Pycnogenol® in Post-COVID-19 Condition

Study Overview
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Brief Summary
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To determine the effect of Pycnogenol® versus placebo on patient-reported health status in people with post COVID-19 condition.

Detailed Description
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The primary aim of this 12-week quadruple blind, single-center randomized controlled trial is to determine the effect of Pycnogenol® (200mg daily) versus placebo on patient-reported health status (EQ-Visual Analogue Scale) in people with post COVID-19 condition. Secondary outcomes include symptoms, fatigue, cognitive function, health-related quality of life, functional exercise capacity and blood biomarkers of inflammation, endothelial function and oxidative stress. Pycnogenol® is a licensed pine tree bark extract (Pinus pinaster ssp. atlantica) and primarly used for the treatment of venous disorders. Various studies reported beneficial effects in other conditions such as diabetes, metabolic syndrome and cardiovascular disorders. Pycnogenol® exerts antioxidative, anti-inflammatory and antiproliferative effects and has been shown to improve vascular endothelial function. Pycnogenol® may have potential to improve the health status of people suffering from post COVID-19 condition. This trial lasts for 12 weeks. Participants are invited to visit the study center four times: screening visit, baseline visit, follow-up 1 visit (6 weeks after baseline visit), follow-up 2 visit (12 weeks after baseline visit). In a substudy using baseline data, the investigators plan to study associations between objectively measured physical activity, severity of post COVID-19 condition, symptom burden and severity (e.g., fatigue, dyspnoea), functional exercise capacity, and health-related quality of life.

Official Title
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Pycnogenol® in People With Post-COVID-19 Condition: a Quadruple-blind, Randomized, Placebo-controlled Trial

Conditions
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Post COVID-19 Condition, Long COVID

Intervention / Treatment
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* Drug: Pycnogenol®
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: SARS-CoV-2 infection confirmed by positive PCR or rapid antigen test for professional use or written medical report Post-COVID condition (WHO definition), i.e., ≥ 3 months after SARS-CoV2 infection and ongoing or recurring symptoms for at least 2 months that cannot be explained by alternative diagnosis Symptoms include fatigue and / or cognitive impairment (brain fog) and / or dyspnea and / or post-exertional malaise Willing to participate and having signed informed consent Sufficient language and cognitive skills Ability to participate in study visits No foreseeable change in medication Exclusion Criteria: Severe comorbidities such as liver or renal failure, advanced COPD or pulmonary fibrosis requiring > 5L oxygen/min at rest, active malignancy, advanced heart failure, cardio-vascular events within the previous 24 weeks (such as unstable coronary artery disease, coronary revascularization, myocardial infarction, stroke, transient ischemic attack, critical limb ischemia, pulmonary embolism, deep vein thrombosis), uncontrolled severe hypertension, uncontrolled diabetes uncontrolled autoimmune or inflammatory disease (the responsible study physician will decide each case on an individual basis) Acute respiratory or other infections (postpone baseline visit until resolved) Clinical diagnosis of a psychiatric disease (e.g., depression, anxiety disorder, schizophrenia) that is untreated and/or unstable (the responsible study physician will decide each case on an individual basis) COVID-19 vaccination less than 4 weeks prior to the baseline visit (i.e., first or second dose of a two-dose vaccination regimen, first dose of a single dose vaccination regimen, booster) or during study participation (booster shot will be offered at screening visit, wait time until baseline visit 4 weeks) Known intolerance of the study drug Regular intake of Pycnogenol® Pregnancy or lactating. For women and transgender individuals of childbearing age, who can anamnestically not exclude a pregnancy, are offered a pregnancy test during the study visits. Being enrolled in another interventional study that may interfere with the current study (the responsible study physician will decide each case on an individual basis)

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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pycnogenol®<br>People with post COVID-19 condition randomly allocated to the Pycnogenol® arm will take 4 capsules of Pycnogenol® per day (4x50mg capsules, 200mg total) over a period of 12 weeks. | Drug: Pycnogenol®<br>* Single center, quadruple blind randomized controlled trial comparing Pycnogenol® versus Placebo.<br>|
| Placebo Comparator: Placebo<br>People with post COVID-19 condition randomly allocated to the Placebo arm will take 4 capsules of Placebo per day (4x50mg capsules, 200mg total) over a period of 12 weeks. | Drug: Placebo<br>* Single center, quadruple blind randomized controlled trial comparing Pycnogenol® versus Placebo.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Health status (EQ-VAS) | EQ-Visual Analogue Scale (EQ-VAS also known as Feeling thermometer) assessed daily over 7 consecutive days prior to the baseline and at the end of the follow-up 2 visit (i.e., study end after 12 weeks). The scale ranges from 0-100 with 0 representing worst health status and 100 representing best health status. | Change from baseline to 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Post COVID-19 symptoms | Symptoms (present/not present) and symptom severity (5- point Likert scale: 1=not bad at all, 2=mild, 3=moderate, 4=severe, 5=very severe) will be assessed using a self-administered online questionnaire. Symptoms will also be recorded in a paper diary and completed on a weekly basis. | Change from baseline to 12 weeks | 
| Fatigue | Functional Assessment of Chronic Illness Therapy-Fatigue Scale (FACIT-F). 13-item questionnaire with a 7-day recall period assessed at baseline and after 12 weeks. The level of fatigue is measured on a 5-point Likert scale (4 = not at all fatigued to 0 = very much fatigued). Individual item scores are summed, with lower scores indicating more severe fatigue. | Change from baseline to 12 weeks | 
| Dyspnea | Symptom domain of the Chronic Respiratory Questionnaire (CRQ) assessed at baseline and after 12 weeks. The questionnaire contains 5 questions; 7-point Likert-type scale ranging from 1 (most severe dyspnea) to 7 (no dyspnea). | Change from baseline to 12 weeks | 
| Cognitive function | Montreal Cognitive Assessment (MoCA) assessed at baseline and after 12 weeks. The cut-off score < 26 for cognitive impairment will be used in this study. | Change from baseline to 12 weeks | 
| Anxiety and depression | Hospital, Anxiety and Depression Scale (HADS) assessed at baseline and after 12 weeks. Symptoms of depression and anxiety (14 questions, 4-point Likert-type scale). | Change from baseline to 12 weeks | 
| Health-related quality of life (EQ-5D-5L) | The EQ-5D-5L assesses the 5 dimensions mobility, self-care, usual activities, pain/discomfort, anxiety/depression. The EQ-5D-5L scores each dimension on five levels of severity ranging from 1 = no problems to 5 = extreme problems. The instrument will be used at baseline and after 12 weeks. | Change from baseline to 12 weeks | 
| Functional exercise capacity | A 30 second Sit-to-Stand (STS) will be performed at baseline and after 12 weeks. The number of repetitions that the participant completes the full sit-to-stand movement on a chair during 30 seconds. A familiarisation test will be done at the screening visit to rule out potential learning effects. | Change from baseline to 12 weeks | 
| Physical activity | Physical activity measured with an accelerometer (ActiGraph wGT3X-BT, Pensacola, FL, USA), which is worn at the right hip over 8 consecutive days prior to the baseline and 12 week study visit. Number of daily steps and time spent in different intensity domains (min per day) will be analysed. | Change from baseline to 12 weeks | 
| Soluble Thrombomodulin (sTM) | Blood biomarker of endothelial health measured with Enzyme-linked Immunosorbent Assay (ELISA) or Luminex (bead-based immunoassay) at baseline and after 12 weeks. | Change from baseline to 12 weeks | 
| von Willebrand Factor antigen (VWF:Ag) | Blood biomarker of endothelial health measured with Enzyme-linked Immunosorbent Assay (ELISA) or Luminex (bead-based immunoassay) at baseline and after 12 weeks. | Change from baseline to 12 weeks | 
| Syndecan-1 | Blood biomarker of endothelial health measured with Enzyme-linked Immunosorbent Assay (ELISA) or Luminex (bead-based immunoassay) at baseline and after 12 weeks. | Change from baseline to 12 weeks | 
| Circulating Cascular Cell Adhesion Molecule-1 (sVCAM 1) | Blood biomarker of endothelial health measured with Enzyme-linked Immunosorbent Assay (ELISA) or Luminex (bead-based immunoassay) at baseline and after 12 weeks. | Change from baseline to 12 weeks | 
| C-reative protein (CRP) | Marker of inflammation (serum) measured at baseline and after 12 weeks by a certified laboratory (Analytica, Zurich, Switzerland). | Change from baseline to 12 weeks | 
| Interleukine 6 (IL 6) | Marker of inflammation measured with Enzyme-linked Immunosorbent Assay (ELISA) or Luminex (bead-based immunoassay) at baseline and after 12 weeks. | Change from baseline to 12 weeks | 
| sCD40L | Marker of coagulation and platelet function measured with Enzyme-linked Immunosorbent Assay (ELISA) or Luminex (bead-based immunoassay) at baseline and after 12 weeks. | Change from baseline to 12 weeks | 
| sP selectin | Adhesion molecule measured with Enzyme-linked Immunosorbent Assay (ELISA) or Luminex (bead-based immunoassay) at baseline and after 12 weeks. | Change from baseline to 12 weeks | 
| D-Dimer | Marker of coagulation and platelet function measured in citrate blood at baseline and after 12 weeks by certified laboratory (Analytica, Zurich, Switzerland). | Change from baseline to 12 weeks | 
| Activated partial thromboplastin time (aPTT) | Marker of coagulation and platelet function measured in citrate blood at baseline and after 12 weeks by certified laboratory (Analytica, Zurich, Switzerland). | Change from baseline to 12 weeks | 
| International normalized ratio (INR) blood test | Marker of coagulation and platelet function measured in citrate blood at baseline and after 12 weeks by certified laboratory (Analytica, Zurich, Switzerland). | Change from baseline to 12 weeks | 
| Total antioxidant capacity (TAC) | Marker of oxidative stress measured in blood plasma at baseline and after 12 weeks. TAC will be measured using the well-established Ferric Reduction Capability of Plasma (FRAP) method using a commercially available kit. | Change from baseline to 12 weeks | 
| Aspartate aminotransferase (ASAT) | Marker of liver function measured in blood serum at baseline and after 12 weeks by a certified laboratory (Analytica, Zurich, Switzerland). | Change from baseline to 12 weeks | 
| Alanine aminotransferase (ALAT) | Livery enzyme measured in blood serum at baseline and after 12 weeks by a certified laboratory (Analytica, Zurich, Switzerland). | Change from baseline to 12 weeks | 
| Gamma glutamyltransferase (γ-GT) | Livery enzyme measured in blood serum at baseline and after 12 weeks by a certified laboratory (Analytica, Zurich, Switzerland). | Change from baseline to 12 weeks | 
| Creatinine | Creatinine including clearance measured in blood serum at baseline and after 12 weeks by a certified laboratory (Analytica, Zurich, Switzerland). | Change from baseline to 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19, post COVID symptoms, Pycnogenol®