Pycnogenol® in Post-COVID-19 Condition (PYCNOVID)

• ClinicalTrials.gov Identifier: NCT05890534
• Recruitment Status: Recruiting
• First Posted: June 6, 2023
• Last Update Posted: June 12, 2023
• Sponsor: University of Zurich
• Information provided by (Responsible Party): University of Zurich

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Post COVID-19 Condition; Long COVID	Drug: Pycnogenol®; Drug: Placebo	Phase 3

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 150 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Data analyst is also masked.
• Primary Purpose: Treatment
• Official Title: Pycnogenol® in People With Post-COVID-19 Condition: a Quadruple-blind, Randomized, Placebo-controlled Trial
• Actual Study Start Date: June 7, 2023
• Estimated Primary Completion Date: December 31, 2024
• Estimated Study Completion Date: June 1, 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: Pycnogenol®; 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®; Single center, quadruple blind randomized controlled trial comparing Pycnogenol® versus Placebo.
Placebo Comparator: Placebo; 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; Single center, quadruple blind randomized controlled trial comparing Pycnogenol® versus Placebo.

Outcome Measures

Primary Outcome Measures :

1. Health status (EQ-VAS) [ Time Frame: Change from baseline to 12 weeks ]
   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.

Secondary Outcome Measures :

1. Post COVID-19 symptoms [ Time Frame: Change from baseline to 12 weeks ]
   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.
2. Fatigue [ Time Frame: Change from baseline to 12 weeks ]
   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.
3. Dyspnea [ Time Frame: Change from baseline to 12 weeks ]
   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).
4. Cognitive function [ Time Frame: Change from baseline to 12 weeks ]
   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.
5. Anxiety and depression [ Time Frame: Change from baseline to 12 weeks ]
   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).
6. Health-related quality of life (EQ-5D-5L) [ Time Frame: Change from baseline to 12 weeks ]
   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.
7. Functional exercise capacity [ Time Frame: Change from baseline to 12 weeks ]
   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.
8. Physical activity [ Time Frame: Change from baseline to 12 weeks ]
   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.
9. Soluble Thrombomodulin (sTM) [ Time Frame: Change from baseline to 12 weeks ]
   Blood biomarker of endothelial health measured with Enzyme-linked Immunosorbent Assay (ELISA) or Luminex (bead-based immunoassay) at baseline and after 12 weeks.
10. von Willebrand Factor antigen (VWF:Ag) [ Time Frame: Change from baseline to 12 weeks ]
    Blood biomarker of endothelial health measured with Enzyme-linked Immunosorbent Assay (ELISA) or Luminex (bead-based immunoassay) at baseline and after 12 weeks.
11. Syndecan-1 [ Time Frame: Change from baseline to 12 weeks ]
    Blood biomarker of endothelial health measured with Enzyme-linked Immunosorbent Assay (ELISA) or Luminex (bead-based immunoassay) at baseline and after 12 weeks.
12. Circulating Cascular Cell Adhesion Molecule-1 (sVCAM 1) [ Time Frame: Change from baseline to 12 weeks ]
    Blood biomarker of endothelial health measured with Enzyme-linked Immunosorbent Assay (ELISA) or Luminex (bead-based immunoassay) at baseline and after 12 weeks.
13. C-reative protein (CRP) [ Time Frame: Change from baseline to 12 weeks ]
    Marker of inflammation (serum) measured at baseline and after 12 weeks by a certified laboratory (Analytica, Zurich, Switzerland).
14. Interleukine 6 (IL 6) [ Time Frame: Change from baseline to 12 weeks ]
    Marker of inflammation measured with Enzyme-linked Immunosorbent Assay (ELISA) or Luminex (bead-based immunoassay) at baseline and after 12 weeks.
15. sCD40L [ Time Frame: Change from baseline to 12 weeks ]
    Marker of coagulation and platelet function measured with Enzyme-linked Immunosorbent Assay (ELISA) or Luminex (bead-based immunoassay) at baseline and after 12 weeks.
16. sP selectin [ Time Frame: Change from baseline to 12 weeks ]
    Adhesion molecule measured with Enzyme-linked Immunosorbent Assay (ELISA) or Luminex (bead-based immunoassay) at baseline and after 12 weeks.
17. D-Dimer [ Time Frame: Change from baseline to 12 weeks ]
    Marker of coagulation and platelet function measured in citrate blood at baseline and after 12 weeks by certified laboratory (Analytica, Zurich, Switzerland).
18. Activated partial thromboplastin time (aPTT) [ Time Frame: Change from baseline to 12 weeks ]
    Marker of coagulation and platelet function measured in citrate blood at baseline and after 12 weeks by certified laboratory (Analytica, Zurich, Switzerland).
19. International normalized ratio (INR) blood test [ Time Frame: Change from baseline to 12 weeks ]
    Marker of coagulation and platelet function measured in citrate blood at baseline and after 12 weeks by certified laboratory (Analytica, Zurich, Switzerland).
20. Total antioxidant capacity (TAC) [ Time Frame: Change from baseline to 12 weeks ]
    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.
21. Aspartate aminotransferase (ASAT) [ Time Frame: Change from baseline to 12 weeks ]
    Marker of liver function measured in blood serum at baseline and after 12 weeks by a certified laboratory (Analytica, Zurich, Switzerland).
22. Alanine aminotransferase (ALAT) [ Time Frame: Change from baseline to 12 weeks ]
    Livery enzyme measured in blood serum at baseline and after 12 weeks by a certified laboratory (Analytica, Zurich, Switzerland).
23. Gamma glutamyltransferase (γ-GT) [ Time Frame: Change from baseline to 12 weeks ]
    Livery enzyme measured in blood serum at baseline and after 12 weeks by a certified laboratory (Analytica, Zurich, Switzerland).
24. Creatinine [ Time Frame: Change from baseline to 12 weeks ]
    Creatinine including clearance measured in blood serum at baseline and after 12 weeks by a certified laboratory (Analytica, Zurich, Switzerland).

