants were randomly assigned to 28 days of once-daily oral treatment with prednisolone (20 mg on days 1–5, 5 mg on days 6–28), B vitamins (thiamine nitrate [B1], 100 mg, pyridoxine hydrochloride [B6] 50 mg, and cyanocobalamin [B12] 500 μg), prednisolone and B vitamins, or placebo. The primary outcome was change in overall symptom severity from baseline to day 28, assessed in the intention-to-treat population (participants who received at least one dose of study drug) at the first follow-up visit after randomisation with a customised Patient-Reported Outcomes Measurement Information System (PROMIS) total T-score. A change of ≥3 points was considered clinically meaningful. Efficacy was assessed using a pre-specified factorial analysis of the main effects of prednisolone and B vitamins. Safety was assessed by analysing frequency and severity of adverse events in all randomised patients (safety population). This completed trial is registered with ClinicalTrials.gov (NCT05638633). Findings Of 2498 patients assessed for eligibility, 323 were randomised and 310 patients had evaluable data for the outcomes. The mean age was 44 (standard deviation (SD) 13) years, 200 participants were women. The mean change in PROMIS T-score was −4·3 (SD 5·1) with prednisolone, −3·2 (SD 5·0) with B vitamins, −4·5 (SD 4·5) with prednisolone plus B vitamins, and −2·9 (SD 4·6) with placebo. The adjusted mean difference between participants treated with prednisolone and those not treated was −1·4 points (95% confidence interval (CI), −2·5 to −0·4; p=0·008), driven primarily by the change in the fatigue subscore (−6·4 points, p < 0·001). B vitamins showed no statistically significant or clinically meaningful difference compared with no B vitamins (adjusted mean difference (MD), −0·1 points; 95% CI, −1·2 to +1·0; p=0·85). Adverse events were equally distributed between groups, with no study-drug-related serious adverse events. Interpretation This trial showed a statistically significant short-term reduction in symptom severity in the five dimensions of the PROMIS score in patients with post-COVID with low-dose prednisolone. However, the effect did not reach the prespecified threshold for clinical relevance. Further research is needed to confirm the efficacy of prednisolone and to determine the optimal dose and treatment duration while balancing benefits against longer-term adverse effects. Funding German Federal Ministry of Research, Technology and Space, Vogel Stiftung Dr. Eckernkamp, Hevert-Arzneimittel GmbH & Co. KG.