Prednisolone and Vitamin B1/6/12 in Patients With Post-Covid-Syndrome

Study Overview
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Brief Summary
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This is a multicenter, randomized, placebo controlled, double-blind phase III trial with four parallel groups studying studying the feasibility of RCT in primary care as well as the effectiveness of treatment with prednisolone and/or vitamin B1/6/12 for PC19S.

Detailed Description
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PC19S affects a considerable portion of patients after an infection with SARS-CoV-2 with a broad range of disabling symptoms. Neurotropic vitamins such as vitamins B1, B6, an B12, and drugs with anti-inflammatory properties such as corticosteroids were suggested to alleviate symptoms. The trial is designed as a two-step approach that will prove the feasibility of recruitment and retention of patients with PC19S in a primary care setting (pilot study, n=100) investigate the effectiveness and safety of the treatment drugs alone and of their combination (confirmatory study, n= 340). The pilot study will be transformed into a confirmatory study if feasibility is given, defined as retention rate of 85% after enrollment of 100 patients. Or on recommendation of the Data Safety and Monitoring Board (DSMB). In addition, blood samples wil be analysed for routine parameters and vitamin B12 derivates as well as cytokines.

Official Title
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Prednisolone and Vitamin B1, B6, and B12 in Patients With Post-COVID-19-Syndrome (PC19S) - a Randomized Controlled Trial in Primary Care

Conditions
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Post-COVID-19 Syndrome

Intervention / Treatment
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* Drug: Prednisolone 20 mg/ 5 mg
* Drug: Vitamin B compound (100mg B1, 50 mg B6, 500 µg B12)
* Drug: Placebo for Vitamin B compound
* Drug: Placebo for Prednisolon