Other Outcome Measures:

1. Adherence to study products [ Time Frame: Baseline to 12 weeks ]
   Adherence to study products (Pycnogenol® and Placebo) will be evaluated during the two follow-up visits (6 and 12 weeks after baseline visit) and the two follow-up phone calls using a standardized assessment form. The number of capsules returned at the study visits will be counted and entered into the database.
2. Post-exertional malaise [ Time Frame: Baseline to 12 weeks ]
   Post-exertional malaise is a frequent symptom in post COVID-19 condition. Study visits and measurements may pose a burden for the participants. At each visit, starting with the baseline visit, participants will be asked whether they experienced a worsening of their symptoms within 3 days after the last study visit (i.e., after 12 weeks). A self-administered questionnaire will be used.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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)

Contacts and Locations

Contacts

Contact: Thomas Radtke, PhD; +41 44 634 63 82; thomas.radtke@uzh.ch

Contact: Manuela Rasi, PhD; +41 44 634 46 55; manuela.rasi@uzh.ch

Locations

Switzerland

University of Zurich, Epidemiology, Biostatistics and Prevention Institute, Department of Public & Global Health; Recruiting

Zürich, Switzerland, 8001

Contact: Jan S Fehr, Prof +41 44 634 46 04 jan.fehr@uzh.ch

Contact: Thomas Radtke, PhD +41 44 634 63 82 thomas.radtke@uzh.ch

Sponsors and Collaborators

University of Zurich

Investigators

• Study Director: Jahn S Fehr, Prof., MD; University of Zurich, EBPI, Department of Public & Global Health
• Principal Investigator: Alexia Anagnostopoulos, MD; University of Zurich, EBPI, Department of Public & Global Health

More Information

• Responsible Party: University of Zurich
• ClinicalTrials.gov Identifier: NCT05890534
• Other Study ID Numbers: 2022-01967
• First Posted: June 6, 2023
• Last Update Posted: June 12, 2023
• Last Verified: June 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University of Zurich:

COVID-19; post COVID symptoms; Pycnogenol®

Additional relevant MeSH terms:

COVID-19; Post-Acute COVID-19 Syndrome; Disease; Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Pathologic Processes; Post-Infectious Disorders; Chronic Disease; Disease Attributes; Pycnogenols; Adjuvants, Immunologic; Immunologic Factors; Physiological Effects of Drugs; Antioxidants; Molecular Mechanisms of Pharmacological Action; Protective Agents; Platelet Aggregation Inhibitors