Following a recommendation from the Data Safety Monitoring Board (DSMB).

This clinical trial aims to learn about the therapeutic value of Methylprednisolone, a well-known immunosuppressant, on cognitive deficits in patients with post-COVID-19 syndrome (PCS). The main questions it aims to answer are: 1) Does Methylprednisolone improve memory function in PCS patients compared to placebo? 2) Does Methylprednisolone improve other patient centered outcomes in PCS patients such as fatigue, mood and quality of life compared to placebo? 3)What are the side effects of Methylprednisolone in this patient population, and how common are they? Participants in this study will be patients with PCS and cognitive deficits, who will be asked to participate for 52 weeks. They will be randomly assigned to one of two groups: One group will receive Methylprednisolone once daily for six weeks, with a dosage reduction after week 4. The other group will receive a matching placebo once daily for six weeks, following the same titration regimen to ensure blinding. Participants will attend outpatient follow-up visits in weeks 8 and 20, with a final telephone follow-up after 52 weeks. Clinical examinations and safety monitoring will be conducted during the treatment phase. This study's results may help develop more effective therapies for this condition.

Around 10-40% of mild COVID-19 patients experience persisting or new symptoms known as post-COVID-19 syndrome (PCS). Neurological symptoms, particularly cognitive deficits and fatigue, are common in PCS, with a higher prevalence in female patients (Boesl et al., 2021; Ceban et al., 2022). The underlying causes of PCS remain unclear, but some evidence suggests autoimmune mechanisms may play a role. Currently, there are no proven treatments for PCS, leading to a need for effective therapies. This randomized controlled trial (RCT) aims to investigate the impact of methylprednisolone, a generally well-tolerated and affordable drug, on cognitive deficits in PCS patients with suspected autoimmune involvement.

The objective is to demonstrate improvement in memory satisfaction as measured by the Multifactorial Memory Questionnaire (MMQ) in patients with post-COVID-19 syndrome treated with Methylprednisolone compared with placebo. Methylprednisolone is a well-known immunosuppressant used for multiple diseases of (suspected) autoimmune etiology.

This is a two-arm, double-blind, randomized, placebo-controlled trial evaluating the effects of Methylprednisolone versus placebo in patients with post-COVID-19 syndrome (PCS) and cognitive deficits. The study spans 52 weeks, and participants will be stratified based on age, sex, and cognitive screening using the Montreal Cognitive Assessment Scale (MoCA). They will be randomly assigned in a 1:1 ratio to receive either Methylprednisolone (including a tapering phase) or placebo for 6 weeks, followed by an additional 6 weeks of open treatment phase with Methylprednisolone after a 6-weeks treatment pause. During the study, follow-up visits will be conducted as outpatient visits in weeks 8 and 20, with a final telephone follow-up after 52 weeks. The screening and baseline examinations will involve recording of medical history, checking inclusion and exclusion criteria, and conducting clinical examinations. The intervention group will receive approximately 1mg/kg body weight oral Methylprednisolone once daily for 6 weeks, with dosage reduction after week 4. The other group will receive a matching placebo once daily for 6 weeks, following the same titration regimen to maintain blinding. The starting dose for both interventions will be Methylprednisolone at approximately 1 mg/kg body weight or matching placebo once per day. Throughout the treatment phase, all participants will undergo safety and monitoring examinations.

This clinical trial is of significant importance as it has the potential to benefit individuals with post-COVID-19 syndrome (PCS) by exploring the effects of Methylprednisolone on cognitive impairment and fatigue. Additionally, it may provide crucial insights into PCS's pathophysiological processes, leading to the development of more effective therapies and improved patient outcomes.

Inclusion Criteria:

• History of confirmed (PCR or serology) SARS-CoV-2 infection according to WHO criteria

• Ongoing symptoms of PCS for ≥ 3 months

• Self-reported cognitive deficits at screening

• Male or female adult who is 18 years or older at the time of informed consent

• Subject is willing, understanding and able to provide informed consent

• Signed informed consent prior to initiation of any trial related measure

• For female subject or divers subjects:

  1. Confirmed post-menopausal state, defined as amenorrhea for at least 12 months, or

  2. If being of childbearing potential:

     1. Negative highly sensitive urine or serum pregnancy test before inclusion, and
     2. Practicing a highly effective birth control method (failure rate of less than 1%)

Exclusion Criteria:

• Any ongoing central nervous system disease
• Any major psychiatric disease within the last 10 years
• Previous medical history of gastric ulcer, osteoporosis and/or previous vertebral fractures, rheumatological disease or metabolic disease including diabetes mellitus
• Ongoing immunosuppressive therapy
• Patient is pregnant or breastfeeding at screening
• MMQ memory satisfaction subdomain >50 points at Screening
• Current malignant disease (including space-occupying brain tumors)
• Body weight <45kg
• Severe lactose intolerance
• Participation in another clinical interventional trial within the last 3 months or five half- lives of the other trial's IMP, if longer than 6 months previous to informed consent
• Patient is institutionalized by order of court or public authority
• Patient who might be dependent on the sponsor, the investigator or the trial site
• Place of living does not allow the subject to attend the planned study visits
• Other conditions that are likely to affect to safety of the study treatment (e.g., severely impaired immune status)

Double-Blind.