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: adult patients (at least 18 years old) history of SARS-CoV-2 infection at least 12 weeks ago (the infection must be documented by either a positive PCR or antibody-Test or be confirmed by the patient's GP) symptoms concerning at least one of the following domains: fatigue, dyspnea, cognition, anxiety, depression above mentioned symptom(s) that developed during or after the SARS-CoV-2 infection, that persist until study inclusion, and that are associated with COVID 19 as assessed by the patients' general practitioner or the local investigator Exclusion Criteria: acute Coronavirus disease (COVID-19) at baseline visit patients who were treated in the intensive care unit because of COVID-19 pregnancy/ breastfeeding diabetes mellitus PC19S symptoms that can be explained by an alternative diagnosis History of severe medical conditions such as concomitant acute infectious disease gastrointestinal ulcer liver disease/liver cirrhosis malabsorption or condition after bariatric surgery chronic airway disease chronic heart failure [New York Heart Association (NYHA) III and IV] neurological disorders untreated hypothyroidism significantly impaired glucuronidation immunodeficiency or a chronically weakened immune system mental disorders active cancer any other severe medical conditions that preclude participation as determined by responsible physician current use of immunosuppressive drugs non-steroidal antiinflammatory drugs (NSAID) fluoroquinolones anticoagulation any other drug that could exhibit clinically relevant interactions with the study medication (as described in Fachinformation Prednisolon STADA®, Predni H Tablinen® Zentiva or Fachinformation Vitamin B komplex Hevert). The decision on the clinical relevance of the interactions is at the discretion of the clinical investigator. systemic treatment with prednisolone for at least 7 days or any parenteral application since the end of the acute phase of COVID-19; treatment with vitamins B1, B6, or B12 in doses equivalent to the dose of the study medi-cation for at least 7 days or any parenteral application since the end of the acute phase of COVID-19; vitamin supplements containing vitamin B1, B6, or B12 should have been ceased at least 4 weeks prior to the inclusion of the study known allergies and contraindications to the intervention drugs need of care and/or peer dependency nursing home residents inability to understand the scope of the study, to follow study procedures and to give informed consent or to attend the study sites participation in another interventional trial at the same time or within the past 3 months before enrolment female patients considering to get pregnant during the first month of the trial and within 1 week after the last dose of study drug(s)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: after Baseline, Randomization to 4 arms: st arm (prednisolone and placebo) nd arm (placebo an Vitamin B compound) rd arm (prednisolone and Vitamin B compound) th arm (placebo and placebo)
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1st arm (prednisolone and placebo)<br>Day 1-5: prednisolone 20mg 1x1 and placebo 1x1 Day 6-28: prednisolone 5mg 1x1 and placebo 1x1 | Drug: Prednisolone 20 mg/ 5 mg<br>* Administration of prednisolone 20 mg for 5 days, followed by prednisolone 5 mg for 23 days.<br>* Other names: N.I.;Drug: Placebo for Vitamin B compound<br>* Administration of placebo for vitamin B compound placebo for 28 days.<br>* Other names: N.I.;|
| Active Comparator: 2nd arm (placebo and Vitamin B compound)<br>Day 1-5: Placebo 1x1 and Vitamin B compound (100 mg B1, 50 mg B6, 500µ B12) 1x1 Day 6-28: placebo 1x1 and Vitamin B compound (100 mg B1, 50 mg B6, 500 µg B12) 1x1 | Drug: Vitamin B compound (100mg B1, 50 mg B6, 500 µg B12)<br>* Administration of vitamin B compound for 28 days.<br>* Other names: Vitamin B complex forte;Drug: Placebo for Prednisolon<br>* Administration of placebo for prednisolone 20 mg for 5 days, followed by placebo for prednisolone 5 mg for 23 days.<br>* Other names: N.I.;|
| Active Comparator: 3rd arm (prednisolone and Vitamin B compound)<br>Day 1-5: prednisolone 20mg 1x1 and Vitamin B compound (100 mg B1, 50 mg B6, 500µg B12) 1x1 Day 6-28: prednisolone 5mg 1x1 and Vitamin B compound (100 mg B1, 50mg B6, 500µg B12) 1x1 | Drug: Prednisolone 20 mg/ 5 mg<br>* Administration of prednisolone 20 mg for 5 days, followed by prednisolone 5 mg for 23 days.<br>* Other names: N.I.;Drug: Vitamin B compound (100mg B1, 50 mg B6, 500 µg B12)<br>* Administration of vitamin B compound for 28 days.<br>* Other names: Vitamin B complex forte;|
| Placebo Comparator: 4rd arm (placebo and placebo)<br>Day 1-5: Placebo 1x1 and placebo 1x1 Day 6-28: placebo 1x1 and placebo 1x1 | Drug: Placebo for Vitamin B compound<br>* Administration of placebo for vitamin B compound placebo for 28 days.<br>* Other names: N.I.;Drug: Placebo for Prednisolon<br>* Administration of placebo for prednisolone 20 mg for 5 days, followed by placebo for prednisolone 5 mg for 23 days.<br>* Other names: N.I.;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pilot phase: Proportion of participants retained after 28 days | feasibility and acceptance of screening and recruitment in primary care; aim > 85 % retention rate of 100 patients enrolled | 4 weeks | 
| Confirmatory phase: Mean difference in PROMIS Total Score from day 0 to day 28 | change in symptom severity to day 28 as assessed by specifically tailored total score based on the patient reported outcome measurement information system (PROMIS) | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PROMIS total and subscores | Severity of each PC19 symptom domain (patient reported outcome measurement information system (PROMIS)) | 6 months | 
| Measure Yourself Medical Outcome Profile (MYMOP) | Severity of three subjectively chosen PC19 symptoms | 6 months | 
| Overall assessment of functional status | Severity of PC19 symptom burden | 6 months | 
| PC19 symptom list | checklist, number of subjectively present symptoms | 6 months | 
| EQ-5D-5L | Health related quality of life, 5 point rating scale, 0 to 20 points, higher scores indicate worse outcomes | 6 months | 
| visual analogue scale | Health related quality of life, 0 to 100 points, higher scores indicate a better outcome | 6 months | 
| PHQ 8 | Depression, 4 point rating scale, 0 to 24 points possible, higher scores indicate a worse outcome | 6 months | 
| Chalder Scale | Fatigue, 4 point rating scale, 0 to 33 points possible, higher values indicate a worse outcome | 6 months | 
| Numeric rating scale for pain | Pain, 10 point rating scale, higher values indicate a worse outcome | 6 months | 
| Testbatterie zur Aufmerksamkeitsprüfung (TAP) | cognitive function (Alertness: reaction time, distractibility: omissions and reaction time, divided attention: omissions, visual scanning: omissions and reaction time, flexibility: reaction time and errors) | 4 weeks | 
| Physical exercise | 1minute Sit-to-Stand-Test, number of repetitions, BORG Scale, oxygen-saturation | 6 months | 
| Use of on-demand medication and change in concomitant medication | intake of on-demand medication, daily drug doses | 6 months | 
| qualitative assessment of acceptance | qualitative interviews with subgroup sample | 6 months | 
| feasibility/acceptance | exploratory questionnaire, rating scales and grades | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prednisolone, Vitamin B1, Vitamin B6, Vitamin B12, PC19S, Fatigue, ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome)